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Petition The White House For Hyperloop - lando2319
https://petitions.whitehouse.gov/petition/fund-musk-san-francisco-la-hyperloop/z9qrqz4x
======
anigbrowl
Wow, PT Barnum was right.
|
/**
* Copyright Amazon.com, Inc. or its affiliates. All Rights Reserved.
* SPDX-License-Identifier: Apache-2.0.
*/
#pragma once
#include <aws/workdocs/WorkDocs_EXPORTS.h>
#include <aws/workdocs/WorkDocsRequest.h>
#include <aws/core/utils/memory/stl/AWSString.h>
#include <utility>
namespace Aws
{
namespace WorkDocs
{
namespace Model
{
/**
*/
class AWS_WORKDOCS_API CreateFolderRequest : public WorkDocsRequest
{
public:
CreateFolderRequest();
// Service request name is the Operation name which will send this request out,
// each operation should has unique request name, so that we can get operation's name from this request.
// Note: this is not true for response, multiple operations may have the same response name,
// so we can not get operation's name from response.
inline virtual const char* GetServiceRequestName() const override { return "CreateFolder"; }
Aws::String SerializePayload() const override;
Aws::Http::HeaderValueCollection GetRequestSpecificHeaders() const override;
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline const Aws::String& GetAuthenticationToken() const{ return m_authenticationToken; }
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline bool AuthenticationTokenHasBeenSet() const { return m_authenticationTokenHasBeenSet; }
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline void SetAuthenticationToken(const Aws::String& value) { m_authenticationTokenHasBeenSet = true; m_authenticationToken = value; }
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline void SetAuthenticationToken(Aws::String&& value) { m_authenticationTokenHasBeenSet = true; m_authenticationToken = std::move(value); }
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline void SetAuthenticationToken(const char* value) { m_authenticationTokenHasBeenSet = true; m_authenticationToken.assign(value); }
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline CreateFolderRequest& WithAuthenticationToken(const Aws::String& value) { SetAuthenticationToken(value); return *this;}
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline CreateFolderRequest& WithAuthenticationToken(Aws::String&& value) { SetAuthenticationToken(std::move(value)); return *this;}
/**
* <p>Amazon WorkDocs authentication token. Not required when using AWS
* administrator credentials to access the API.</p>
*/
inline CreateFolderRequest& WithAuthenticationToken(const char* value) { SetAuthenticationToken(value); return *this;}
/**
* <p>The name of the new folder.</p>
*/
inline const Aws::String& GetName() const{ return m_name; }
/**
* <p>The name of the new folder.</p>
*/
inline bool NameHasBeenSet() const { return m_nameHasBeenSet; }
/**
* <p>The name of the new folder.</p>
*/
inline void SetName(const Aws::String& value) { m_nameHasBeenSet = true; m_name = value; }
/**
* <p>The name of the new folder.</p>
*/
inline void SetName(Aws::String&& value) { m_nameHasBeenSet = true; m_name = std::move(value); }
/**
* <p>The name of the new folder.</p>
*/
inline void SetName(const char* value) { m_nameHasBeenSet = true; m_name.assign(value); }
/**
* <p>The name of the new folder.</p>
*/
inline CreateFolderRequest& WithName(const Aws::String& value) { SetName(value); return *this;}
/**
* <p>The name of the new folder.</p>
*/
inline CreateFolderRequest& WithName(Aws::String&& value) { SetName(std::move(value)); return *this;}
/**
* <p>The name of the new folder.</p>
*/
inline CreateFolderRequest& WithName(const char* value) { SetName(value); return *this;}
/**
* <p>The ID of the parent folder.</p>
*/
inline const Aws::String& GetParentFolderId() const{ return m_parentFolderId; }
/**
* <p>The ID of the parent folder.</p>
*/
inline bool ParentFolderIdHasBeenSet() const { return m_parentFolderIdHasBeenSet; }
/**
* <p>The ID of the parent folder.</p>
*/
inline void SetParentFolderId(const Aws::String& value) { m_parentFolderIdHasBeenSet = true; m_parentFolderId = value; }
/**
* <p>The ID of the parent folder.</p>
*/
inline void SetParentFolderId(Aws::String&& value) { m_parentFolderIdHasBeenSet = true; m_parentFolderId = std::move(value); }
/**
* <p>The ID of the parent folder.</p>
*/
inline void SetParentFolderId(const char* value) { m_parentFolderIdHasBeenSet = true; m_parentFolderId.assign(value); }
/**
* <p>The ID of the parent folder.</p>
*/
inline CreateFolderRequest& WithParentFolderId(const Aws::String& value) { SetParentFolderId(value); return *this;}
/**
* <p>The ID of the parent folder.</p>
*/
inline CreateFolderRequest& WithParentFolderId(Aws::String&& value) { SetParentFolderId(std::move(value)); return *this;}
/**
* <p>The ID of the parent folder.</p>
*/
inline CreateFolderRequest& WithParentFolderId(const char* value) { SetParentFolderId(value); return *this;}
private:
Aws::String m_authenticationToken;
bool m_authenticationTokenHasBeenSet;
Aws::String m_name;
bool m_nameHasBeenSet;
Aws::String m_parentFolderId;
bool m_parentFolderIdHasBeenSet;
};
} // namespace Model
} // namespace WorkDocs
} // namespace Aws
|
A new report from RealClearInvestigations reveals that the anti-Trump “whistleblower” who prompted the current impeachment proceedings against President Trump is a registered Democrat who worked with a Democratic National Committee opposition researcher who dug up dirt on the Trump campaign during the 2016 election.
Federal documents reveal that the whistleblower, Eric Ciaramella, previously worked in the Obama administration with former Vice President Joe Biden and former CIA Director John Brennan. RealClear reports that Ciaramella remained there into the Trump administration, and headed the Ukraine desk at the National Security Council, eventually transitioning into the West Wing, until June 2017.
He then “left his National Security Council posting in the White House’s West Wing in mid-2017 amid concerns about negative leaks to the media. He has since returned to CIA headquarters in Langley, Virginia,” RealClearInvestigations reported. Ciaramella is a Yale graduate who reportedly speaks Russian, Ukrainian, and Arabic.
Officials told RealClear that Ciaramella strongly opposed Trump’s foreign policy.
“He didn’t exactly hide his passion with respect to what he thought was the right thing to do with Ukraine and Russia, and his views were at odds with the president’s policies,” a former senior White House official said.
Politico reported on a Ukrainian-American woman who consulted for the Democratic National Committee, and “met with top officials in the Ukrainian Embassy in Washington in an effort to expose ties between Trump, top campaign aide Paul Manafort and Russia.” The woman, Alexandra Chalupa, was paid $412,000 from 2004 to June 2016 by the DNC.
Ciaramella invited Chalupa to meetings and events at the White House, RealClear reported, documents confirming one occasion in November 2015. She also visited the White House with Ukrainian lobbyists seeking aid from Obama.
Chalupa said she shared her findings with both the DNC and Hillary Clinton’s campaign. Politico reports that “Chalupa told a senior DNC official that, when it came to Trump’s campaign, ‘I felt there was a Russia connection.'” Chalupa also said that the Ukrainian embassy worked directly with reporters digging for Trump-Russia ties.
Before Ciaramella filed his “whistleblower complaint,” he sought “guidance” from House Intelligence Committee Chairman Adam Schiff’s staff and other Obama-era NSC staff recently employed by Schiff’s office. Before this “guidance” was public knowledge, the Chairman was adamant on hearing the “whistleblower” testimony.
“We need to speak with the whistleblower,” Schiff and other Democrats proclaimed. As soon as Ciaramella’s partisanship and collaboration was discovered, Schiff and the Democrats flipped to preventing the testimony from happening and moving their hearings behind closed doors. |
Air Bleu
Air Bleu (Société Anonyme Air Bleu) was a French airline company between 1935 and 1940 that specialised in the delivery of mail within France.
Air Bleu started operations on the 10 July 1935 with Caudron Simoun aircraft operating four different airmail routes across France, the aircraft would leave Le Bourget in the morning and return later in the afternoon.
In August 1936 services were stopped and the aircraft grounded due to financial problems, mainly due to a new surcharge on the cost of letters reducing the volume of mail. In June 1937 the company was reformed with the French state owning 52% and Air France 24% of the new company.
In September 1939 the airline was requisitioned for military duties and operated a mail service between Paris and London. In June 1940 the fleet was reduced to just the Caudron Goélands and by September 1940 the fleet was transferred to Air France and the company was dissolved.
Fleet
12 x Caudron Simoun
5 x Caudron Goéland
2 x Potez 630 (fighter aircraft converted into mail carriers)
See also
Didier Daurat
Raymond Vanier
References
Category:Defunct airlines of France
Category:Airlines established in 1935
Category:Airlines disestablished in 1940
Category:1935 establishments in France
Category:1940 disestablishments in France |
1. Field of the Invention
The present invention is in the field of synthesis methods for the preparation of commercial cephalosporin antibiotics, of which there are presently a significant number, these therapeutic agents now being in their fourth generation. The large variety of side chains to be found in commercial cephalosporins and the significant economic importance of the cephalosporins has placed increased importance on achieving more economic and efficient methods of preparing key intermediates which permit ready synthesis of the various cephalosporins.
One of these key intermediates is 7-amino-cephalosporanic acid (7-ACA), which may be represented by the following formula: ##STR1## Currently, 7-ACA is produced from Cephalosporin C. Cephalosporin C itself is a fermentation product which is the starting point for nearly all currently marketed cephalosporins. However, synthetic manipulation to produce these various commercial cephalosporins basically starts in most cases with the 7-aminocephalosporanic acid, which must be derived from the Cephalosporin C by cleavage of the 7-aminoadipoyl side chain. Typical commercial cephalosporins derived synthetically from 7-ACA, and which thus have the 3-acetyloxymethylene side chain, include cefotaxime, cephaloglycin, cephalothin, and cephapirin.
Another of the key intermediates is 7-aminodeacetylcephalosporanic acid (7-ADAC), which may be represented by the following formula: ##STR2## Currently, 7-ADAC is also produced from Cephalosporin C by removal of the 7-D-.alpha.-aminoadipoyl side chain, together with conversion of the 3-acetyloxymethyleneside chain to 3-hydroxymethyl. 7-ADAC is a useful intermediate compound in the synthesis of cephalosporins containing modified substituents at the C-3 position.
Currently, the method of choice in the art for cleaving the 7-aminoadipoyl side chain is chemical. The basic imino-halide process requires blocking of the amino and carboxyl groups on the(7-aminoadipoyl side chain, and several methods for accomplishing this are currently used. However, as presently employed, the chemical cleavage process has serious disadvantages. Among these are the requirements of a multi-step and complex process, extremely low operating temperatures, expensive reagents, significant quantities of process by-products resulting in effluent treatment problems, and purification of a highly impure starting material before chemical treatment begins. Consequently, there has been an ongoing search for a microbiological or fermentative process which would achieve enzymatic deacylation of Cephalosporin C to provide 7-aminocephalosporanic acid on a more economic basis than the chemical process currently in use.
However, this search for a successful microbiological process has largely proved futile. This is a result, as is made clear in the literature, of the structure, and especially the stereochemistry, of the-aminoadipoyl side chain of the Cephalosporin C molecule, since penicillin has been successfully deacylated by enzymatic cleavage using penicillin acylase produced by a variety of microorganisms. Reports of successful one-step enzymatic deacylation of Cephalosporin C in the literature, on the otherhand, are often unreproducible or provide only very marginal yields.
Accordingly, the present invention is particularly in the field of preparing the key cephalosporin intermediate 7-ACA, and more particularly, in the field of bioprocesses for the preparation of 7-ACA.
To date, the search for a successful bioprocess for making 7-ACA has largely proved futile, certainly with respect to one of commercial scale. For example, while it has been possible to prepare 6-amino penicillanic acid (6-APA) by direct fermentation and/or by enzymatic treatment of penicillin G, leaving only ring expansion necessary to give 7-ADCA, it has been found that, unfortunately, the Cephalosporium or Streptomyces enzymes which carry out ring expansion in the normal metabolic pathways of these microorganisms do not accept 6-APA as a substrate. These enzymes, which are collectively referred to in the art as the DAOCS or expandase enzyme, are defined As enzymes which catalyze the expansion of penam ring structures found in penicillin-type molecules to ceph-3-em rings, as found in the cephalosporins. Hereafter, these enzymes will be referred to collectively as "the expandase enzyme".
A substrate on which the expandase enzyme does operate is penicillin N, which upon ring expansion and hydroxylation, gives deacetylcephalosporanic acid (DAC). Here, it is only necessary to cleave the (D)-.alpha.-aminoadipoyl side chain to give 7-ADAC, but this side chain has proven stubbornly resistant to enzymatic cleavage, giving only unacceptably low yields.
In accordance with the present invention it has been possible to achieve an efficient bioprocess wherein a penicillin compound (having an adipoyl side chain) is produced by a novel fermentation process in high titers, said penicillin compound being an acceptable substrate for the expandase enzyme which is produced in situ by the same microorganism which produces the penicillin compound, having been transformed to express said expandase enzyme. The expandase enzyme then operates to ring expand the penicillin compound to a cephalosporin compound in high yields.
The adipoyl-7-ADCA produced by in situ action of the expandase enzyme has a 3-methyl (--CH.sub.3) side lo chain, whereas 7-ACA, the final product, has a 3-acetyloxymethyl [--CH.sub.2 OC(O)CH.sub.3 ] side chain. In order to convert the 3-methyl to a 3-acetyloxymethyl side chain, in accordance with the present invention there is also expressed in situ two further enzyme activities in addition to the expandase activity. These are, in order, an hydroxylase and an acetyltransferase, and both are the expression products of genes with which the microorganism producing the penicillin compound has also been transformed. The hydroxylase enzyme converts the 3-methyl side chain of adipoyl-7-ADCA to 3-hydroxymethyl, and the acetyltransferase enzyme converts this 3-hydroxymethyl side chain to the 3-acetyloxymethyl side chain of 7-ACA.
And, importantly in the last critical step of the method of the present invention, the side chain of the penicillin compound, now a cephalosporin compound, is removable by another enzyme system in surprisingly high yields. The unexpected result of this unique, total bioprocess which comprises the present invention, is the production of 7-ACA in surprisingly high yields, and with sufficient economy to represent a reasonable alternative to currently used methods of chemical and biochemical processing.
2. Brief Description of the Prior Art
The novel bioprocess of the present invention provides a unique and surprisingly efficient method for preparing 7-ACA as an economically viable alternative to current chemical synthesis. Continuing efforts in the art to devise such a bioprocess have experienced repeated failure. For example, EP-A-0 422 790 discloses DNA encoding isopenicillin N:acyl-CoA acyltransferase activity of Aspergillus nidulans and its use in generating useful cephalosporins in penicillin-producing fungi, which has not heretofore been accomplished in the art. But, this is described as being by way of disruption or displacement of the acyltransferase gene along with addition of genes encoding the epimerase and expandase enzymes from cephalosporin-producing organisms; moreover, no useful transformation and expression result is actually achieved, apparently. Furthermore, had transformation been successful, it still would not have been useful for the purposes of the present invention, since the problem of how to remove the D-.alpha.-aminoadipoyl side chain would still remain. Such a failed attempt in the art to obtain significant results in producing commercial cephalosporin intermediates from penicillin-producing fungi cultures is in complete contrast to the results achieved with the method of the present invention.
The first enzymatic bioprocess step in the method of the present invention is ring expansion of adipoyl-6-APA, carried out by an expandase enzyme which is the expression product of an expandase gene with which the non-recombinant P. chryaogenum host as been transformed. The use of synch an expandase enzyme has been explored in the prior art. For example, Cantwell et al., in Curr Genet (1990) 17:213-221, have proposed a bioprocess for preparing 7-ADCA by ring expansion of penicillin V followed by enzymatic hydrolysis of the resulting deacetoxycephalosporin V to form 7-ADCA. This proposal is based on the availability of a cloned penicillin N expandase gene (cefE) from S. clavuligerus: Kovacevic et al., J. Bacteriol. (1989) 171:754-760; and Ingolia et al. U.S. Pat. No. 5,070,020. However, since the expandase operates on penicillin N, its natural substrate, but not on penicillin V, the proposal requires genetic engineering to produce a modified expandase gene which can ring-expand the penicillin V. The required modification was not achieved by Cantwell et al., however, and they only succeeded in transforming Penicillium chrysogenum with the cef E gene from Streptomyces clavuligerus and getting low-level expression of the DAOCS (expandase) enzyme.
The expandase enzyme has been well studied in the art, both with respect to its activity and its genetic sequence. For example, in Wolfe U.S. Pat. Nos. 4,510,246 and 4,536,476, cyclase, epimerase and ring expansion enzymes were isolated separately from a cell free extract of prokaryotic .beta.-lactam producing organisms, including Streptomyces clavuligerus, to provide stable enzyme reagents. Dotzlaf U.S. Pat. No. 5,082,772 (EP-A-0 366 354) describes an isolated and purified expandase enzyme from S. clavuligerus which is characterized, including by a terminal residue and amino acid composition, and is said to have a molecular weight of about 34,600 Daltons. This is in contrast, however, to the molecular weight of 29,000 assigned to what would appear to be the same enzyme in U.S. Pat. No. 4,536,476. EP-A-0 233 715 discloses isolation and endonuclease restriction map characterization of the expandase gene obtained from S. clavuligerus and expression of recombinant expandase-encoding DNA (yielding active expandase enzyme) in an S. clavuligerus strain lacking the capability of cephalosporin production. Ingolia et al. U.S. Pat. No. 5,070,020 (EP-A-0 341 892) discloses the DNA sequence encoding the expandase enzyme obtained from S. clavuligerus and describes the transformation of a P. chrysogenum strain with an expression vector containing said DNA sequence, thereby obtaining expression of the expandase enzyme. While it is suggested that this enzyme is useful for the expansion of substrates other than penicillin N, there is no actual demonstration of such an expansion.
The work described above has focused on the expandase enzyme derived from prokaryotic S. clavuligerus. An enzyme apparently having the same ring expansion activity is also expressed by strains of eukaryotic Cephalosporium acremonium (also referred to as Acremonium chrysogenum). However, in such strains expandase activity is expressed by a bifunctional gene (cefEF), which also expresses the DACS (hydroxylase) activity whose natural function is to convert the desacetoxycephalosporanic acid (DAOC) product of the expandase enzyme to deacetyl cephalosporin C (DAC). The result of this expression is a single, but bifunctional expandase/hydroxylase enzyme. While there have been efforts to separate the activities of these two gene products, none have yet been successful. For example, EP-A-0 281 391 discloses the isolation and DNA sequence identification of the DAOCS/DAOS gene obtained from C. acremonium ATCC 11550 together with the corresponding amino acid sequence of the enzyme. A Penicillium is transformed and expresses the enzymes, however, the attempted conversion of penicillins G and V to the corresponding cephalosporins is never demonstrated. Further, despite a suggestion that genetic engineering techniques provide a ready means to separate the genetic information encoding DAOCS from DAGS and separately express them, no actual demonstration of such separation is set forth.
The DAOCS/DACS (expandase/hydroxylase) enzyme of C. acremonium has also been well studied in the art, both with respect to its activity and its characteristics and genetic sequence. For example, in Demain U.S. Pat. Nos. 4,178,210; 4,248,966; and 4,307,192 various penicillin-type starting materials are treated with a cell-free extract of C. acremonium which epimerizes and expands the ring to give a cephalosporin antibiotic product. Wu-Kuang Yeh U.S. Pat. No. 4,753,881 describes the C. acremonium enzyme in terms of its isoelectric point, molecular weights, amino acid residues, ratio of hydroxylase to expandase activities and peptide fragments.
The acetyltransferase enzyme of C. acremonium has also been described in the art, with respect to its activity, characteristics, restriction mapping, and nucleotide and amino acid sequences. For example, see EP-A-0 437 378 and EP-A-0 450 758.
The prior art discussed above deals with only a single aspect of the present invention, i.e., the transformation of a P. chrysogenum strain with genes expressing the expandase and expandase/hydroxylase enzymes and obtaining expression of those enzymes. The art, however, has only used the expressed enzymes to ring-expand penicillin N, not penicillins G and V. Even in that case, penicillin N has a 7-position side chain which cannot be cleaved enzymatically to leave a free amino group. The present invention is based on the surprising discovery that an adipoyl side chain can be efficiently added by a P. chrysogenum strain, that the expandase enzyme expressed in situ can use that compound efficiently as a substrate for ring expansion to adipoyl 7-ADCA, that hydroxylase and acetyltransferase enzymes also expressed La situ can use the adipoyl-7-ADCA as a substrate to produce the 3-acetoxymethyl side chain of 7-ACA, and that the adipoyl side chain can then be efficiently removed by yet another enzyme to give 7-ACA. While various isolated fragments of the present invention may be found in the prior art, there has been no suggestion that they be combined to give the unexpected results obtained with the method of the present invention.
For example, production of 6-adipoyl penicillanic acid is known in the art; see Ballio, A. et al., Nature (1960) 185, 97-99. The enzymatic expansion of 6-adipoyl penicillanic acid, but only on an in vitro basis, is also known in the art; see Baldwin et al., Tetrahedron (1987) 43, 3009-3014; and EP-A-0 268 343. And, enzymatic cleavage of adipoyl side chains is also known in the art; see for example, Matsuda et al., J. Bact. (1987) 169, 5815-5820.
The adipoyl side chain has the following structure: COOH--(CH.sub.2).sub.4 --CO--, while two side chains of closely related structure are those of glutaryl, having the following formula: COOH--(CH.sub.2).sub.3 --CO--, and of (D)-.alpha.-aminoadipoyl, having the formula: COOH--CH(NH.sub.2)--(CH.sub.2).sub.3 --CO--. The enzymatic cleavage of glutaryl side chains is known in the art. See, e.g., Shibuya et al., Agric. Biol. Chem. (1981) 45, 1561-1567, and U.S. Pat. No. 3,960,662; Matsuda and Komatsu, J. Bact. (1985) 163, 1222-1228; Matsuda et al., J. Bact. (1987) 169, 5815-5820; Jap. 53-086084 (1978--Banyu Pharmaceutical Co. Ltd.); and Jap. 52-128293 (1977--Banyu Pharmaceutical Co. Ltd.). Also, EPA-A-0 453 048 describes methods for improving the adipoyl-cleaving activity of the glutaryl acylase produced by Pseudomonas SY-77-1. By substituting different amino acids at certain locations within the alpha-subunit, a three to five times higher rate of adipoyl cleavage (from adipoyl-serine) was observed. It should be noted that although FP-A-0 453 048, apparently, demonstrates an acylase with improved activity towards adipoyl-side chains, it does not describe any ways (either chemical or through a bioprocess in any way analogous to that described in the instant specification) in which an adipoyl-cephalosporin might be generated in the first place.
Where a (D)-.alpha.-aminoadipoyl side chain is present, it is known in the art to first enzymatically remove the amino group and shorten the side chain with a (D)-amino acid oxidase, leaving a glutaryl (GL-7) side chain, with removal of the glutaryl side chain by a second enzyme (glutaryl acylase). Such a two-step cleavage is disclosed in Matsuda U.S. Pat. No. 3,960,662; EP-A-0 275 901; Jap. 61-218057 (1988--Komatsu, Asahi Chemical Industry Co.); WO 90/12110 (1990--Wong, Biopure Corp.); and EP-A-0 436 355, Isogai et al., also Bio/Technology (1991) 9, 188-191.
It is also known in the art to carry out one-step cleavage of the (D)-.alpha.-aminoadipoyl side chain, particularly using recombinant techniques. See, e.g.:
One-step (D)-.alpha.-aminoadipoyl side chain cleavage:
Jap. 53-94093 (Meiji, Pseudomonas sp. BN-188); PA0 Jap. 52-143289 (=U.S. Pat. No. 4,141,790, Meiji, Aspergillus sp.); PA0 U.S. Pat. No. 4,774,179 (Asahi 1988, Pseudomonas sp. SE-83 and SE-495), =Jap. 61-21097 and Jap. 61-152286; PA0 Fr. Pat. 2,241,557 (Aries 1975, Bacillus cereus var. fluorescens); PA0 Jap. 52-082791 (Toyo Jozo 1977, Bacillus megaterium NRRL B 5385); PA0 EP-A-0 321 849 (Hoechst, Pseudomonas, Bacillus subtilis, .gamma.-glutamyl transpeptidase); PA0 EP-A-0 283 218 and U.S. Pat. No. 4,981,789 (Merck, Arthrobacter viscosus); PA0 Jap. 60-110292 (Asahi 1985, Comamonas, recombinant E. coli with gene from Comamonas sp. SY-77-1, one-step conversion); PA0 Jap. 61-152-286 (Asahi 1986, Pseudomonas, recombinant E. coli with gene from Pseudomonas sp. SE83, genetic sequences described and claimed, one step process already claimed in U.S. Pat. No. 4,774,179); PA0 Jap. 63-74488 (Asahi 1988, Trigonopsis variabilis, Comamonas, recombinant E. coli expression of D-amino acid oxidase and GL-7-ACA acylase construct). PA0 EP-A-0 475 652 (Fujisawa, cephalosporin C acylase and its production via recombinant technology).
EP-A-0 322 032, EP-A-0 405 846, and U.S. Pat. No. 5,104,800 (Merck, Bacillus megaterium); PA1 1) maintaining in a culture medium capable of sustaining its growth, a strain of Penicillium chrysogenum which produces isopenicillin N and adding to said culture medium an adipate feedstock comprising any one or more of adipic acid, or its salts and esters which are capable of being assimilated and utilized by said strain of Penicillium chrysogenum to produce adipoyl-6-aminopenicillanic acid (adipoyl-6-APA), whereby said adipoyl-6-APA is produced; PA1 2) carrying out the following enzymatic conversions by in situ expression of the corresponding gene: PA1 3) contacting said adipoyl-7-ADAC with an adipoyl amidase whereby the adipoyl side chain is removed and the 7-ADAC product is formed; and said product is then isolated. PA1 1) maintaining in a culture medium capable of sustaining its growth, a strain of Penicillium chrysogenum which produces isopenicillin N and adding to said culture medium an adipate feedstock comprising any one or more of adipic acid, or its salts and esters which are capable of being assimilated and utilized by said strain of Penicillium chrysogenum to produce. adipoyl-6-aminopenicillanic acid (adipoyl-6-APA), whereby said adipoyl-6-APA is produced; PA1 2) carrying out the following enzymatic conversions by in situ expression of the corresponding gene: PA1 3) contacting said adipoyl-7-ACA with an adipoyl amidase whereby the adipoyl side chain is removed and the 7-ACA product is formed; and said product is then isolated. PA1 "7-ACA" means 3-[(acetoyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid; PA1 "adipoyl-6-APA" means [2S-(2.alpha., 5.alpha., 6.beta.)]-3,3-dimethyl-7-oxo-6-[hexane-1,6-dioyl) amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; PA1 "adipoyl-7-ADCA" means 3-methyl-7-[(hexane-1,6-dioyl)amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4. 2.0]oct-2-ene-2-carboxylic acid; and PA1 "adipoyl-7-ADAC" means 3-hydroxymethyl-7-[(hexane-1,6-dioyl)amino]-3-methyl-8-oxo-5-thia-1-azabic yclo [4.2.0]oct-2-ene-2-carboxylic acid. PA1 Cephalosporium acremonium PA1 Cephalosporium sp. PA1 Emericellopsis PA1 Paecilomyces PA1 Scopulariopsis PA1 Diheterospora PA1 Spiroidium PA1 Anoxiopsis PA1 Streptomyces clavuligerus PA1 S. lipmanii PA1 S. wadayamensis PA1 S. todorominensis PA1 S. filipinensis cephamycini PA1 S. heteromorphus PA1 S. panayensis PA1 S. griseus PA1 S. cattleya PA1 Nocardia lactamdurans PA1 Flavobacterium sp. PA1 Alcaligenes denitrificans PA1 Mycoplana bullata PA1 Providencia rettgeri PA1 Lysobacter lactamgenus
One-Step-Recombinant: Ceph C.fwdarw.7-ACA:
Various aspects of methods for producing 7-ADAC are known in the art. For example, see U.S. Pat. Nos. 3,304,236 and 3,972,774 (Eli Lilly & Co.); EP-A-0 454 478 (Shionogi & Co., Ltd.); and published Japanese application 04 53,499 (Shionogi & Co., Ltd.).
Reference to Copending Application
Reference is made to copending application Ser. No. 07/933,469, filed Aug. 28, 1992 (Attorney Docket No. 18532IA), which discloses a bioprocess for making 7-ADCA that relies on expression of the activity of the expandase enzyme in a P. chrysogenum transformant in the same manner as the bioprocess for making 7-ADAC and 7-ACA described herein. However, in the present bioprocess, additional transformations are utilized for the expression of additional enzymatic activities, in order to achieve a wholly different recombinant metabolic pathway to distinct final products, none of which is suggested in the copending application.
In order to facilitate a better understanding of the method of the present invention and the teachings of the prior art references discussed above, set out immediately below is a representation of the various stages in the metabolic pathways leading to adipoyl-6-APA, adipoyl-7-ADCA, adipoyl-7-ACA, and 7-ACA, the intermediate products, and the enzymes which carry out the transformations involved. ##STR3## |
/*********************************************************\
* File: SRPEmissiveFixedFunctions.cpp *
*
* Copyright (C) 2002-2013 The PixelLight Team (http://www.pixellight.org/)
*
* This file is part of PixelLight.
*
* Permission is hereby granted, free of charge, to any person obtaining a copy of this software
* and associated documentation files (the "Software"), to deal in the Software without
* restriction, including without limitation the rights to use, copy, modify, merge, publish,
* distribute, sublicense, and/or sell copies of the Software, and to permit persons to whom the
* Software is furnished to do so, subject to the following conditions:
*
* The above copyright notice and this permission notice shall be included in all copies or
* substantial portions of the Software.
*
* THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING
* BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND
* NONINFRINGEMENT. IN NO EVENT SHALL THE AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM,
* DAMAGES OR OTHER LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING
* FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN THE SOFTWARE.
\*********************************************************/
//[-------------------------------------------------------]
//[ Includes ]
//[-------------------------------------------------------]
#include <PLRenderer/RendererContext.h>
#include <PLRenderer/Renderer/VertexBuffer.h>
#include <PLRenderer/Renderer/FixedFunctions.h>
#include <PLRenderer/Texture/Texture.h>
#include <PLRenderer/Material/Material.h>
#include <PLRenderer/Material/Parameter.h>
#include <PLRenderer/Effect/EffectManager.h>
#include <PLMesh/Mesh.h>
#include <PLMesh/MeshHandler.h>
#include <PLMesh/MeshLODLevel.h>
#include <PLScene/Scene/SceneContainer.h>
#include <PLScene/Visibility/SQCull.h>
#include <PLScene/Visibility/VisPortal.h>
#include <PLScene/Visibility/VisContainer.h>
#include "PLCompositing/FixedFunctions/SRPEmissiveFixedFunctions.h"
//[-------------------------------------------------------]
//[ Namespace ]
//[-------------------------------------------------------]
using namespace PLCore;
using namespace PLGraphics;
using namespace PLRenderer;
using namespace PLMesh;
using namespace PLScene;
namespace PLCompositing {
//[-------------------------------------------------------]
//[ RTTI interface ]
//[-------------------------------------------------------]
pl_implement_class(SRPEmissiveFixedFunctions)
//[-------------------------------------------------------]
//[ Public functions ]
//[-------------------------------------------------------]
/**
* @brief
* Default constructor
*/
SRPEmissiveFixedFunctions::SRPEmissiveFixedFunctions() :
TextureFiltering(this)
{
}
/**
* @brief
* Destructor
*/
SRPEmissiveFixedFunctions::~SRPEmissiveFixedFunctions()
{
}
//[-------------------------------------------------------]
//[ Private functions ]
//[-------------------------------------------------------]
/**
* @brief
* Sets correct texture filtering modes
*/
void SRPEmissiveFixedFunctions::SetupTextureFiltering(Renderer &cRenderer, uint32 nStage) const
{
// Anisotropic filtering
if (TextureFiltering > 1) {
cRenderer.SetSamplerState(nStage, Sampler::MagFilter, TextureFiltering::Anisotropic);
cRenderer.SetSamplerState(nStage, Sampler::MinFilter, TextureFiltering::Anisotropic);
cRenderer.SetSamplerState(nStage, Sampler::MipFilter, TextureFiltering::Anisotropic);
cRenderer.SetSamplerState(nStage, Sampler::MaxAnisotropy, TextureFiltering);
// Bilinear filtering
} else if (TextureFiltering > 0) {
cRenderer.SetSamplerState(nStage, Sampler::MagFilter, TextureFiltering::Linear);
cRenderer.SetSamplerState(nStage, Sampler::MinFilter, TextureFiltering::Linear);
cRenderer.SetSamplerState(nStage, Sampler::MipFilter, TextureFiltering::Linear);
// No filtering
} else {
cRenderer.SetSamplerState(nStage, Sampler::MagFilter, TextureFiltering::None);
cRenderer.SetSamplerState(nStage, Sampler::MinFilter, TextureFiltering::None);
cRenderer.SetSamplerState(nStage, Sampler::MipFilter, TextureFiltering::None);
}
}
/**
* @brief
* Draws recursive
*/
void SRPEmissiveFixedFunctions::DrawRec(Renderer &cRenderer, const SQCull &cCullQuery) const
{
// Get the fixed functions interface (when we're in here, we know that it must exist!)
FixedFunctions *pFixedFunctions = cRenderer.GetFixedFunctions();
// Get scene container
const VisContainer &cVisContainer = cCullQuery.GetVisContainer();
// Set the new scissor rectangle
cRenderer.SetScissorRect(&cVisContainer.GetProjection().cRectangle);
// Render all visible scene nodes of this scene container
Iterator<VisNode*> cIterator = cVisContainer.GetVisNodes().GetIterator();
while (cIterator.HasNext()) {
// Get visibility node and scene node
const VisNode *pVisNode = cIterator.Next();
SceneNode *pSceneNode = pVisNode->GetSceneNode();
if (pSceneNode) {
// Set the current world matrix
pFixedFunctions->SetTransformState(FixedFunctions::Transform::World, pVisNode->GetWorldMatrix());
// Is this scene node a portal?
if (pVisNode->IsPortal()) {
// Get the target cell visibility container
const VisContainer *pVisCell = static_cast<const VisPortal*>(pVisNode)->GetTargetVisContainer();
if (pVisCell) {
// Draw the target cell
if (pVisCell->GetCullQuery())
DrawRec(cRenderer, *pVisCell->GetCullQuery());
// Set the previous scissor rectangle
cRenderer.SetScissorRect(&cVisContainer.GetProjection().cRectangle);
}
// Is this scene node a container? We do not need to check for cells because we will
// NEVER receive cells from SQCull directly, they are ONLY visible through portals! (see above)
} else if (pVisNode->IsContainer()) {
// Draw this container without special processing
if (static_cast<const VisContainer*>(pVisNode)->GetCullQuery())
DrawRec(cRenderer, *static_cast<const VisContainer*>(pVisNode)->GetCullQuery());
// Set the previous scissor rectangle
cRenderer.SetScissorRect(&cVisContainer.GetProjection().cRectangle);
// This must just be a quite boring scene node :)
} else {
// Here we draw the stuff by hand in order to minimize state changes and other overhead
const MeshHandler *pMeshHandler = pSceneNode->GetMeshHandler();
if (pMeshHandler && pMeshHandler->GetVertexBuffer() && pMeshHandler->GetNumOfMaterials()) {
// Get the used mesh
const Mesh *pMesh = pMeshHandler->GetResource();
if (pMesh) {
// Get buffers
const MeshLODLevel *pLODLevel = pMesh->GetLODLevel(0);
if (pLODLevel && pLODLevel->GetIndexBuffer()) {
IndexBuffer *pIndexBuffer = pLODLevel->GetIndexBuffer();
const Array<Geometry> &lstGeometries = *pLODLevel->GetGeometries();
// Draw mesh
bool bFirst = true;
for (uint32 nMat=0; nMat<pMeshHandler->GetNumOfMaterials(); nMat++) {
// Get mesh material
const Material *pMaterial = pMeshHandler->GetMaterial(nMat);
if (pMaterial && !pMaterial->GetEffect()) {
// Draw geometries
for (uint32 nGeo=0; nGeo<lstGeometries.GetNumOfElements(); nGeo++) {
// Is this geometry active and is it using the current used mesh material?
const Geometry &cGeometry = lstGeometries[nGeo];
if (cGeometry.IsActive() && nMat == cGeometry.GetMaterial()) {
// Bind textures
// Emissive map (stage 0)
const Texture *pTexture = nullptr;
const Parameter *pParameter = pMaterial->GetParameter(Material::EmissiveMap);
if (pParameter)
pTexture = pParameter->GetValueTexture();
if (pTexture) {
pTexture->Bind(0);
SetupTextureFiltering(cRenderer, 0);
// First draw call?
if (bFirst) {
bFirst = false;
// Bind buffers
cRenderer.SetIndexBuffer(pIndexBuffer);
pFixedFunctions->SetVertexBuffer(pMeshHandler->GetVertexBuffer());
// Setup cull mode
static const String sTwoSided = "TwoSided";
pParameter = pMaterial->GetParameter(sTwoSided);
cRenderer.SetRenderState(RenderState::CullMode, (pParameter && pParameter->GetValue1f() == 1.0f) ? Cull::None : Cull::CCW);
// Set emissive color - we do this in here by changing the ambient color for this material...
static const String sEmissiveColor = "EmissiveColor";
pParameter = pMaterial->GetParameter(sEmissiveColor);
if (pParameter) {
float fEmissiveColor[3] = { 1.0f, 1.0f, 1.0f };
pParameter->GetValue3f(fEmissiveColor[0], fEmissiveColor[1], fEmissiveColor[2]);
pFixedFunctions->SetColor(Color4(fEmissiveColor[0], fEmissiveColor[1], fEmissiveColor[2], 1.0f));
} else {
pFixedFunctions->SetColor(Color4::White);
}
}
// Draw geometry
cRenderer.DrawIndexedPrimitives(
cGeometry.GetPrimitiveType(),
0,
pMeshHandler->GetVertexBuffer()->GetNumOfElements()-1,
cGeometry.GetStartIndex(),
cGeometry.GetIndexSize()
);
}
}
}
}
}
}
}
}
}
}
}
}
//[-------------------------------------------------------]
//[ Private virtual PLScene::SceneRendererPass functions ]
//[-------------------------------------------------------]
void SRPEmissiveFixedFunctions::Draw(Renderer &cRenderer, const SQCull &cCullQuery)
{
// Fixed functions support required
FixedFunctions *pFixedFunctions = cRenderer.GetFixedFunctions();
if (pFixedFunctions) {
// Reset all render states to default
cRenderer.GetRendererContext().GetEffectManager().Use();
cRenderer.SetRenderState(RenderState::BlendEnable, true);
cRenderer.SetRenderState(RenderState::ScissorTestEnable, true);
// Set the initial world matrix
pFixedFunctions->SetTransformState(FixedFunctions::Transform::World, cCullQuery.GetSceneContainer().GetTransform().GetMatrix());
// Draw recursive from front to back
DrawRec(cRenderer, cCullQuery);
}
}
//[-------------------------------------------------------]
//[ Namespace ]
//[-------------------------------------------------------]
} // PLCompositing
|
---
title: "Kubernetes 设置"
nav-title: Kubernetes
nav-parent_id: deployment
nav-pos: 7
---
<!--
Licensed to the Apache Software Foundation (ASF) under one
or more contributor license agreements. See the NOTICE file
distributed with this work for additional information
regarding copyright ownership. The ASF licenses this file
to you under the Apache License, Version 2.0 (the
"License"); you may not use this file except in compliance
with the License. You may obtain a copy of the License at
http://www.apache.org/licenses/LICENSE-2.0
Unless required by applicable law or agreed to in writing,
software distributed under the License is distributed on an
"AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY
KIND, either express or implied. See the License for the
specific language governing permissions and limitations
under the License.
-->
This page describes how to deploy a *Flink Job* and *Session cluster* on [Kubernetes](https://kubernetes.io).
* This will be replaced by the TOC
{:toc}
{% info %} This page describes deploying a [standalone](#cluster_setup.html) Flink cluster on top of Kubernetes.
You can find more information on native Kubernetes deployments [here]({{ site.baseurl }}/zh/ops/deployment/native_kubernetes.html).
## Setup Kubernetes
Please follow [Kubernetes' setup guide](https://kubernetes.io/docs/setup/) in order to deploy a Kubernetes cluster.
If you want to run Kubernetes locally, we recommend using [MiniKube](https://kubernetes.io/docs/setup/minikube/).
<div class="alert alert-info" markdown="span">
<strong>Note:</strong> If using MiniKube please make sure to execute `minikube ssh 'sudo ip link set docker0 promisc on'` before deploying a Flink cluster.
Otherwise Flink components are not able to self reference themselves through a Kubernetes service.
</div>
## Flink Docker image
Before deploying the Flink Kubernetes components, please read [the Flink Docker image documentation](docker.html),
[its tags](docker.html#image-tags), [how to customize the Flink Docker image](docker.html#customize-flink-image) and
[enable plugins](docker.html#using-plugins) to use the image in the Kubernetes definition files.
## Deploy Flink cluster on Kubernetes
Using [the common resource definitions](#common-cluster-resource-definitions), launch the common cluster components
with the `kubectl` command:
```sh
kubectl create -f flink-configuration-configmap.yaml
kubectl create -f jobmanager-service.yaml
```
Note that you could define your own customized options of `flink-conf.yaml` within `flink-configuration-configmap.yaml`.
Then launch the specific components depending on whether you want to deploy a [Session](#deploy-session-cluster) or [Job](#deploy-job-cluster) cluster.
You can then access the Flink UI via different ways:
* `kubectl proxy`:
1. Run `kubectl proxy` in a terminal.
2. Navigate to [http://localhost:8001/api/v1/namespaces/default/services/flink-jobmanager:webui/proxy](http://localhost:8001/api/v1/namespaces/default/services/flink-jobmanager:webui/proxy) in your browser.
* `kubectl port-forward`:
1. Run `kubectl port-forward ${flink-jobmanager-pod} 8081:8081` to forward your jobmanager's web ui port to local 8081.
2. Navigate to [http://localhost:8081](http://localhost:8081) in your browser.
3. Moreover, you could use the following command below to submit jobs to the cluster:
{% highlight bash %}./bin/flink run -m localhost:8081 ./examples/streaming/WordCount.jar{% endhighlight %}
* Create a `NodePort` service on the rest service of jobmanager:
1. Run `kubectl create -f jobmanager-rest-service.yaml` to create the `NodePort` service on jobmanager. The example of `jobmanager-rest-service.yaml` can be found in [appendix](#common-cluster-resource-definitions).
2. Run `kubectl get svc flink-jobmanager-rest` to know the `node-port` of this service and navigate to [http://<public-node-ip>:<node-port>](http://<public-node-ip>:<node-port>) in your browser.
3. If you use minikube, you can get its public ip by running `minikube ip`.
4. Similarly to the `port-forward` solution, you could also use the following command below to submit jobs to the cluster:
{% highlight bash %}./bin/flink run -m <public-node-ip>:<node-port> ./examples/streaming/WordCount.jar{% endhighlight %}
You can also access the queryable state of TaskManager if you create a `NodePort` service for it:
1. Run `kubectl create -f taskmanager-query-state-service.yaml` to create the `NodePort` service on taskmanager. The example of `taskmanager-query-state-service.yaml` can be found in [appendix](#common-cluster-resource-definitions).
2. Run `kubectl get svc flink-taskmanager-query-state` to know the `node-port` of this service. Then you can create the [QueryableStateClient(<public-node-ip>, <node-port>]({% link dev/stream/state/queryable_state.zh.md %}#querying-state) to submit the state queries.
In order to terminate the Flink cluster, delete the specific [Session](#deploy-session-cluster) or [Job](#deploy-job-cluster) cluster components
and use `kubectl` to terminate the common components:
```sh
kubectl delete -f jobmanager-service.yaml
kubectl delete -f flink-configuration-configmap.yaml
# if created then also the rest service
kubectl delete -f jobmanager-rest-service.yaml
# if created then also the queryable state service
kubectl delete -f taskmanager-query-state-service.yaml
```
### Deploy Session Cluster
A *Flink Session cluster* is executed as a long-running Kubernetes Deployment.
Note that you can run multiple Flink jobs on a *Session cluster*.
Each job needs to be submitted to the cluster after the cluster has been deployed.
A *Flink Session cluster* deployment in Kubernetes has at least three components:
* a *Deployment* which runs a [JobManager]({{ site.baseurl }}/concepts/glossary.html#flink-jobmanager)
* a *Deployment* for a pool of [TaskManagers]({{ site.baseurl }}/concepts/glossary.html#flink-taskmanager)
* a *Service* exposing the *JobManager's* REST and UI ports
After creating [the common cluster components](#deploy-flink-cluster-on-kubernetes), use [the Session specific resource definitions](#session-cluster-resource-definitions)
to launch the *Session cluster* with the `kubectl` command:
```sh
kubectl create -f jobmanager-session-deployment.yaml
kubectl create -f taskmanager-session-deployment.yaml
```
To terminate the *Session cluster*, these components can be deleted along with [the common ones](#deploy-flink-cluster-on-kubernetes) with the `kubectl` command:
```sh
kubectl delete -f taskmanager-session-deployment.yaml
kubectl delete -f jobmanager-session-deployment.yaml
```
### Deploy Job Cluster
A *Flink Job cluster* is a dedicated cluster which runs a single job.
You can find more details [here](#start-a-job-cluster).
A basic *Flink Job cluster* deployment in Kubernetes has three components:
* a *Job* which runs a *JobManager*
* a *Deployment* for a pool of *TaskManagers*
* a *Service* exposing the *JobManager's* REST and UI ports
Check [the Job cluster specific resource definitions](#job-cluster-resource-definitions) and adjust them accordingly.
The `args` attribute in the `jobmanager-job.yaml` has to specify the main class of the user job.
See also [how to specify the JobManager arguments](docker.html#jobmanager-additional-command-line-arguments) to understand
how to pass other `args` to the Flink image in the `jobmanager-job.yaml`.
The *job artifacts* should be available from the `job-artifacts-volume` in [the resource definition examples](#job-cluster-resource-definitions).
The definition examples mount the volume as a local directory of the host assuming that you create the components in a minikube cluster.
If you do not use a minikube cluster, you can use any other type of volume, available in your Kubernetes cluster, to supply the *job artifacts*.
Alternatively, you can build [a custom image](docker.html#start-a-job-cluster) which already contains the artifacts instead.
After creating [the common cluster components](#deploy-flink-cluster-on-kubernetes), use [the Job cluster specific resource definitions](#job-cluster-resource-definitions)
to launch the cluster with the `kubectl` command:
```sh
kubectl create -f jobmanager-job.yaml
kubectl create -f taskmanager-job-deployment.yaml
```
To terminate the single job cluster, these components can be deleted along with [the common ones](#deploy-flink-cluster-on-kubernetes)
with the `kubectl` command:
```sh
kubectl delete -f taskmanager-job-deployment.yaml
kubectl delete -f jobmanager-job.yaml
```
## Appendix
### Common cluster resource definitions
`flink-configuration-configmap.yaml`
{% highlight yaml %}
apiVersion: v1
kind: ConfigMap
metadata:
name: flink-config
labels:
app: flink
data:
flink-conf.yaml: |+
jobmanager.rpc.address: flink-jobmanager
taskmanager.numberOfTaskSlots: 2
blob.server.port: 6124
jobmanager.rpc.port: 6123
taskmanager.rpc.port: 6122
queryable-state.proxy.ports: 6125
jobmanager.memory.process.size: 1600m
taskmanager.memory.process.size: 1728m
parallelism.default: 2
log4j-console.properties: |+
# This affects logging for both user code and Flink
rootLogger.level = INFO
rootLogger.appenderRef.console.ref = ConsoleAppender
rootLogger.appenderRef.rolling.ref = RollingFileAppender
# Uncomment this if you want to _only_ change Flink's logging
#logger.flink.name = org.apache.flink
#logger.flink.level = INFO
# The following lines keep the log level of common libraries/connectors on
# log level INFO. The root logger does not override this. You have to manually
# change the log levels here.
logger.akka.name = akka
logger.akka.level = INFO
logger.kafka.name= org.apache.kafka
logger.kafka.level = INFO
logger.hadoop.name = org.apache.hadoop
logger.hadoop.level = INFO
logger.zookeeper.name = org.apache.zookeeper
logger.zookeeper.level = INFO
# Log all infos to the console
appender.console.name = ConsoleAppender
appender.console.type = CONSOLE
appender.console.layout.type = PatternLayout
appender.console.layout.pattern = %d{yyyy-MM-dd HH:mm:ss,SSS} %-5p %-60c %x - %m%n
# Log all infos in the given rolling file
appender.rolling.name = RollingFileAppender
appender.rolling.type = RollingFile
appender.rolling.append = false
appender.rolling.fileName = ${sys:log.file}
appender.rolling.filePattern = ${sys:log.file}.%i
appender.rolling.layout.type = PatternLayout
appender.rolling.layout.pattern = %d{yyyy-MM-dd HH:mm:ss,SSS} %-5p %-60c %x - %m%n
appender.rolling.policies.type = Policies
appender.rolling.policies.size.type = SizeBasedTriggeringPolicy
appender.rolling.policies.size.size=100MB
appender.rolling.strategy.type = DefaultRolloverStrategy
appender.rolling.strategy.max = 10
# Suppress the irrelevant (wrong) warnings from the Netty channel handler
logger.netty.name = org.apache.flink.shaded.akka.org.jboss.netty.channel.DefaultChannelPipeline
logger.netty.level = OFF
{% endhighlight %}
`jobmanager-service.yaml`
{% highlight yaml %}
apiVersion: v1
kind: Service
metadata:
name: flink-jobmanager
spec:
type: ClusterIP
ports:
- name: rpc
port: 6123
- name: blob-server
port: 6124
- name: webui
port: 8081
selector:
app: flink
component: jobmanager
{% endhighlight %}
`jobmanager-rest-service.yaml`. Optional service, that exposes the jobmanager `rest` port as public Kubernetes node's port.
{% highlight yaml %}
apiVersion: v1
kind: Service
metadata:
name: flink-jobmanager-rest
spec:
type: NodePort
ports:
- name: rest
port: 8081
targetPort: 8081
nodePort: 30081
selector:
app: flink
component: jobmanager
{% endhighlight %}
`taskmanager-query-state-service.yaml`. Optional service, that exposes the TaskManager port to access the queryable state as a public Kubernetes node's port.
{% highlight yaml %}
apiVersion: v1
kind: Service
metadata:
name: flink-taskmanager-query-state
spec:
type: NodePort
ports:
- name: query-state
port: 6125
targetPort: 6125
nodePort: 30025
selector:
app: flink
component: taskmanager
{% endhighlight %}
### Session cluster resource definitions
`jobmanager-session-deployment.yaml`
{% highlight yaml %}
apiVersion: apps/v1
kind: Deployment
metadata:
name: flink-jobmanager
spec:
replicas: 1
selector:
matchLabels:
app: flink
component: jobmanager
template:
metadata:
labels:
app: flink
component: jobmanager
spec:
containers:
- name: jobmanager
image: flink:{% if site.is_stable %}{{site.version}}-scala{{site.scala_version_suffix}}{% else %}latest # The 'latest' tag contains the latest released version of Flink for a specific Scala version. Do not use the 'latest' tag in production as it will break your setup automatically when a new version is released.{% endif %}
args: ["jobmanager"]
ports:
- containerPort: 6123
name: rpc
- containerPort: 6124
name: blob-server
- containerPort: 8081
name: webui
livenessProbe:
tcpSocket:
port: 6123
initialDelaySeconds: 30
periodSeconds: 60
volumeMounts:
- name: flink-config-volume
mountPath: /opt/flink/conf
securityContext:
runAsUser: 9999 # refers to user _flink_ from official flink image, change if necessary
volumes:
- name: flink-config-volume
configMap:
name: flink-config
items:
- key: flink-conf.yaml
path: flink-conf.yaml
- key: log4j-console.properties
path: log4j-console.properties
{% endhighlight %}
`taskmanager-session-deployment.yaml`
{% highlight yaml %}
apiVersion: apps/v1
kind: Deployment
metadata:
name: flink-taskmanager
spec:
replicas: 2
selector:
matchLabels:
app: flink
component: taskmanager
template:
metadata:
labels:
app: flink
component: taskmanager
spec:
containers:
- name: taskmanager
image: flink:{% if site.is_stable %}{{site.version}}-scala{{site.scala_version_suffix}}{% else %}latest # The 'latest' tag contains the latest released version of Flink for a specific Scala version. Do not use the 'latest' tag in production as it will break your setup automatically when a new version is released.{% endif %}
args: ["taskmanager"]
ports:
- containerPort: 6122
name: rpc
- containerPort: 6125
name: query-state
livenessProbe:
tcpSocket:
port: 6122
initialDelaySeconds: 30
periodSeconds: 60
volumeMounts:
- name: flink-config-volume
mountPath: /opt/flink/conf/
securityContext:
runAsUser: 9999 # refers to user _flink_ from official flink image, change if necessary
volumes:
- name: flink-config-volume
configMap:
name: flink-config
items:
- key: flink-conf.yaml
path: flink-conf.yaml
- key: log4j-console.properties
path: log4j-console.properties
{% endhighlight %}
### Job cluster resource definitions
`jobmanager-job.yaml`
{% highlight yaml %}
apiVersion: batch/v1
kind: Job
metadata:
name: flink-jobmanager
spec:
template:
metadata:
labels:
app: flink
component: jobmanager
spec:
restartPolicy: OnFailure
containers:
- name: jobmanager
image: flink:{% if site.is_stable %}{{site.version}}-scala{{site.scala_version_suffix}}{% else %}latest # The 'latest' tag contains the latest released version of Flink for a specific Scala version. Do not use the 'latest' tag in production as it will break your setup automatically when a new version is released.{% endif %}
env:
args: ["standalone-job", "--job-classname", "com.job.ClassName", <optional arguments>, <job arguments>] # optional arguments: ["--job-id", "<job id>", "--fromSavepoint", "/path/to/savepoint", "--allowNonRestoredState"]
ports:
- containerPort: 6123
name: rpc
- containerPort: 6124
name: blob-server
- containerPort: 8081
name: webui
livenessProbe:
tcpSocket:
port: 6123
initialDelaySeconds: 30
periodSeconds: 60
volumeMounts:
- name: flink-config-volume
mountPath: /opt/flink/conf
- name: job-artifacts-volume
mountPath: /opt/flink/usrlib
securityContext:
runAsUser: 9999 # refers to user _flink_ from official flink image, change if necessary
volumes:
- name: flink-config-volume
configMap:
name: flink-config
items:
- key: flink-conf.yaml
path: flink-conf.yaml
- key: log4j-console.properties
path: log4j-console.properties
- name: job-artifacts-volume
hostPath:
path: /host/path/to/job/artifacts
{% endhighlight %}
`taskmanager-job-deployment.yaml`
{% highlight yaml %}
apiVersion: apps/v1
kind: Deployment
metadata:
name: flink-taskmanager
spec:
replicas: 2
selector:
matchLabels:
app: flink
component: taskmanager
template:
metadata:
labels:
app: flink
component: taskmanager
spec:
containers:
- name: taskmanager
image: flink:{% if site.is_stable %}{{site.version}}-scala{{site.scala_version_suffix}}{% else %}latest # The 'latest' tag contains the latest released version of Flink for a specific Scala version. Do not use the 'latest' tag in production as it will break your setup automatically when a new version is released.{% endif %}
env:
args: ["taskmanager"]
ports:
- containerPort: 6122
name: rpc
- containerPort: 6125
name: query-state
livenessProbe:
tcpSocket:
port: 6122
initialDelaySeconds: 30
periodSeconds: 60
volumeMounts:
- name: flink-config-volume
mountPath: /opt/flink/conf/
- name: job-artifacts-volume
mountPath: /opt/flink/usrlib
securityContext:
runAsUser: 9999 # refers to user _flink_ from official flink image, change if necessary
volumes:
- name: flink-config-volume
configMap:
name: flink-config
items:
- key: flink-conf.yaml
path: flink-conf.yaml
- key: log4j-console.properties
path: log4j-console.properties
- name: job-artifacts-volume
hostPath:
path: /host/path/to/job/artifacts
{% endhighlight %}
{% top %}
|
Poor economics
It was July 24, 1991, when former finance minister Manmohan Singh presented his first budget. It’s widely hailed as a landmark event that has irreversibly and positively changed India. This euphoria is accompanied by cries for a new generation of reforms. What these reforms are and how they can impact the people is something we shall return to later. The 1991 budget speech alone was not the harbinger of the neo-liberal economic policy trajectory. The Indian rupee had been devalued twice before the budget. Former Prime Minister Rajiv Gandhi’s call to take India into the 21st century led to a huge profligacy in imports that led to the foreign exchange reserve crisis, the pretext for ushering in the reforms. Two decades later, one thing is certain: we have succeeded in creating two Indias. If the quality of life of everybody has substantially improved, then growing income inequalities would be seen as an index of relative poverty and not absolute poverty. However, the widespread agrarian distress, suicides by farmers and the drastic reduction in the per capita availability of foodgrains and pulses show the rise of absolute poverty among certain sections of people. The luminosity of ‘Shining India’ is, therefore, directly proportional to the deprivation of ‘suffering India’.
While Singh continues to be hailed, unfortunately, due credit is seldom given to former PM PV Narasimha Rao who chose Singh to head the finance ministry. In fact, as his government entered its last year, Rao, in a candid admission, said that the reform process did not guarantee the people basic “rights to food, work, shelter, education, health and information through national determination”.
Speaking at the World Summit for Social Development in Copenhagen in 1995, Rao said: “Today, the world stands at the crossroads of history even as it struggles to free itself from the attitudes of the Cold War era. We are at the crossroads because we know that certain paradigms of development, which placed the State alone at the Centre, did not succeed. There is now a swing to the other side, namely the tendency to put an untrammelled Market alone at the Centre. While the new enthusiasm sweeps over the countries, one cannot help the uneasy feeling that what is needed really is a certain Market Plus; otherwise, the poor and the weak are likely to suffer exclusion due to the imperfections of the Market. The inadequacy in both these approaches stems from the failure to place the people at the Centre. This centrality of the people is extremely important. We have to empower the people themselves as the central strategy to social and economic development to sustain human progress.”
Is it possible to achieve such economic and social empowerment of the people under the neo-liberal dispensation? The elusive objective of “inclusive growth” can only be achieved if there is a radical departure from such a trajectory. This requires a new set of reforms that will provide food security, health and education to our people. It also requires the need to protect our people from increased dispossession, like it has happened with the process of land acquisition. One of the hallmarks of neo-liberalism is the opening of newer avenues for capital accumulation. One such is the acquisition of land from farmers at throwaway prices for super profits. Such “accumulation by dispossession”, as an American intellectual defines, is nothing new in the history of capitalist development. Remember how over 50 million dispossessed people in Europe moved to the then ‘free world’ (the US, Australia etc)? But today’s dispossessed have no such avenues and are thus condemned to misery.
The Left has been seeking a new land acquisition law to replace the anachronistic 1894 law. This law must ensure that apart from adequate compensation and future employment, the dispossessed must also have a share in the rise in the value of the land post-acquisition. Further, these people must be legally protected so that they can defend themselves against land and real estate mafias.
The government’s constant refrain, however, is that it doesn’t have enough resources to implement a comprehensive food security legislation or the right to education law. This is not only absurd but is a lie given the mega scams that this neo-liberal trajectory has facilitated. There is no dearth of resources; there is a dearth of political will to take on the corrupt politician-bureaucrat-businessmen nexus that is looting these resources.
Instead of focusing on such real reforms, there is a clamour for what is fashionably termed as ‘Gen Next’ reforms like the permission for 100% foreign investment in retail trade. This would ruin thousands of people who are today engaged in such trade. Far from the socio-economic empowerment that we have been speaking of, such reforms will only lead to greater deprivation. There is also a clamour for financial reforms: privatisation of the pension funds; increasing foreign investment levels in the insurance sector; banking reforms etc.
If India managed to protect itself from the devastating impact of the global finance crisis, it is because the Left parties had stopped the UPA 1 government from undertaking these reforms. It would be disastrous for India to undertake such reforms today. Proper attention must be paid to the reforms that are required for providing better livelihood to our people.
Sitaram Yechury is CPI(M) Politburo member and Rajya Sabha MP. The views expressed by the author are personal. |
Q:
User.where(:id =>1).where(:id => 2) with ActiveRecord doesn't work
Simply put:
pry(main)> User.where(:id =>1).where(:id => 2).first
User Load (0.4ms) SELECT "users".* FROM "users" WHERE "users"."id" = 2 LIMIT 1
#user 2 is returned
How can I make it run:
pry(main)> User.where(:id =>1).where(:id => 2).first
User Load (0.4ms) SELECT "users".* FROM "users" WHERE "users"."id" = 1 AND "users"."id" = 2 LIMIT 1
#this way no user is returned, because I'm narrowing it down as much as possible
A:
With the help of arel you can do this:
t = User.arel_table
User.where(t[:id].eq("1").and(t[:id].eq("2")))
|
AFA Executive Director Ken Wu stands alongside a row of Sitka spruce and western hemlock trees growing in a line out of a nurse log in the unprotected FernGully Grove near Port Renfrew. (Photo by TJ Watt)
Old-growth forest discovered outside Port Renfrew
Environmental group reaches out to government for funding to purchase and protect the land
The new forest is nicknamed FurnGully Grove, due to its vast understory of ferns, which makes it a good habitat for Roosevelt elk, black-tailed deer, wolves, cougars, and black bears, said AFA officials.
FurnGully Grove is also home to an 11-foot wide Sitka spruce tree, the 10th largest in Canada, according to the B.C. Big Tree Registry, as well as many other six to eight feet wide giants.
However, this new-found natural gem’s existence could potentially be in danger, as the land is owned by TimberWest and could be logged at any time, said AFA.
“This is the most impressive unprotected Sitka spruce grove we’ve come across in years,” said Ken Wu, AFA executive director.
“Finding a grove of unprotected giant Sitka spruce is highly significant, given that the vast majority them on Vancouver Island have been logged in the valley bottoms where they grow.”
The forest that was discovered earlier this year, called Jurassic Grove, is located along a three-kilometre stretch between Jordan River and Port Renfrew and is described as another Avatar Grove because of its accessibility, gentle terrain, and amazing trees.
“Lowland old-growth groves on southern Vancouver Island with the classic giants like this are about as rare as finding a Sasquatch these days – over 95 per cent of the forests like this have been logged on the South Island,” said Wu.
Though there are no proposed plans of logging Jurassic Grove, and there is no survey tape indicating FernGully will be logged yet, Wu said the groves need to be bought and protected by the province.
He added that TimberWest has agreed to not log some contentious sites they they own in the past, such as the Koksilah Ancient Forest, and hopes they will do the same for FernGully.
AFA campaigner Andrea Inness agreed suggesting the provincial government implement a land acquisition fund to buy and protect endangered ecosystems on private lands.
“On Crown lands, where most ancient forests remain, the B.C. government needs to implement a comprehensive, science-based plan to protect the remaining old-growth forests, while also supporting First Nations land use plans and financing sustainable economic development and diversification in those communities in lieu of old-growth logging,” said Inness.
A man walks through a thicket of sword ferns in the unprotected FernGully Grove near Port Renfrew (Photo by TJ Watt) |
Q:
Loading a page but not into a container div using jQuery
I have a drop down that I select a file type from, I then want it to fire at a page that generates a file depending on what was selected and forces a download of it using header in php. Here's the jQuery.
$('#exportdropdown').change(function(){
var searchinput = $('#searchinput').val();
var maxrec = $('#navdropdown option:selected').text();
$('.loadCont').fadeIn();
if($('#importbutton').hasClass('clickedButton')){
$.get('export.php', {filter: 'import', maxrecords: maxrec, type: 'xls'});
}else{
$.get('export.php', {filter: 'export', maxrecords: maxrec, type: 'xls'});
}
$('.loadCont').delay('600').fadeOut();
});
I'm forcing the type at the moment for testing, but it doesn't seem to work how I expected. When you address the file with the data below so export.php?filter='import'&maxrecords=15&type='xls' it forces the download fine. Just not using the jQuery method. Anything obvious that stands out to someone more experienced?
A:
Ajax is pointless here, all you are doing is requesting a link which pushes a file to your browser. Try:
window.location.href = "export.php?filter=" + filter + "&maxrecords=" + maxrecords + "&type=" + type;
|
"On-demand" access to a multi-purpose collection of best practice standards.
On-demand" information has been chosen by clinicians as one of their preferred modes of interaction with computers when in need of information about evidence-based practices. However, most of the clinicians' information needs remain unmet, especially due to a lack of easy access to resources that are able to satisfy these needs in a timely manner. We present three scenarios indicating opportunities for a clinical information system to present interdisciplinary standards at the point-of-care. In each scenario, we highlight the importance of context of use and the opportunities offered by the clinical workflow for providing access to relevant "on-demand" information. We also present an XML model for structuring non-physician interdisciplinary standards, in an effort to fulfill the requirements exposed by the three scenarios. |
Q:
Encapsular media queries de tamaño específico sin que interfieran en otros con características similares
Buenos días a todos. Por fin me uno a esta gran comunidad después de mucho tiempo queriendo hacerlo!
Tengo las siguientes media queries:
/* Atributo "only" para que navegadores antiguos detecten los mediaqueries */
/* Diseño para móviles landscape y portrait */
@media only screen and (min-width:320px)
{
body{
background-color: red;
}
}
/* Diseño para tablets landscape y portrait. Incluidos Ipad y Ipad Pro */
@media only screen and (min-width:768px){
body{
background-color: yellow;
}
}
/* Diseño para resto de escritorios superiores a 1366px,
que es la resolución máxima de Ipad Pro */
@media only screen and (min-width:1366px){
body{
background-color: black;
}
}
Ahora bien, si navegamos desde Laptops con pantallas de 1366x768, aplicaría los estilos destinados a Ipads, dado que la resolución máxima de estos equipos es de 1366px.
Si cambiase el min-width:1366px por min-width:1365px, el Ipad Pro dejaría de estar incluido y por lo tanto se vería la versión de escritorio (cosa que no quiero).
He probado a incluir en los mediaqueries, condicionales con min-device-width y max-device-width, pero claro, a mi entender, si tienes dos mediaqueries con mínima resolución idéntica, se ejecutaría el último escrito. Es decir:
/* Móviles */
@media only screen and (min-width:320px) and (max-device-width:767px)
{
body{
background-color: red;
}
}
/* Ipads */
@media only screen and (min-width:768px) and (max-device-width:1366px){
body{
background-color: yellow;
}
}
/* Resto de equipos */
@media only screen and (min-width:768px) and (max-device-width:1920px){
body{
background-color: black;
}
}
En este caso se ejecutaría siempre el último medaquery y los Ipads quedarían con entorno de escritorio. Al menos así ha respondido mi navegador...
La forma correcta de hacer esto sería:
/* Resto de equipos */
@media only screen and (min-width:1367px){
body{
background-color: black;
}
}
¿Pero qué pasa con los portátiles/laptops que sí tienen esta resolución?
¿Es posible encapsular esto de alguna manera para que haga lo que quiero? Que todo equipo que no sea Ipad, aunque tenga esa resolución, muestre la versión de escritorio.
¿O tengo que acostumbrarme a que Ipad forma parte de las resoluciones de escritorio?
A:
Puedes escribir estilos específicos para tabletas añadiendo condiciones que comprueben el pixel ratio a tus media queries. Se puede hacer con -webkit-device-pixel-ratio (y sus variaciones max y min).
El iPad Pro tiene un pixel ratio de 2 (fuente), entonces lo que harías es indicar que los estilos quieres que sean para dispositivos que tengan un tamaño mínimo de 1366px Y un pixel ratio máximo de 1.5 (por poner un ejemplo).
Entonces podrías tener algo como esto:
Nota: no tengo un iPad Pro a mano, así que no he podido probar este código
/* Resto de equipos */
@media only screen and (min-width:768px) and (max-device-width:1920px) and (-webkit-max-device-pixel-ratio:1.5) {
body{
background-color: black;
}
}
|
Finally, the more efficient implementation of localStorage DOM API has landed and sticks in Firefox 23, currently on the Nightly channel. The first build having the patches has id 20130416030901.
More about the motivation and details in my previous post on DOM storage code overhaul.
I want to thank all involved people, namely Vladan Djeric, Marco Bonardo and Olli Pettay for their help, ideas and mainly reviews of this large change. Thanks! |
'Real Housewives of New Jersey's' Joe Giudice to be deported to Italy after prison
Paul Zimmerman/Getty Images for Mount Airy Casino Resort(YORK COUNTY, PA) — Joe Giudice, the husband of Real Housewives of New Jersey star Teresa Giudice, has been ordered deported to Italy following his prison sentence for fraud.
Officials with Immigration and Customs Enforcement confirmed to ABC News that a judge ruled on the deportation in immigration court Wednesday morning. Joe has 30 days to appeal the decision.
Giudice is currently serving a 41-month prison sentence at the Allenwood Federal Correctional Institute in Pennsylvania for mail, wire and bankruptcy fraud and is scheduled to be released next year. His wife, Teresa, served just over 11 months in jail for the same crimes and was released in 2015. The couple have four daughters: 17-year-old Gia, 14-year-old Gabriella, 12-year-old Milania and nine-year-old Audriana.
Back in January, Teresa implied she’d move to Italy to be with her husband should he be deported.
“I mean, Italy’s a beautiful place to live,” Giudice said at the RHONJ reunion on Bravo. “I wouldn’t mind, you know, I’m just saying. Listen, whatever God has planned for me, that’s what’s going to happen. I will embrace it the best I can.” |
A less government conservative Republican from Livingston County, MI
Opinions on this blog are those of the author and do not necessarily represent the opinions of the Livingston County Republican Party.
Chairman of LCRP since January 2013
Monday, December 31, 2007
I'm going to catch some heat for this by some, but that's too bad. I look at the direction of the party today under Bush compared to the philosophy of 1994. I am a 1994 Republican, otherwise known as a less government conservative. I do not support the mass increases in government spending, governmental regulations, and decrease in our freedoms. That is why I am going to vote for Ron Paul in the 2008 primary. This may surprise some, but really shouldn't. Those that really know my politics well know that I have a strong libertarian streak.
First of all, I am not a "9/11 truther". I am not a stormfronter nutjob. I am not supporting surrender. I am not a democrat causing mischief. Those are the labels that opposition on both the right and the left used to paint Ron Paul supporters. I am simply a 1994 style less government conservative. Reduced spending. Reduced regulation. No Patriot Act style regulations, whether it be in the name of the "War on drugs" or "war on terror" or under presidents named Bush or Clinton.
I look at the issues that matter most to me.
1. Freedoms. Few are consistent. Ron Paul is. When Bill Clinton pushed for his intrusive "anti-terror" acts, gun grabs, and sneak and peak measures, Ron Paul stood up and said it was wrong. When Bush pushed for the Patriot Act with many of Clinton's provisions, Ron Paul stood up and said it was wrong. Ron Paul has a consistent 18 year voting record and leadership record of standing up for freedoms, no matter who is president. From free speech, to the right to keep and bear arms, to the 4th amendment on search and seizure.
2. Spending. Ron Paul stayed consistent here and voted against bad spending bills. This is one of the things that is killing our party. We suck less than the democrats here, but suck less still sucks.
3. NAFTA and GATT. Can I say that I told you so one this one. GATT was the worst of the bunch when unelected bureaucrats at the WTO have veto power over our trade. That's unacceptable. I'm not opposed to free trade, but I am opposed to managed trade designed as free trade that hurts our manufacturing and blue collar base.
4. Judges. I'm not worried about Ron Paul here.
5. Consistency. I do not have to worry about Ron Paul putting his finger in the wind and changing his stance for the media or the political winds.
6. Life issues. Ron Paul is pro-life.
7. Character. Something lacking in many politicians today.
For 12 months, my ideological and my pragmatic sides have battled over who I am going to support. More often than not recently, my pragmatic side has won. Not this time. In the end, I thought this to myself - How often does a pro-freedom candidate gain this much traction with fundraising? I have never seen it.
I'm not going to attack other candidates here. With SCOTUS as my number one issue, I will vote for any republican over any democrat running in the general election unless there is another retirement and Bush gets a solid conservative through the democrat senate and the firewall of extremist Chuck Schumer. We are IMO one, maybe two judge away from stopping the neo-lochnerization of the courts. We may or may not get that from the republicans, but the last MODERATE judge (let alone conservative) given to us by the democrats was Byron White from JFK.
However, this is the primary, and no candidate so far as won my vote based on perceived "electableness." My definition of electable is different than the pundits and media which anointed Bob Dole and John Kerry as electable when neither were. Unless it is clear as day to my gut on electablity, I'm going ideological over pragmatism.
This is my Barry Goldwater 1964 moment. "Extremism is defense of liberty is no vice" I am voting for Ron Paul for President on January 15.
Wednesday, December 26, 2007
Bipartisanship is not always a good thing. It's oftentimes a very bad thing, like this turkey right here.
CRAWFORD, Texas - President Bush, still voicing concern about special project spending by Congress, signed a $555 billion bill Wednesday that funds the Iraq war well into 2008 and keeps government agencies running through next September.
Bush's signed the massive spending bill as he flew on Air Force One to his Texas ranch here to see in the new year. His signature on the legislation caps a long-running fight with the Democratic-run Congress.
"I am disappointed in the way the Congress compiled this legislation, including abandoning the goal I set early this year to reduce the number and cost of earmarks by half," the president said in a statement. "Instead, the Congress dropped into the bill nearly 9,800 earmarks that total more than $10 billion. These projects are not funded through a merit-based process and provide a vehicle for wasteful government spending."
"There is still more to be done to rein in government spending," Bush said. "In February I will submit my budget proposal for fiscal year 2009, which will once again restrain spending, keep taxes low, and continue us on a path towards a balanced budget. I look forward to working with the Congress in the coming year to ensure taxpayer dollars are spent wisely."
That's not good enough Bush. You talked the game, but YOU signed it. You voiced disapproval, but when push came to shove, YOU signed it since you got what you wanted. You could have vetoed it.
To the democrats - YOU control congress. YOU promised fiscal restraint. This is YOUR bill. YOU spent this.
This is over a half a TRILLION dollars in spending, including 10 billion in earmarks. This is a bipartisan turkey of a budget and a Christmas gift from Washington tantamont to a lump of coal.
late last week, then backed former Massahusetts Gov. Mitt Romney, one of the Iowa frontrunners.
Dianne Bystrom, an Iowa State University political science professor, said Tancredo's exit and endorsement of Romney could shake up the volatile Republican field.
"Tancredo throwing his support behind Romney comes at a key time when Romney is trying to fight off the surge of Mike Huckabee," Bystrom told The Des Moines Register. "For Romney, it probably couldn't have come at a better time."
Tancredo claimed victory on immigration, the cause that drew him into the race in the first place, arguing that his stance in favor of strict enforcement forced the entire field to move toward his position.
In fact, bowing out was the only way to ensure that the momentum behind the anti-illegal immigration movement wouldn't flame out, he said.(snip)
This could be interesting to see. The primary is coming up fast, so we'll see what happens. I do wonder if Tancredo's name will still be on the ballot. I think he will be in Michigan.
After months of careful negotiation, pro-gun legislation was passed through Congress today. The National Rifle Association (NRA) worked closely with Senator Tom Coburn (R-Okla.) to address his concerns regarding H.R. 2640, the National Instant Check System (NICS) Improvement Act. These changes make a good bill even better. The end product is a win for American gun owners.
Late yesterday, anti-gun Senator Ted Kennedy (D-MA), failed to delay progress of this pro-gun measure. The Violence Policy Center, the Coalition to Stop Gun Violence and other gun control and gun ban groups are opposed to the passage of this legislation because of the many pro-gun improvements contained within.
The NICS Improvement Act does the following to benefit gun owners:
Permanently prohibits the FBI from charging a “user fee” for NICS checks.
Requires all federal agencies that impose mental health adjudications or commitments to provide a process for “relief from disabilities.” Extreme anti-gun groups like the Violence Policy Center and Coalition to Stop Gun Violence have expressed “strong concerns” over this aspect of the bill—surely a sign that it represents progress for gun ownership rights.
Prevents reporting of mental adjudications or commitments by federal agencies when those adjudications or commitments have been removed.
Requires removal of expired, incorrect or otherwise irrelevant records. Today, totally innocent people (e.g., individuals with arrest records, who were never convicted of the crime charged) are sometimes subject to delayed or denied firearm purchases because of incomplete records in the system.
Provides a process of error correction if a person is inappropriately committed or declared incompetent by a federal agency. The individual would have an opportunity to correct the error-either through the agency or in court.
Prevents use of federal “adjudications” that consist only of medical diagnoses without findings that the people involved are dangerous or mentally incompetent. This would ensure that purely medical records are never used in NICS. Gun ownership rights would only be lost as a result of a finding that the person is a danger to themselves or others, or lacks the capacity to manage his own affairs.
Improves the accuracy and completeness of NICS by requiring federal agencies and participating states to provide relevant records to the FBI. For instance, it would give states an incentive to report those who were adjudicated by a court to be "mentally defective," a danger to themselves, a danger to others or suicidal.
Provides that if a person applies for relief from disabilities and the agency fails to act on the application within a year—for any reason, including lack of funds—the applicant can seek immediate review of his application in federal court.
Allows awards of attorney’s fees to applicants who successfully challenge a federal agency’s denial of relief in court.
Requires that federal agencies notify all people being subjected to a mental health “adjudication” or commitment process about the consequences to their firearm ownership rights, and the availability of future relief.
Earmarks 3-10% of federal implementation grants for use in operating state “relief from disabilities” programs.
Elimination of all references to Bureau of Alcohol, Tobacco, Firearms and Explosives regulations defining adjudications, commitments, or determinations related to Americans’ mental health. Instead, the bill uses terms previously adopted by the Congress.On Wednesday evening, by unanimous consent, the U.S. House accepted the Senate amendment to H.R. 2640. The legislation is headed to the President's desk for his signature into law
Much has been made of the bill's bi-partisan, triangulating support: Democrats! Republicans! The National Rifle Association! The Brady Campaign! Beyond this cheery bon temps, little public attention has been paid to what the bill actually does beyond its title. And that's because if you start looking at the details of the bill--especially after NRA-backed changes made by Oklahoma Senator Tom Coburn--it becomes clear that the measure is nothing less than a pro-gun Trojan Horse. That's why my organization, the Violence Policy Center, and other national gun control groups, have voiced their strong concerns about the version of the bill that was passed by Congress. Concerns that have been validated by none other than the NRA which, after the bill's passage issued a press release which crowed:
Gun Owners of America and its supporters took a knife in the back yesterday, as Senator Chuck Schumer (D-NY) out-smarted his congressional opposition into agreeing on a so-called "compromise" on HR 2640 -- a bill which now goes to the President's desk.
The bill -- known as the Veterans Disarmament Act to its opponents -- is being praised by the National Rifle Association and the Brady Campaign.
The Brady Bunch crowed "Victory! U.S. Congress Strengthens Brady Background Check System." The NRA stated that last minute changes to the McCarthy bill made a "good bill even better [and that] the end product is a win for American gun owners."
But Gun Owners of America has issued public statements decrying this legislation.
The core of the bill's problems is section 101(c)(1)(C), which makes you a "prohibited person" on the basis of a "medical finding of disability," so long as a veteran had an "opportunity" for some sort of "hearing" before some "lawful authority" (other than a court). Presumably, this "lawful authority" could even be the psychiatrist himself.
Note that unlike with an accused murderer, the hearing doesn't have to occur. The "lawful authority" doesn't have to be unbiased. The veteran is not necessarily entitled to an attorney -- much less an attorney financed by the government.
So what do the proponents have to say about this?
ARGUMENT: The Veterans Disarmament Act creates new avenues for prohibited persons to seek restoration of their gun rights.
ANSWER: What the bill does is to lock in -- statutorily -- huge numbers of additional law-abiding Americans who will now be denied the right to own a firearm.
And then it "graciously" allows these newly disarmed Americans to spend tens of thousands of dollars for a long-shot chance to regain the gun rights this very bill takes away from them.
More to the point, what minimal gains were granted by the "right hand" are taken away by the "left." Section 105 provides a process for some Americans diagnosed with so-called mental disabilities to get their rights restored in the state where they live. But then, in subsection (a)(2), the bill stipulates that such relief may occur only if "the person will not be likely to act in a manner dangerous to public safety and that the GRANTING OF THE RELIEF WOULD NOT BE CONTRARY TO THE PUBLIC INTEREST." (Emphasis added.)
Um, doesn't this language sound similar to those state codes (like California's) that have "may issue" concealed carry laws -- where citizens "technically" have the right to carry, but state law only says that sheriffs MAY ISSUE them a permit to carry? When given such leeway, those sheriffs usually don't grant the permits!
Prediction: liberal states -- the same states that took these people's rights away -- will treat almost every person who has been illegitimately denied as a danger to society and claim that granting relief would be "contrary to the public interest."
Let's make one thing clear: the efforts begun during the Clinton Presidency to disarm battle-scarred veterans -- promoted by the Brady Anti-Gun Campaign -- is illegal and morally reprehensible.
But section 101(c)(1)(C) of HR 2640 would rubber-stamp those illegal actions. Over 140,000 law-abiding veterans would be statutorily barred from possessing firearms.
True, they can hire a lawyer and beg the agency that took their rights away to voluntarily give them back. But the agency doesn't have to do anything but sit on its hands. And, after 365 days of inaction, guess what happens? The newly disarmed veteran can spend thousands of additional dollars to sue. And, as the plaintiff, the wrongly disarmed veteran has the burden of proof.
Language proposed by GOA would have automatically restored a veteran's gun rights if the agency sat on its hands for a year. Unfortunately, the GOA amendment was not included.
The Veterans Disarmament Act passed the Senate and the House yesterday -- both times WITHOUT A RECORDED VOTE. That is, the bill passed by Unanimous Consent, and was then transmitted to the White House.
Long-time GOA activists will remember that a similar "compromise" deal helped the original Brady Law get passed. In 1993, there were only two or three senators on the floor of that chamber who used a Unanimous Consent agreement (with no recorded vote) to send the Brady bill to President Clinton -- at a time when most legislators had already left town for their Thanksgiving Break.
Gun owners can go to http://www.gunowners.org/news/nws9402.htm to read about how this betrayal occurred 14 years ago.
With your help, Gun Owners of America has done a yeoman's job of fighting gun control over the years, considering the limited resources that we have. Together, we were able to buck the Brady Campaign/NRA coalition in 1999 (after the Columbine massacre) and were able to defeat the gun control that was proposed in the wake of that shooting.
Yesterday, we were not so lucky. But we are not going to go away. GOA wants to repeal the gun-free zones that disarm law-abiding Americans and repeal the other gun restrictions that are on the books. That is the answer to Virginia Tech. Unfortunately, the House and Senate chose the path of imposing more gun control.
So our appeal to you is this -- please help us to grow this coming year. Please help us to get more members and activists. If you add $10 to your membership renewal this year, we can reach new gun owners in the mail and tell them about GOA.
Please urge your friends to join GOA... and, at the very least, make sure they sign up for our free e-mail alerts so that we can mobilize more gun owners than ever before!
Sunday, December 23, 2007
It's close to election time and the robocalls and political phone calls are back.
The worst offenders once again are American Family Voices. I've gotten four calls by those jerks, all spewing BS against Mike Rogers. It's run by Bill Clinton democrats like David Wilhelm (Ex-DNC chair) and Mike Lux (Clinton aide, political director of People for the unAmerican Way). Mike Lux runs the show at AFV. If they have a toll free number, someone should give them a taste of their own medicine and make them lose a lot of their union and Soros money. I did find a business number from back in 03. 202.628.7772 ext. 126 (Business number). Maybe some of you readers can call him up and ask Mike Lux to stop flooding you with robocalls.
With the January primary coming up, some of the campaigns are calling people. I got two surveybots on my answering machine. I haven't made up my decision yet, but if you want to lose my vote real quickly, call me with push polls, robocalls, and attack ads. I really think political phone calls cost more votes than they gain. I can not tell you how many people were pissed off at the calls bombarding their homes during last election season. Think about this. We had all the interest groups robocalling them, at least seven from Mike Lux and American Family voices alone. We had the call centers for the campaigns and political parties themselves. With races for governor, senate, congress, state reps, and everyone else, that all adds up. People at home eating dinner do not like being disturbed and invaded by solicitations over the phone. That goes double for those in a profession viewed on the same level as a used car salesman. I got more complaints about this than anything else over last election season, and I think these calls cost us about 2% in the polls.
Both parties are guilty of this. Mike Lux may be the worst, but he's not the only one.
Sunday, December 16, 2007
Some good news. The State Senate passed the house bill legalizing MMA in Michigan. It's now in Granholm's hands. The vote was 22-12 from what I can remember and did not go on partisan lines. It took members in both parties to pass this one and the alliances were not what I'm used to seeing.
Some bad news. Phone taxes were raised. This comes right after Granholm says she'll never raise taxes again.
Tuesday, December 11, 2007
Apologize for the lack of updates, but it's the middle of law exam period. I just finished the first one yesterday and it was a grizzly bear to deal with to say the least. There won't be much here for at least a week and a half.
Thursday, December 06, 2007
An outright ban on smoking in workplaces -- restaurants and bars included -- was approved by the House on Wednesday, giving anti-smoking activists their biggest victory in the Capitol so far.
Smoking would still be allowed in casinos, cigar bars, horse racetracks and bingo halls, under the legislation.
The bill faces opposition in the Republican-controlled Senate, where restaurant owners and other opponents are certain to try to kill it.
Gov. Jennifer Granholm has said she would support a workplace smoking ban.
The 56-46 House vote was the result of months of hearings and lobbying by anti-smoking groups who argued that second-hand smoke is a health hazard.
If smoking is so damn bad for you that government can not allow PRIVATE businesses to make a choice whether to allow it in their places far away from the people's republic of Lansing - than ban the damn things altogether. I oppose that as well, but I could respect that decision. This is just another instance of big government claiming to know best in how to regulate another person's privately owned business. With the way government is running their own ship and tax policies, we don't need their "help" in doing so.
As far as smoking itself goes, there are places here in Livingston County which do not allow smoking. The Copper Pickle banned it completely. That is their choice, and they should be entitled to make their choice. Other places rely on smokers for their business. That should be their choice at the same time. In fact this ban hurts existing smoke free places, as that is a niche they can use in their marketing.
The big government statists here aren't pushing to ban smoking in public buildings. That's already the case for the most part. Public buildings are government buildings. The statists are pushing to tell what private business are allowed to do on their own property. That's not right, and the senate needs to kill this turkey of a bill and keep the goon squads off the backs of private businesses.
Monday, December 03, 2007
The Detroit News has a very interesting story, particulary for guys like me who follow the stuff in politics that nobody likes to follow - campaign finance. If you are a candidate in either party, this is a must read.
Brett McRae is always cleaning up after politicians.
When he was a student, he worked his way through law school as a janitor at the state House of Representatives. Now as a campaign finance consultant, the 50-year-old Charlotte man keeps elections clean.
"A person's political reputation can really be trashed by things that can be found in those filings," said McRae, "like if you were late or made a questionable expenditure or took money from someone you shouldn't have."
I don't belong to the same political party as McRae, but he's earned my respect. Guys like McRae, and his Republican counterpart at state party (who has stayed there through several chairs for obvious reasons), are the type of people that each candidate needs to talk to. Why? I'll let him say it.
"For a lot of campaigns, the financial reporting gets shuffled to the bottom of the deck," he said, even though late fees and penalties can be costly and mistakes can be politically embarrassing. "This way, the staff can concentrate on winning the election."
The worst campaign finance debacle I've seen was this, almost two years ago which I covered under. Why a good treasurer is a must. I sat on that information for two years before it was picked up by the papers. I didn't turn him in, since the state automaticly catched those who don't. The only people I told were Joe Hune's campaign who kept it quiet since there was no reason to attack. Joe was winning big, and his opponent was not running a credible campaign. I could have called the paper then, but I actually felt sorry for the guy. I don't think he knew what he was getting into.
Most candidates, of all parties, are completely ignorant when it comes to campaign finance matters. I do not mean that as an insult. Most just don't know all of the ins and outs of it. Like the candidates, I was baptized by fire when I was volunteered at 22 years old to be a PAC treasurer. I thought it was something easy. I didn't know what I was getting into. At the same time, it was one of the best things to happen to me. Today, I'm a veteran at this stuff, one of the go to guys in the party on this, and hopefully taught a few people some things as well. I'm proud of two things with my campaign finance work. I've never been fined for an error. That means I did not have any failure to files, or any late filings (nor indictments or convictions). I have not had an error or omissions notice in five years (mistakes since corrected). I still have a lot to learn, especially on federal matters, but I don't make many mistakes outside of being a little too cautious at times. I don't play games with this stuff.
I can also catch a lot of errors as well, and turned the MEA in for non-disclosure. I don't turn in everyone, even in the opposing party, but they knew better and I thought their non-disclosure was deliberate since they did not want their cards saying "East Lansing" on them.
In campaigns there are two things. There are things you can contol, and things you can't control. Campaign finance situations are things that can be controlled. THE most important thing a candidate can do is hire or get a good treasurer to volunteer for the campaign.
Michigan has full disclosure. That's something that is very important to know. There are a few people whose money I will stay the hell away from if I am running for political office. I will have a lot of explaining to do if I report donations from people like Mark Foley (obvious reasons), Josh Sugarmann (for anti-2nd Amendment views), or illegal sources. (Corporations, foreigners). Good Treasurers can screen this, and that goes double on the illegal sources.
For those interesting in running or forming PAC's, there are manuals on campaign finance laws at the Elections Division of the Secretary of State's office. Click Here for Sec of State That is a must read if you are interesting in running.
If you run, know what you are getting into on this stuff and be prepared. All it takes is one major screw up to destroy the entire campaign. As the old saying goes, "Prior planning prevents poor performance."
This calls for some concern. Hopefully this does not turn into Chapter 7 liquidation. From the AP
Delphi Corp. has sought a three-month extension of its right to control its bankruptcy reorganization, saying the credit crunch has made it difficult for the company to obtain Chapter 11 exit-financing.
In papers filed with the U.S. Bankruptcy Court in Manhattan late Friday, Delphi asked a judge to extend until March 31 its deadline to develop a Chapter 11 plan. That deadline currently is set to expire Dec. 31.
The company, the largest supplier of parts to General Motors Corp., also sought to move until the end of May its deadline to win creditors' support for the plan.
(snip)
Delphi has been in bankruptcy reorganization since October 2005. As credit markets have tightened recently, Delphi has scaled back the amount of money it intends to borrow to pay off its creditors. That has resulted in changes to its Chapter 11 plan and caused delays, it said.
In its court papers, Delphi cited "severe dislocations in the capital markets that began late in the second quarter of 2007 and that have increased in severity during the third and fourth quarters of 2007." Those financing difficulties, among other things, forced the company to offer its creditors repayment terms that were less generous than it initially expected.
Cash payments, for example, were reduced by $3 billion. The company amended its reorganization plan to instead give unsecured creditors, which are being paid mainly with new Delphi stock, the option to buy additional shares at a discount through a rights offering. GM will get a combination of cash, new debt and new convertible preferred stock.
I don't think I need to tell anyone how important Delphi is in Michigan.
This is a case of pick your poison. Instead of being hung, drawn and quartered, we're just getting the electric chair thanks to Granholm zapping this state to death with her Matt Millenesqe leadership.
Now we got 22% surcharge on all businesses that pay the MBT. Cought it up!
I should mention that the service tax DID become law for a brief period, but apparently, the legislature said that the service tax law could be ignored. I'm uncertain about that, and would need to read that in depth to see if the intent matches the actual words of the law. They aren't trustworthy enough for me to take their word for it.
Sunday, December 02, 2007
WASHINGTON -- House leaders agreed late Friday to hike fuel economy standards 40 percent by 2020 to a fleet-wide average of 35 miles per gallon, a landmark deal that clears the way for a House vote by Wednesday.
The increase would be the first for passenger cars since 1985, marking a dramatic defeat for automakers, which have successfully foiled efforts to force increases for more than two decades.
U.S. Rep. John Dingell, D-Dearborn, and House Speaker Nancy Pelosi, D-Calif., finalized an agreement for raising corporate average fuel economy standards during a telephone call Friday evening.
(snip)
The deal will be very expensive for automakers. GM chairman and CEO Rick Wagoner has said a similar bill could cost the Detroit automaker more than $40 billion over the next decade. A Bush administration analysis of a similar proposal said it could cost automakers more than $100 billion.
Automakers grudgingly decided to support it because there were no other options, and their political capital is waning. They have criticized the CAFÉ system, saying it distorts the marketplace by forcing them at times to offer incentives to sell smaller cars in order to meet the requirements.
(snip)
It will no doubt hike the price of cars by forcing automakers to add expensive items like gasoline-electric hybrid engines and likely require automakers to make more lighter, smaller vehicles. It may force Detroit to shrink production of its SUVs and trucks, its largest most profitable vehicles.
If passed, the bill would give Democrats a big achievement to tout to voters who have put up with skyrocketing gas prices.
It would also hand President Bush a domestic achievement that would surely be part of his legacy, since it largely dovetails with his State of the Union proposal in January to hike fuel efficiency standards by an average of 4 percent per year over 10 years.
This also doesn't do jack to lower gas prices. We need less big government and less democrat/Bush sneering of American cars. Let the market decide.
If you want to lower gas prices, the first thing to do is open up domestic energy sources. ANWR, Coal, and especially nuclear. Put more research into cold fusion, and then afterward tell OPEC to perform unnatural acts on themselves. |
Hannen Columbarium
The Hannen Columbarium is a columbarium mausoleum – a resting place for the cremated remains of the deceased – built for the Hannen family of Wargrave, Berkshire, England and designed by Edwin Lutyens.
Columbarium
Lutyens became acquainted with the Hannen family in about 1897 and from 1902 to 1905 employed Nicholas Hannen as an architectural trainee.
The Hannen Columbarium was built in 1906–07 to house the ashes of Nicholas's father, Sir Nicholas Hannen, a barrister, diplomat and judge who died in Shanghai in 1900.
Lutyens was commissioned in 1905, and produced a columbarium design combining Byzantine Revival with Arts and Crafts and with classical architectural lines, in the form of a square building of red-brick, red-tile, glass-tile and stonework, sited in the south-east of the graveyard of St. Mary's Church, Wargrave. Within – in Lutyens's words – is "a circular cella within four piers, which carry intersecting arches forming pendentives and completed by a saucer dome." The cilla is decorated with text from Luke, chapter 20, verse 38: 'He Is Not The God Of The Dead But Of The Living For All Live Unto Him'.
The Columbarium is a Grade II* listed building. It was restored in 1985, but concerns exist as to its condition. It forms Lutyens's earliest mausoleum design, and (with Heathcote in Ilkley), is recognised as an embodiment of the point at which he fully incorporated classical architecture in his designs.
See also
Wargrave War Memorial, also designed by Lutyens
Grade II* listed buildings in Berkshire
References
Category:Buildings and structures completed in 1906
Category:Byzantine Revival architecture in the United Kingdom
Category:Grade II* listed buildings in Berkshire
Category:Mausoleums in England
Category:Monuments and memorials in Berkshire
Columbarium |
Q:
Gramian matrix test
Are there some test to know if a matrix $M$ is gramian ? $M$ is gramian if it exists a matrix W such $M=W^HW$. Also if it is possible to determine $W$.
Thanks
A:
Gramian matrix is positive-definite. So it's possible to find square root. It will be symmetrical so this it is possible to write such decomposition for any positive definite matrix. The solution of $M=WW^{T}$ it is not unique, because starting from nonsymmetric matrix $A$ one can construct matrix $B=AA^T$ and then a symmetric solution of $B=WW^T$.
|
Litecoin (LTC) Down $0.51 Over Past 4 Hours, Fares the Worst Out of Top Cryptos to Start the Day; Started Today Down 0.81%
Litecoin 4 Hour Price Update
Updated May 24, 2020 07:18 PM GMT (03:18 PM EST)
Litecoin came into the current 4 hour candle down 1.18% ($0.51) from the open of the last 4 hour candle, marking the 3rd candle in a row it has gone down. Relative to other instruments in the Top Cryptos asset class, Litecoin ranked 3rd since the last 4 hour candle in terms of percentage price change.
Litecoin Daily Price Recap
The choppiness in the recent daily price action of Litecoin continues; to start today, it came in at a price of 43.86 US dollars, down 0.81% ($0.36) since yesterday. This move happened on lower volume, as yesterday’s volume was down 38.28% from the day before — and down 34.12% from the same day the week before. Those trading within the Top Cryptos asset class should know that Litecoin was the worst performer in the class during yesterday. Here is a daily price chart of Litecoin.
Litecoin Technical Analysis
Moving average crossovers are always interesting, so let’s start there: Litecoin crossed below its 50 day moving average yesterday. For another vantage point, consider that Litecoin’s price has gone up 16 of the previous 30 trading days.
Overheard on Twitter
For laughs, fights, or genuinely useful information, let’s see what the most popular tweets pertaining to Litecoin for the past day were:
#Litecoin’s hashrate on 5/23/2017 was 6.8142 T
#LTC’s hashrate today, 5/23/2020 is 201.6057 TThe current hashrate is only about 64 T above the bottom over the past 2 years (around 137 Te), yet is still over 29.5x higher than 3 years ago.
The #Litecoin community is plagued with bullying!. When Some asshole who has been in #crypto one week and instantly an expert! Yes that old chestnut! Just remember when you hurl that onslaught of abuse there is another human on the receiving end! #Crypto is about COMMUNITY. |
Q:
How to set the position of a MessageBox using tkinter
I have been looking all over to see if I can find any help with this and haven't gotten anywhere
My program is a simple tkinter menu that is set to be in a default position in the top left corner of the screen, however when I press the X button it loads the message box in the center of the screen.
How do I make it so that it snaps the message box to the corner?
root = Tk()
root.geometry('%dx%d+%d+%d' % (300, 224, 0, 0))
root.resizable(0,0)
def exitroot():
if tkMessageBox.askokcancel("Quit", "Are you sure you want to quit?"):
with open(settings, 'wb') as csvfile:
writedata = csv.writer(csvfile, delimiter=',', quotechar='|', quoting=csv.QUOTE_MINIMAL)
writedata.writerow([setpass])
writedata.writerow([opcolour] + [bkcolour])
writedata.writerow([menu_background_status] + [menu_internet_status])
root.destroy()
root.protocol("WM_DELETE_WINDOW", exitroot)`
If any extra code is needed then let me know, and thanks in advance.
A:
You will need to build a custom Toplevel() window and then tell it to re-position to the corner of the root window. We can do this with the Toplevel() class and the winfo() methods.
import tkinter as tk
# import Tkinter as tk # for Python 2.X
class MessageWindow(tk.Toplevel):
def __init__(self, title, message):
super().__init__()
self.details_expanded = False
self.title(title)
self.geometry("300x75+{}+{}".format(self.master.winfo_x(), self.master.winfo_y()))
self.resizable(False, False)
self.rowconfigure(0, weight=0)
self.rowconfigure(1, weight=1)
self.columnconfigure(0, weight=1)
self.columnconfigure(1, weight=1)
tk.Label(self, text=message).grid(row=0, column=0, columnspan=3, pady=(7, 7), padx=(7, 7), sticky="ew")
tk.Button(self, text="OK", command=self.master.destroy).grid(row=1, column=1, sticky="e")
tk.Button(self, text="Cancel", command=self.destroy).grid(row=1, column=2, padx=(7, 7), sticky="e")
root = tk.Tk()
root.geometry("300x224")
root.resizable(0, 0)
def yes_exit():
print("do other stuff here then root.destroy")
root.destroy()
def exit_root():
MessageWindow("Quit", "Are you sure you want to quit?")
root.protocol("WM_DELETE_WINDOW", exit_root)
root.mainloop()
Results:
Personally I would build this all in one class inheriting from Tk(), make the buttons even with ttk buttons and use a label to reference the built in question image located at ::tk::icons::question like this:
import tkinter as tk
import tkinter.ttk as ttk
# import Tkinter as tk # for Python 2.X
class GUI(tk.Tk):
def __init__(self):
super().__init__()
self.geometry("300x224")
self.resizable(0, 0)
self.protocol("WM_DELETE_WINDOW", self.exit_window)
def yes_exit(self):
print("do other stuff here then self.destroy")
self.destroy()
def exit_window(self):
top = tk.Toplevel(self)
top.details_expanded = False
top.title("Quit")
top.geometry("300x100+{}+{}".format(self.winfo_x(), self.winfo_y()))
top.resizable(False, False)
top.rowconfigure(0, weight=0)
top.rowconfigure(1, weight=1)
top.columnconfigure(0, weight=1)
top.columnconfigure(1, weight=1)
tk.Label(top, image="::tk::icons::question").grid(row=0, column=0, pady=(7, 0), padx=(7, 7), sticky="e")
tk.Label(top, text="Are you sure you want to quit?").grid(row=0, column=1, columnspan=2, pady=(7, 7), sticky="w")
ttk.Button(top, text="OK", command=self.yes_exit).grid(row=1, column=1, sticky="e")
ttk.Button(top, text="Cancel", command=top.destroy).grid(row=1, column=2, padx=(7, 7), sticky="e")
if __name__ == "__main__":
GUI().mainloop()
Results:
|
An algorithm for RELAX NG validation
James Clark ([email protected])
2002-02-13
Table of contents
This document describes an algorithm for validating an XML document
against a RELAX NG schema. This algorithm is based on the idea of
what's called a derivative (sometimes called a residual).
It is not the only possible algorithm for RELAX NG validation. This
document does not describe any algorithms for transforming a RELAX NG
schema into simplified form, nor for determining whether a RELAX NG
schema is correct.
We use Haskell to describe the
algorithm. Do not worry if you don't know Haskell; we use only a tiny
subset which should be easily understandable.
Basics
First, we define the datatypes we will be using. URIs and local
names are just strings.
Note that there is an Element pattern rather than a
Ref pattern. In the simplified XML representation of
patterns, every ref element refers to an
element pattern. In the internal representation of
patterns, we can replace each reference to a ref pattern
by a reference to the element pattern that the
ref pattern references, resulting in a cyclic data
structure. (Note that even though Haskell is purely functional it can
handle cyclic data structures because of its laziness.)
In the instance, elements and attributes are labelled with QNames;
a QName is a URI/local name pair.
An XML document is represented as a ChildNode. There are
two kinds of child node:
a TextNode containing a string;
an ElementNode containing a name (of type
QName), a Context, a set of attributes
(represented as a list of AttributeNodes, each of which
will be an AttributeNode), and a list of children
(represented as a list of ChildNodes).
The key concept used by this validation technique is the concept of
a derivative. The derivative of a pattern p with
respect to a node x is a pattern for what's left of
p after matching x; in other words, it is a
pattern that matches any sequence that when appended to x
will match p.
If we can compute derivatives, then we can determine whether a
pattern matches a node: a pattern matches a node if the derivative of
the pattern with respect to the node is nullable.
It is desirable to be able to compute the derivative of a node in a
streaming fashion, making a single pass over the tree. In order
to do this, we break down an element into a sequence of components:
a start-tag open containing a QName
a sequence of zero or more attributes
a start-tag close
a sequence of zero or more children
an end-tag
We compute the derivative of a pattern with respect to an element
by computing its derivative with respect to each component in turn.
We can now explain why we need the After pattern. A
pattern After xy is a pattern that
matches x followed by an end-tag followed by
y. We need the After pattern in
order to be able to express the derivative of a pattern with respect
to a start-tag open.
The central function is childNode which computes the
derivative of a pattern with respect to a ChildNode and a
Context:
Perhaps the trickiest part of the algorithm is in computing the
derivative with respect to a start-tag open. For this,
we need a helper function; applyAfter takes
a function and applies it to the second operand of
each After pattern.
We rely here on the fact that After patterns are
restricted in where they can occur. Specifically, an
After pattern cannot be the descendant of any pattern
other than a Choice pattern or another After
pattern; also the first operand of an After pattern can
neither be an After pattern nor contain any
After pattern descendants.
For Interleave, OneOrMoreGroup or After we compute the derivative in a
similar way to textDeriv but with an important twist.
The twist is that instead of applying interleave,
group and after directly to the result of
recursively applying startTagOpenDeriv, we instead use
applyAfter to push the interleave,
group or after down into the second operand
of After. Note that the following definitions ensure
that the invariants on where After patterns can occur are
maintained.
We make use of the standard Haskell function flip
which flips the order of the arguments of a function of two arguments.
Thus, flip applied to a function of two arguments
f and an argument x returns a function of one
argument g such that g(y) =
f(y, x).
Computing the derivative with respect to an attribute done in a
similar to computing the derivative with respect to a text node. The
main difference is in the handling of Group, which has to
deal with the fact that the order of attributes is not significant.
Computing the derivative of a Group pattern with respect
to an attribute node works the same as computing the derivative of an
Interleave pattern.
The case where the list of children is empty is treated as if there
were a text node whose value were the empty string. See rule
(weak match 3) in the RELAX NG spec.
childrenDeriv cx p [] = childrenDeriv cx p [(TextNode "")]
In the case where the list of children consists of a single text
node and the value of the text node consists only of whitespace, the
list of children matches if the list matches either with or without
stripping the text node. Note the similarity with
valueMatch.
Optimizations
Computing nullable
The nullability of a pattern can be determined straightforwardly as
the pattern is being constructed. Instead of computing
nullable repeatedly, it should be computed once when the
pattern is constructed and stored as a field in the pattern.
Interning patterns
Additional optimizations become possible if it is possible to
efficiently determine whether two patterns are equal. We don't want to
have to completely walk the structure of both patterns to determine
equality. To make efficient comparison possible, we intern
patterns in a hash table. Two interned patterns are equal if and only
if they are the same object (i.e. == in Java terms).
(This is similar to the way that Strings are interned to
make Symbols which can be compared for equality using
==.) To make interning possible, there are two notions
of identity defined on patterns each with a corresponding hash
function:
interned identity is simply object identity (i.e. ==
or Object.equals in Java); for a hash function, we can
use Object.hash in Java or the address of the object in
C/C++
uninterned identity uses the type of the pattern, the
interned identity of subpatterns, and the identity of any other
parts of the pattern; similarly, the uninterned hash function calls
the interned hash function on subpatterns
To intern patterns, we maintain a set of patterns implemented as a
hash table. The hash table used uninterned identity and the
corresponding uninterned hash function. When a new pattern is
constructed, any subpatterns must first be interned. The pattern is
interned by looking it up in the hash table. If it is found, we throw
the new pattern away and instead return the existing entry in the hash
table. If it is not found, we store the pattern in the hash table
before returning it. (This is basically hash-consing.)
Avoiding exponential blowup
In order to avoid exponential blowup with some patterns, it is
essential for the choice function to eliminate redundant
choices. Define the choice-leaves of a pattern to be the
concatenation of the choice-leaves of its operands if the the pattern
is a Choice pattern and the empty-list otherwise.
Eliminating redundant choices means ensuring that the list of
choice-leaves of the constructed pattern contains no duplicates. One
way to do this is to for choice to walk the choice-leaves
of one operand building a hash-table of the set of choice-leaves of
that operand; then walk the other operand using this hash-table to
eliminate any choice-leaf that has occurred in the other operand.
Memoization
Memoization is an optimization technique that can be applied to any
pure function that has no side-effects and whose return value depends
only on the value of its arguments. The basic idea is to remember
function calls. A table is maintained that maps lists of arguments
values to previously computed return values for those arguments. When
a function is called with a particular list of arguments, that list of
arguments is looked up in the table. If an entry is found, then the
previously computed value is returned immediately. Otherwise, the
value is computed as usual and then stored in the table for future
use.
The functions startTagOpenDeriv,
startTagCloseDeriv and endTagDeriv defined
above can be memoized efficiently.
Memoizing textDeriv is suboptimal because although the
textDeriv takes the string value of the text node and the
context as arguments, in many cases the result does not depends on
these arguments. Instead we can distinguish two different cases for
the content of an element. One case is that the content contains no
elements (i.e. it's empty or consists of just a string). In this case,
we can first simplify pattern using a textOnlyDeriv that
replaces each Element pattern by NotAllowed.
This can be efficiently memoized.
In this case, textOnlyDeriv will always be followed
by endTagDeriv, so we can fold the functionality
of endTagDeriv into textOnlyDeriv.
In the other case, the content of the element contains one or more
child elements. In this case, any text nodes can match only
Text patterns (because of the restrictions in section 7.2
of the RELAX NG specification). The derivative of a Text
pattern with respect to a text node does not depend on either the
value of the text node or the context. We therefore introduce a
mixedTextDeriv function, which can be efficiently
memoized, for use in this case.
Another important special case of textDeriv that can
be memoized efficiently is when we can determine statically that a
pattern is consistent with some datatype. More precisely, we can
define a pattern p to be consistent with a datatype
d if and only if for any two strings
s1s2, and any two
contexts c1c2, if
datatypeEqualds1c1s2c2,
then
textDerivc1ps1
is the same as
textDerivc2ps2.
In this case, we can combine the string and context arguments into a
single argument representing the value of the datatype that the string
represents in the context; this can be much more efficiently memoized
than the general case.
The attDeriv function can be memoized more efficiently
by splitting it into two function. The first function is a
startAttributeDeriv function that works like
startTagOpenDeriv and depends just on the
QName of the attribute. The second stage works in the
same way to the case when the children of an element contain a single
string.
Error handling
So far, the algorithms presented do nothing more than compute
whether or not the node is valid with respect to the pattern.
However, a user will not appreciate a tool that simply reports that
the document is invalid, without giving any indication of where the
problem occurs or what the problem is.
The most important thing is to detect invalidity as soon as
possible. If an implementation can do this, then it can tell the user
where the problem occurs and it can protect the application from
seeing invalid data. If we consider the XML document to be a sequence
of SAX-like events, then detecting the error as soon as
possible, means that the implementation must detect when an
initial sequence s of events is such that there is no valid
sequence of events that starts with s.
This is straightforward with the algorithm above. Detecting the
error as soon as possible is equivalent to detecting when the current
pattern becomes NotAllowed. Note that this relies on the
choice, interleave, group and
after functions recognizing the algebraic identities
involving NotAllowed. The current pattern immediately
before it becomes NotAllowed describes what was expected
and can be used to diagnose the error.
It some scenarios it may be sufficient to produce a single error
message for an invalid document, and to cease validation as soon as it
is determined that the document is invalid. In other scenarios, it
may desirable to attempt to recover from the error and continute
validation so as to find subsequent errors in the document. Jing
recovers from validation errors as follows:
If startTagOpenDeriv causes an error, then Jing first
tries to recover on the assumption that some required elements have
been omitted. In effect, it transforms the pattern by making the
first operand of each Group optional and then retries
startTagOpenDeriv. If this still causes an error, then
the purposes of validating following siblings, it ignores the
element. For the purpose of validating the element itself, it searches
the whole schema for element patterns with a name class
that contains the name of the start-tag open. If it finds one or more
such element patterns, then it uses a choice
of the content of all element patterns that have a
name-class that contains the name of the start-tag open with maximum
specificity. A name-class that contains the name by virtue of a
name element is considered more specific than one that
contains the name by virtue of a nsName or
anyName element; similarly, a name-class that contains
the name by virtue of a nsName element is considered more
specific than one that contains the name by virtue of a
anyName element. If there is no such element pattern,
then it validates only any maximal subtrees rooted in an element for
which the schema does contain an element
pattern. Anything outside the maximal subtrees is ignored.
If startAttributeDeriv causes an error, then it
recovers by ignoring the attribute.
If startTagCloseDeriv causes an error, it recovers by
replacing all attribute patterns by
empty.
If textDeriv (used only for an attribute value or for
an element that contains no child elements) causes an error, then it
recovers by replacing the first operands of all top-level
After patterns (i.e. After patterns not
inside another After pattern) by empty.
If mixedTextDeriv causes an error, it recovers by
ignoring the text node.
If endTagDeriv causes an error, it recovers by using
a choice of the second operands of all top-level
After patterns. |
Disclosure : This site contains affiliate links to products. We may receive a commission for purchases made through these links.
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include config.mk
r2_version=$(VERSION)
frida_version=12.11.17
ifeq ($(strip $(frida_os)),)
ifeq ($(shell uname -o 2> /dev/null),Android)
frida_os := android
else
frida_os := $(shell uname -s | tr '[A-Z]' '[a-z]' | sed 's,^darwin$$,macos,')
endif
endif
frida_arch := $(shell uname -m | sed -e 's,i[0-9]86,x86,g' -e 's,armv7l,arm,g' -e 's,aarch64,arm64,g')
frida_os_arch := $(frida_os)-$(frida_arch)
WGET?=wget
CURL?=curl
DESTDIR?=
ifeq ($(shell uname),Darwin)
SO_EXT=dylib
else
SO_EXT=so
endif
CC?=gcc
CXX?=g++
CFLAGS+=-fPIC
LDFLAGS+=-shared -fPIC
CFLAGS+=-g
LDFLAGS+=-g
# R2
CFLAGS+=$(shell pkg-config --cflags r_core r_io r_util)
ifeq ($(frida_os),android)
LDFLAGS+=$(subst -lssl,,$(shell pkg-config --libs r_core r_io r_util))
else
LDFLAGS+=$(shell pkg-config --libs r_core r_io r_util)
endif
R2_PLUGDIR=$(shell r2 -H R2_USER_PLUGINS)
ifeq ($(R2_PLUGDIR),)
r2:
@echo Please install r2
@exit 1
endif
CXXFLAGS+=$(CFLAGS)
USE_ASAN?=0
ifeq ($(USE_ASAN),1)
ASAN_CFLAGS=-fsanitize=address,integer,undefined
ASAN_LDFLAGS=$(ASAN_CFLAGS)
CFLAGS+=$(ASAN_CFLAGS)
LDFLAGS+=$(ASAN_LDFLAGS)
endif
# FRIDA
FRIDA_SDK=ext/frida-$(frida_os)-$(frida_version)/libfrida-core.a
FRIDA_SDK_URL=https://github.com/frida/frida/releases/download/$(frida_version)/frida-core-devkit-$(frida_version)-$(frida_os_arch).tar.xz
FRIDA_CPPFLAGS+=-Iext/frida
ifeq ($(frida_os),android)
FRIDA_LIBS+=ext/frida/libfrida-core.a
else
FRIDA_LIBS+=ext/frida/libfrida-core.a -lresolv
endif
# OSX-FRIDA
ifeq ($(shell uname),Darwin)
LDFLAGS+=-Wl,-exported_symbol,_radare_plugin
ifeq ($(frida_os),macos)
FRIDA_LDFLAGS+=-Wl,-no_compact_unwind
FRIDA_LIBS+=-framework Foundation
endif
ifeq ($(frida_os),ios)
FRIDA_LIBS+=-framework UIKit
FRIDA_LIBS+=-framework CoreGraphics
else
ifeq ($(frida_os),macos)
FRIDA_LIBS+=-lbsm
endif
endif
ifeq ($(frida_os),macos)
FRIDA_LIBS+=-framework AppKit
endif
endif
ifeq ($(frida_os),android)
LDFLAGS+=-landroid -llog -lm
STRIP_SYMBOLS=yes
endif
ifeq ($(STRIP_SYMBOLS),yes)
LDFLAGS+=-Wl,--version-script,ld.script
LDFLAGS+=-Wl,--gc-sections
endif
LDFLAGS+=-Wl,-dead_strip
# CYLANG
CFLAGS+=-DWITH_CYLANG=$(WITH_CYLANG)
ifeq ($(WITH_CYLANG),1)
CYLANG_CPPFLAGS+=-Iext/cycript/src
CYLANG_ARCHIVE=ext/cycript/src/.libs/libcycript.a
CYLANG_LIBS+=$(CYLANG_ARCHIVE)
CYLANG_OBJ=src/cylang.o
else
CYLANG_CPPFLAGS=
CYLANG_ARCHIVE=
CYLANG_LIBS=
CYLANG_OBJ=
endif
all: .git/modules/ext ext/frida
$(MAKE) io_frida.$(SO_EXT)
deb:
$(MAKE) -C dist/debian
IOS_ARCH=arm64
#armv7
IOS_ARCH_CFLAGS=$(addprefix -arch ,$(IOS_ARCH))
IOS_CC=xcrun --sdk iphoneos gcc $(IOS_ARCH_CFLAGS)
IOS_CXX=xcrun --sdk iphoneos g++ $(IOS_ARCH_CFLAGS)
.PHONY: io_frida.$(SO_EXT)
# XXX we are statically linking to the .a we should use shared libs if exist
ios: r2-sdk-ios/$(r2_version)
$(MAKE) \
CFLAGS="-Ir2-sdk-ios/include -Ir2-sdk-ios/include/libr" \
LDFLAGS="-Lr2-sdk-ios/lib -lr -shared -fPIC" \
CC="$(IOS_CC)" CXX="$(IOS_CXX)" frida_os=ios frida_arch=arm64
r2-sdk-ios/$(r2_version):
rm -rf r2-sdk-ios
wget http://radare.mikelloc.com/get/$(r2_version)/radare2-ios-arm64-$(r2_version).tar.gz
mkdir -p r2-sdk-ios/$(r2_version)
tar xzvf radare2-ios-arm64-$(r2_version).tar.gz -C r2-sdk-ios
mv r2-sdk-ios/*/* r2-sdk-ios
rm -f radare2-ios-arm64-$(r2_version).tar.gz
.PHONY: ext/frida
ext/swift-frida/index.js: .gitmodules node_modules
git submodule update --init
ext/frida: $(FRIDA_SDK)
[ "`readlink ext/frida`" = frida-$(frida_os)-$(frida_version) ] || \
(cd ext && rm -f frida ; ln -fs frida-$(frida_os)-$(frida_version) frida)
config.mk:
./configure
io_frida.$(SO_EXT): src/io_frida.o $(CYLANG_OBJ)
pkg-config --cflags r_core
$(CXX) $^ -o $@ $(LDFLAGS) $(FRIDA_LDFLAGS) $(FRIDA_LIBS) $(CYLANG_LIBS)
src/io_frida.o: src/io_frida.c $(FRIDA_SDK) src/_agent.h
$(CC) -c $(CFLAGS) $(FRIDA_CPPFLAGS) $< -o $@
.git/modules/ext:
git submodule update --init
ext/swift-frida/node_modules: ext/swift-frida/index.js ext/swift-frida/index.js
cd ext/swift-frida && npm i
src/_agent.h: src/_agent.js
xxd -i < $< > $@
src/_agent.js: src/agent/index.js src/agent/plugin.js node_modules
npm run build
node_modules: package.json
mkdir -p node_modules
npm i
R2A_ROOT=$(shell pwd)/radare2-android-libs
R2S=~/prg/radare2/sys/android-shell.sh
android:
# git clean -xdf
rm -rf ext
# building for arm64
touch src/io_frida.c
$(R2S) aarch64 $(MAKE) android-arm64 frida_os=android
ifeq ($(STRIP_SYMBOLS),yes)
$(R2S) aarch64 aarch64-linux-android-strip io_frida.so
endif
cp -f io_frida.so /tmp/io_frida-$(r2_version)-android-arm64.so
# git clean -xdf
touch src/io_frida.c
rm -rf ext
# building for arm
$(R2S) arm $(MAKE) android-arm frida_os=android
ifeq ($(STRIP_SYMBOLS),yes)
$(R2S) arm arm-linux-androideabi-strip io_frida.so
endif
cp -f io_frida.so /tmp/io_frida-$(r2_version)-android-arm.so
radare2-android-arm64-libs:
wget -c http://termux.net/dists/stable/main/binary-aarch64/radare2_${r2_version}_aarch64.deb
wget -c http://termux.net/dists/stable/main/binary-aarch64/radare2-dev_${r2_version}_aarch64.deb
mkdir -p $(R2A_ROOT)
cd $(R2A_ROOT) ; 7z x -y ../radare2_${r2_version}_aarch64.deb ; tar xzvf data.tar.gz || tar xJvf data.tar.xz
cd $(R2A_ROOT) ; 7z x -y ../radare2-dev_${r2_version}_aarch64.deb ; tar xzvf data.tar.gz || tar xJvf data.tar.xz
ln -fs $(R2A_ROOT)/data/data/com.termux/files/
R2A_DIR=$(R2A_ROOT)/data/data/com.termux/files/usr
android-arm64: radare2-android-arm64-libs
$(MAKE) frida_os=android frida_arch=arm64 CC=ndk-gcc CXX=ndk-g++ \
CFLAGS="-I$(R2A_DIR)/include/libr $(CFLAGS)" \
LDFLAGS="-L$(R2A_DIR)/lib $(LDFLAGS)" SO_EXT=so
radare2-android-arm-libs:
wget -c http://termux.net/dists/stable/main/binary-arm/radare2_${r2_version}_arm.deb
wget -c http://termux.net/dists/stable/main/binary-arm/radare2-dev_${r2_version}_arm.deb
mkdir -p $(R2A_ROOT)
cd $(R2A_ROOT) ; 7z x -y ../radare2_${r2_version}_arm.deb ; tar xzvf data.tar.gz || tar xJvf data.tar.xz
cd $(R2A_ROOT) ; 7z x -y ../radare2-dev_${r2_version}_arm.deb ; tar xzvf data.tar.gz || tar xJvf data.tar.xz
ln -fs $(R2A_ROOT)/data/data/com.termux/files/
android-arm: radare2-android-arm-libs
$(MAKE) frida_os=android frida_arch=arm CC=ndk-gcc CXX=ndk-g++ \
CFLAGS="-I$(R2A_DIR)/include/libr $(CFLAGS)" \
LDFLAGS="-L$(R2A_DIR)/lib $(LDFLAGS)" SO_EXT=so
clean:
$(RM) src/*.o src/_agent.js src/_agent.h
$(RM) -rf $(R2A_DIR)
cycript-clean clean2:
-$(MAKE) -C ext/cycript clean
mrproper: clean
$(RM) $(FRIDA_SDK)
$(RM) -r ext/cycript
$(RM) -r ext/frida-$(frida_version)
$(RM) ext/frida
$(RM) -r ext/node
install:
mkdir -p $(DESTDIR)/"$(R2_PLUGDIR)"
cp -f io_frida.$(SO_EXT)* $(DESTDIR)/"$(R2_PLUGDIR)"
symstall:
mkdir -p $(DESTDIR)/"$(R2_PLUGDIR)"
ln -fs $(shell pwd)/io_frida.$(SO_EXT)* $(DESTDIR)/"$(R2_PLUGDIR)"
uninstall:
$(RM) $(DESTDIR)/"$(R2_PLUGDIR)/io_frida.$(SO_EXT)"
release:
$(MAKE) android STRIP_SYMBOLS=yes
$(MAKE) -C dist/debian
indent fix: node_modules
node_modules/.bin/semistandard --fix src/agent/*.js
frida-sdk: ext/frida-$(frida_os)-$(frida_version)
rm -f ext/frida
cd ext && ln -fs frida-$(frida_os)-$(frida_version) frida
ext/frida-$(frida_os)-$(frida_version):
@echo FRIDA_SDK=$(FRIDA_SDK)
$(MAKE) $(FRIDA_SDK)
$(FRIDA_SDK):
rm -f ext/frida
mkdir -p $(@D)/_
ifeq ($(USE_WGET),1)
$(WGET) -cO frida-sdk.tar.xz $(FRIDA_SDK_URL)
tar xJvf frida-sdk.tar.xz -C $(@D)/_
else
curl -Ls $(FRIDA_SDK_URL) | xz -d | tar -C $(@D)/_ -xf -
endif
mv $(@D)/_/* $(@D)
rmdir $(@D)/_
#mv ext/frida ext/frida-$(frida_os)-$(frida_version)
cd ext && ln -fs frida-$(frida_os)-$(frida_version) frida
update: ext/cycript/ext/node/lib
-cd ext/cycript && git submodule update && $(RM) ext/frida/libfrida-core.a
ifeq ($(WITH_CYLANG),1)
ext/cycript/ext/node/lib:
mkdir -p ext/cycript ext/node/lib
cd ext/cycript && git submodule init && git submodule update
-cd ext/cycript && yes n | patch -p1 < ../../cycript.patch
ext/cycript/configure: ext/cycript/ext/node/lib
cd ext/cycript && $(SHELL) ./autogen.sh
ifeq ($(shell uname),Darwin)
CLANG=-rpath /Applications/Xcode.app/Contents/Developer/Toolchains/XcodeDefault.xctoolchain/usr/lib /Applications/Xcode.app/Contents/Developer/Toolchains/XcodeDefault.xctoolchain/usr/lib/libclang.dylib
else
CLANG=no
endif
ext/cycript/Makefile: ext/cycript/configure
CFLAGS="$(CFLAGS)" \
CXXFLAGS="$(CXXFLAGS)" \
LDFLAGS="$(LDFLAGS)" \
cd ext/cycript && \
$(SHELL) ./configure \
--disable-console \
--disable-engine \
--disable-shared \
--enable-static \
--with-libclang="$(CLANG)" \
--with-python=/usr/bin/python-config
ext/cycript/src/.libs/libcycript.a: ext/cycript/Makefile
$(MAKE) -C ext/cycript CFLAGS="$(CFLAGS)" CXXFLAGS="$(CXXFLAGS)" LDFLAGS="$(LDFLAGS)" V=1 -j4
src/cylang.o: src/cylang.cpp $(CYLANG_ARCHIVE)
$(CXX) -c -std=c++11 $(CFLAGS) $(CXXFLAGS) $(FRIDA_CPPFLAGS) $(CYLANG_CPPFLAGS) $< -o $@
else
ext/cycript/ext/node/lib:
@echo do nothing
src/cylang.o:
touch src/cylang.o
endif
.PHONY: all clean install uninstall release symstall
|
Louisiana school must stop Bible giveaways, judge says
NEW ORLEANS (AP) -- A federal judge ordered a public school system to stop allowing in-school Bible giveaways, saying the practice violates the First Amendment separation of church and state.
NEW ORLEANS (AP) — A federal judge ordered a public school system to stop allowing in-school Bible giveaways, saying the practice violates the First Amendment separation of church and state.
“Distribution of Bibles is a religious activity without a secular purpose” and amounts to school board promotion of Christianity, U.S. District Judge Carl J. Barbier ruled in a case brought by the American Civil Liberties Union of Louisiana against the Tangipahoa Parish School Board.
As requested by both sides, Barbier made a summary judgment based only on the written briefs — something judges may do only if the law is absolutely clear.
Defense attorney Christopher M. Moody said late yesterday that the school board decided to appeal the ruling to the 5th U.S. Circuit Court of Appeal.
“We think our chances on appeal are very good,” he said.
The ACLU filed the lawsuit for an anonymous family whose daughter said she felt pressured into taking a Bible even though she doesn't believe in God. The girl was called Jane Roe and her father John Roe out of fear of retaliation by schoolmates and neighbors, the ACLU has said.
Jane Roe was a fifth-grader at Loranger Middle School when The Gideons International visited on May 9, 2007. Principal Andre Pellerin notified fifth-grade teachers that the group would be on campus all day, giving away Bibles outside his office. His e-mail said, “Please stress to students that they DO NOT have to get a bible,” according to Barbier.
However, the judge wrote, even procedures upheld as neutral for secondary school students might be out of bounds for “an impressionable young elementary-age child.”
He cited a ruling that upheld a West Virginia county's system of putting both religious and nonreligious material on a secondary school table where school students could walk past it. Grade-school children might not understand that the school board was not endorsing any of the materials, the 4th Circuit Court of Appeal said in that case.
At Loranger, the table outside the principal's office also created the impression that the school was endorsing Christianity, Barbier wrote.
Moody said the school board was working on a policy along the lines of the one cited by Barbier, but it was still being developed. But, he said, the board believes the current policy is legal. |
Nice IP 320
WOW! This Island Packet 320 is your chance to own a well-designed, well-built family cruising sailboat that is one of the IP fleet favorites. Moderate 4' 3" draft gives wide cruising range - from offshore to shallow bays. Cutter rig with 48' 1" airdraft cruises under 50' bridges.
Very thoughtful use of interior space to maximize comfort, headroom - 6' 4" - and storage. Airconditioning/heat when great cross ventilation through several opening ports and hatches is just not enough for comfort. U-shaped fully equipped galley is perfect for gourmet chef and casual cook. Sleep 7 and entertain all your new anchorage/marina friends aboard in roomy cockpit or large salon.
Lift out companionway boards and place in dedicated storage shelf under companionway steps. Walk down 5 teak steps to interior. Observe 6' 4" headroom throughout interior. Note U-shaped galley to starboard and navigation station to port at foot of companionway. Walk through bi-fold door into navigation station and lift folding table to full height to make privacy wall for aft cabin. Fold down to table height for chart table work. Proceed aft to observe queen size berth, cedar lined hanging locker and storage bins.
Exit aft cabin and navigation station and proceed forward to salon. Notice how design with spacious headroom, ports and hatches gives light, airy feel. Lower double teak table from bulkhead storage to look at ample protected shelf storage behind table for fragile glasses, bottles and dishes. Open table to full width to see how 7 or more people will sit around table for meals and entertainment. Refold and replace table to storage position and pull out port settee into double berth. Note shelf storage above settees and under settees. Walk forward and open head door to port. Observe nonskid sole, curved vanity with fiddled edges, mirror, manual marine toilet, separate wand shower, shower curtain, and sump drain for shower. Exit head and open center forward door to master suite. Note pullman double berth, cedar lined lockers and cabinet and shelf storage. Open cabinet forward of berth for anchor locker access.
Move aft to companionway and remove ladder to observe engine access.
ACCOMMODATIONS
Island Packet 320 is very roomy and comfortable for a couple as well as up to 7 family and friends for weekend or long range cruising. Entertain and relax in cockpit with full length contour cushioned seats with back cushions surrounding binnacle mounted cockpit table that opens to reach whole cockpit and stores folded down. Everyone enjoys the raised stern rail seats!
You will appreciate Island Packet's attention to design, decor and efficient utilization of space. Imagine 6' 4" headroom throughout a 32' sailboat! The lovely teak trimmed interior with teak and holly sole and navy cushions give classic yacht look and feel. Amazing number of opening ports and hatches maximize cross ventilation. Plus - airconditioning/heating when desired at dock. Spacious salon seats up to 7 on two settees around a double folding teak table. Table stores up on bulkhead in front of full length rack for dishes, bottles, glass storage. U-shaped galley across from navigation station with folding chart table are very workable designs without consuming unnecessary space. Sleep 4 in two private cabins with double berths. Port salon settee converts to single berth. Starboard settee converts to double berth. Private enclosed head has wand shower separate from vanity and sink, and manual toilet.
Cockpit seats up to 9 comfortably
Seat 6 on full length contour cushioned seats
Cockpit table opens to double size and stores folded down
2 stern rail raised cushioned seats
Molded sugar scoop swim platform with full transom
Teak cushioned helm seat with cushioned back rest
Insulated cooler in cockpit
6' 4" headroom
Teak trimmed interior
Teak and holly sole
Navy settee cushions - like new
Sleeps 7
Airconditioning/reverse cycle heat vents to each cabin and head
Ample storage in lockers, cabinets, drawers throughout
Formica fiddled countertops
Overhead teak handrails
9 screened stainless steel ports
5 screened overhead hatches
3 Dorade vents
Private head
Separate wand shower with curtain, sump pump drains on either tack
Molded curved vanity with stainless steel sink and faucet
Teak trimmed mirror in head
GALLEY
Well designed U-shaped galley has all the equipment and storage for gourmet meals while on a long cruise. Ample fiddled counter space with extended shelf makes preparation and cleanup a breeze.
If you're looking for a comfortable, elegant cruiser designed with safety, durability and classic appearance in mind, take a serious look at this Island Packet 320.
This yacht is your chance to own a well-designed, well-built family cruising sailboat that is one of the IP fleet favorites. Moderate 4' 3" draft gives wide cruising range - from offshore to shallow bays. Cutter rig with 48' 1" airdraft cruises under 50' bridges. Very thoughtful use of interior space to maximize comfort, headroom - 6' 4" - and storage. Airconditioning/heat when great cross ventilation through several opening ports and hatches is not sufficient. U-shaped fully equipped galley is perfect for gourmet chef and casual cook. Sleep 7 and entertain all your new anchorage/marina friends aboard in roomy cockpit or large salon.
DISCLAIMER
Owner's personal items excluded.
The Company offers the details of this vessel in good faith but cannot guarantee or warrant the accuracy of this information nor warrant the condition of the vessel. A buyer should instruct his agents, or his surveyors, to investigate such details as the buyer desires validated. This vessel is offered subject to prior sale, price change, or withdrawal without notice. |
Q:
Print file out 1 character at a time in the terminal - Python
This program opens a file and prints the text out to the terminal 1 character at a time and at a predetermined speed using time.sleep()
Simple and maybe, if you think like me, pretty cool..
GitHub
from time import sleep
import sys
BLINK = 0.2
chars_in_line = 50
def open_file(fn):
with open(fn, "r") as f:
for line in f:
if line:
yield line
def type_out_text_to_line(text, end="", sep="", line_chars=None, blink=0.2):
if not text:
return ""
c = line_chars
for i, j in enumerate(text):
sys.stdout.flush()
sleep(blink)
print(j, end=end, sep=sep)
if line_chars:
if i + 1 == c:
print()
c += line_chars
return ""
print("\n\tSTART PRINTING\n")
for text in open_file('example.txt'):
if len(text) > 1:
print(type_out_text_to_line(text, line_chars=chars_in_line, blink=BLINK, sep=""))
print("\n\tEND PRINTING\n")
A:
I would recommend just using the built in functionality of print to do the flushing. Though I am an advocate for breaking things out into classes and functions, you should use built in functionality when you can.
Making code complex for no reason results in two things:
1) More bugs.
2) More programmers who want to wring your neck down the road because they have to maintain or fix your software.
So you can simplify your code like this:
from time import sleep
BLINK = 0.2
print("\n\tSTART PRINTING\n")
with open('example.txt') as f:
for line in f:
for char in line:
print(char, flush=True, end='')
sleep(BLINK)
print("\n\tEND PRINTING\n")
If you want to make this into a function (to make it easier to import/export) then I would do following:
from time import sleep
def time_print_file(filename, print_rate, **print_kwargs):
"""
INPUT:
filename: The path to the file to be printing
print_rate: The delay used to print each character
print_kwargs: keyword arguments accepted by pythons
print statement. (Except `end` and `flush`)
"""
print_kwargs.pop('flush', None) # We don't allow the flush print-keyword
print_kwargs.pop('end', None) # We don't allow the end print-keyword
with open(filename) as f:
for line in f:
for char in line:
print(char, flush=True, end='', **print_kwargs)
sleep(print_rate)
if __name__ == '__main__':
print("\n\tSTART PRINTING\n")
time_print_file(filename='example.txt', print_rate=0.2)
print("\n\tEND PRINTING\n")
|
Other states are copying Louisiana’s model. Texas, where I attend school, is going to introduce its own voucher program. Texas' program will be modeled after Louisiana's. If a voucher program passes in Texas, it will likely fund creationist schools with millions of taxpayer dollars.
Tell the Texas legislature not to use public money to fund creationist schools. Tell them not to pass this creationist voucher program.
If Texas passes a voucher program, there is a large chance that creationist schools using anti science curriculums will receive millions of dollars in public money. This has happened in other states like Louisiana.
Funding creationism with public money is unconstitutional. It also harms our students, our state, and our country.
When our students are not taught real science, they're not only deprived of a rigorous education; they won't get jobs in science, technology, and academia. |
# Copyright 2019 MilaGraph. All Rights Reserved.
#
# Licensed under the Apache License, Version 2.0 (the "License");
# you may not use this file except in compliance with the License.
# You may obtain a copy of the License at
#
# http://www.apache.org/licenses/LICENSE-2.0
#
# Unless required by applicable law or agreed to in writing, software
# distributed under the License is distributed on an "AS IS" BASIS,
# WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
# See the License for the specific language governing permissions and
# limitations under the License.
#
# Author: Zhaocheng Zhu
"""
Dataset module of GraphVite
Graph
- :class:`BlogCatalog`
- :class:`Youtube`
- :class:`Flickr`
- :class:`Hyperlink2012`
- :class:`Friendster`
- :class:`Wikipedia`
Knowledge Graph
- :class:`Math`
- :class:`FB15k`
- :class:`FB15k237`
- :class:`WN18`
- :class:`WN18RR`
- :class:`Wikidata5m`
- :class:`Freebase`
Visualization
- :class:`MNIST`
- :class:`CIFAR10`
- :class:`ImageNet`
"""
from __future__ import absolute_import, division
import os
import glob
import shutil
import logging
import gzip, zipfile, tarfile
import multiprocessing
from collections import defaultdict
import numpy as np
from . import cfg
logger = logging.getLogger(__name__)
class Dataset(object):
"""
Graph dataset.
Parameters:
name (str): name of dataset
urls (dict, optional): url(s) for each split,
can be either str or list of str
members (dict, optional): zip member(s) for each split,
leave empty for default
Datasets contain several splits, such as train, valid and test.
For each split, there are one or more URLs, specifying the file to download.
You may also specify the zip member to extract.
When a split is accessed, it will be automatically downloaded and decompressed
if it is not present.
You can assign a preprocess for each split, by defining a function with name [split]_preprocess::
class MyDataset(Dataset):
def __init__(self):
super(MyDataset, self).__init__(
"my_dataset",
train="url/to/train/split",
test="url/to/test/split"
)
def train_preprocess(self, input_file, output_file):
with open(input_file, "r") as fin, open(output_file, "w") as fout:
fout.write(fin.read())
f = open(MyDataset().train)
If the preprocess returns a non-trivial value, then it is assigned to the split,
otherwise the file name is assigned.
By convention, only splits ending with ``_data`` have non-trivial return value.
See also:
Pre-defined preprocess functions
:func:`csv2txt`,
:func:`top_k_label`,
:func:`induced_graph`,
:func:`edge_split`,
:func:`link_prediction_split`,
:func:`image_feature_data`
"""
def __init__(self, name, urls=None, members=None):
self.name = name
self.urls = urls or {}
self.members = members or {}
for key in self.urls:
if isinstance(self.urls[key], str):
self.urls[key] = [self.urls[key]]
if key not in self.members:
self.members[key] = [None] * len(self.urls[key])
elif isinstance(self.members[key], str):
self.members[key] = [self.members[key]]
if len(self.urls[key]) != len(self.members[key]):
raise ValueError("Number of members is inconsistent with number of urls in `%s`" % key)
self.path = os.path.join(cfg.dataset_path, self.name)
def relpath(self, path):
return os.path.relpath(path, self.path)
def download(self, url):
from six.moves.urllib.request import urlretrieve
save_file = os.path.basename(url)
if "?" in save_file:
save_file = save_file[:save_file.find("?")]
save_file = os.path.join(self.path, save_file)
if save_file in self.local_files():
return save_file
logger.info("downloading %s to %s" % (url, self.relpath(save_file)))
urlretrieve(url, save_file)
return save_file
def extract(self, zip_file, member=None):
zip_name, extension = os.path.splitext(zip_file)
if zip_name.endswith(".tar"):
extension = ".tar" + extension
zip_name = zip_name[:-4]
if extension == ".txt":
return zip_file
elif member is None:
save_file = zip_name
else:
save_file = os.path.join(os.path.dirname(zip_name), os.path.basename(member))
if save_file in self.local_files():
return save_file
if extension == ".gz":
logger.info("extracting %s to %s" % (self.relpath(zip_file), self.relpath(save_file)))
with gzip.open(zip_file, "rb") as fin, open(save_file, "wb") as fout:
shutil.copyfileobj(fin, fout)
elif extension == ".tar.gz" or extension == ".tar":
if member is None:
logger.info("extracting %s to %s" % (self.relpath(zip_file), self.relpath(save_file)))
with tarfile.open(zip_file, "r") as fin:
fin.extractall(save_file)
else:
logger.info("extracting %s from %s to %s" % (member, self.relpath(zip_file), self.relpath(save_file)))
with tarfile.open(zip_file, "r").extractfile(member) as fin, open(save_file, "wb") as fout:
shutil.copyfileobj(fin, fout)
elif extension == ".zip":
if member is None:
logger.info("extracting %s to %s" % (self.relpath(zip_file), self.relpath(save_file)))
with zipfile.ZipFile(zip_file) as fin:
fin.extractall(save_file)
else:
logger.info("extracting %s from %s to %s" % (member, self.relpath(zip_file), self.relpath(save_file)))
with zipfile.ZipFile(zip_file).open(member, "r") as fin, open(save_file, "wb") as fout:
shutil.copyfileobj(fin, fout)
else:
raise ValueError("Unknown file extension `%s`" % extension)
return save_file
def get_file(self, key):
file_name = os.path.join(self.path, "%s_%s.txt" % (self.name, key))
if file_name in self.local_files():
return file_name
urls = self.urls[key]
members = self.members[key]
preprocess_name = key + "_preprocess"
preprocess = getattr(self, preprocess_name, None)
if len(urls) > 1 and preprocess is None:
raise AttributeError(
"There are non-trivial number of files, but function `%s` is not found" % preprocess_name)
extract_files = []
for url, member in zip(urls, members):
download_file = self.download(url)
extract_file = self.extract(download_file, member)
extract_files.append(extract_file)
if preprocess:
result = preprocess(*(extract_files + [file_name]))
if result is not None:
return result
elif os.path.isfile(extract_files[0]):
logger.info("renaming %s to %s" % (self.relpath(extract_files[0]), self.relpath(file_name)))
shutil.move(extract_files[0], file_name)
else:
raise AttributeError(
"There are non-trivial number of files, but function `%s` is not found" % preprocess_name)
return file_name
def local_files(self):
if not os.path.exists(self.path):
os.mkdir(self.path)
return set(glob.glob(os.path.join(self.path, "*")))
def __getattr__(self, key):
if key in self.__dict__:
return self.__dict__[key]
if key in self.urls:
return self.get_file(key)
raise AttributeError("Can't resolve split `%s`" % key)
def csv2txt(self, csv_file, txt_file):
"""
Convert ``csv`` to ``txt``.
Parameters:
csv_file: csv file
txt_file: txt file
"""
logger.info("converting %s to %s" % (self.relpath(csv_file), self.relpath(txt_file)))
with open(csv_file, "r") as fin, open(txt_file, "w") as fout:
for line in fin:
fout.write(line.replace(",", "\t"))
def top_k_label(self, label_file, save_file, k, format="node-label"):
"""
Extract top-k labels.
Parameters:
label_file (str): label file
save_file (str): save file
k (int): top-k labels will be extracted
format (str, optional): format of label file,
can be 'node-label' or '(label)-nodes':
- **node-label**: each line is [node] [label]
- **(label)-nodes**: each line is [node]..., no explicit label
"""
logger.info("extracting top-%d labels of %s to %s" % (k, self.relpath(label_file), self.relpath(save_file)))
if format == "node-label":
label2nodes = defaultdict(list)
with open(label_file, "r") as fin:
for line in fin:
node, label = line.split()
label2nodes[label].append(node)
elif format == "(label)-nodes":
label2nodes = {}
with open(label_file, "r") as fin:
for i, line in enumerate(fin):
label2nodes[i] = line.split()
else:
raise ValueError("Unknown file format `%s`" % format)
labels = sorted(label2nodes, key=lambda x: len(label2nodes[x]), reverse=True)[:k]
with open(save_file, "w") as fout:
for label in sorted(labels):
for node in sorted(label2nodes[label]):
fout.write("%s\t%s\n" % (node, label))
def induced_graph(self, graph_file, label_file, save_file):
"""
Induce a subgraph from labeled nodes. All edges in the induced graph have at least one labeled node.
Parameters:
graph_file (str): graph file
label_file (str): label file
save_file (str): save file
"""
logger.info("extracting subgraph of %s induced by %s to %s" %
(self.relpath(graph_file), self.relpath(label_file), self.relpath(save_file)))
nodes = set()
with open(label_file, "r") as fin:
for line in fin:
nodes.update(line.split())
with open(graph_file, "r") as fin, open(save_file, "w") as fout:
for line in fin:
if not line.startswith("#"):
u, v = line.split()
if u not in nodes or v not in nodes:
continue
fout.write("%s\t%s\n" % (u, v))
def edge_split(self, graph_file, files, portions):
"""
Divide a graph into several splits.
Parameters:
graph_file (str): graph file
files (list of str): file names
portions (list of float): split portions
"""
assert len(files) == len(portions)
logger.info("splitting graph %s into %s" %
(self.relpath(graph_file), ", ".join([self.relpath(file) for file in files])))
np.random.seed(1024)
portions = np.cumsum(portions, dtype=np.float32) / np.sum(portions)
files = [open(file, "w") for file in files]
with open(graph_file, "r") as fin:
for line in fin:
i = np.searchsorted(portions, np.random.rand())
files[i].write(line)
for file in files:
file.close()
def link_prediction_split(self, graph_file, files, portions):
"""
Divide a normal graph into a train split and several test splits for link prediction use.
Each test split contains half true and half false edges.
Parameters:
graph_file (str): graph file
files (list of str): file names,
the first file is treated as train file
portions (list of float): split portions
"""
assert len(files) == len(portions)
logger.info("splitting graph %s into %s" %
(self.relpath(graph_file), ", ".join([self.relpath(file) for file in files])))
np.random.seed(1024)
nodes = set()
edges = set()
portions = np.cumsum(portions, dtype=np.float32) / np.sum(portions)
files = [open(file, "w") for file in files]
num_edges = [0] * len(files)
with open(graph_file, "r") as fin:
for line in fin:
u, v = line.split()[:2]
nodes.update([u, v])
edges.add((u, v))
i = np.searchsorted(portions, np.random.rand())
if i == 0:
files[i].write(line)
else:
files[i].write("%s\t%s\t1\n" % (u, v))
num_edges[i] += 1
nodes = list(nodes)
for file, num_edge in zip(files[1:], num_edges[1:]):
for _ in range(num_edge):
valid = False
while not valid:
u = nodes[int(np.random.rand() * len(nodes))]
v = nodes[int(np.random.rand() * len(nodes))]
valid = u != v and (u, v) not in edges and (v, u) not in edges
file.write("%s\t%s\t0\n" % (u, v))
for file in files:
file.close()
def image_feature_data(self, dataset, model="resnet50", batch_size=128):
"""
Compute feature vectors for an image dataset using a neural network.
Parameters:
dataset (torch.utils.data.Dataset): dataset
model (str or torch.nn.Module, optional): pretrained model.
If it is a str, use the last hidden model of that model.
batch_size (int, optional): batch size
"""
import torch
import torchvision
from torch import nn
logger.info("computing %s feature" % model)
if isinstance(model, str):
full_model = getattr(torchvision.models, model)(pretrained=True)
model = nn.Sequential(*list(full_model.children())[:-1])
num_worker = multiprocessing.cpu_count()
data_loader = torch.utils.data.DataLoader(dataset,
batch_size=batch_size, num_workers=num_worker, shuffle=False)
model = model.cuda()
model.eval()
features = []
with torch.no_grad():
for i, (batch_images, batch_labels) in enumerate(data_loader):
if i % 100 == 0:
logger.info("%g%%" % (100.0 * i * batch_size / len(dataset)))
batch_images = batch_images.cuda()
batch_features = model(batch_images).view(batch_images.size(0), -1).cpu().numpy()
features.append(batch_features)
features = np.concatenate(features)
return features
class BlogCatalog(Dataset):
"""
BlogCatalog social network dataset.
Splits:
graph, label, train, test
Train and test splits are used for link prediction purpose.
"""
def __init__(self):
super(BlogCatalog, self).__init__(
"blogcatalog",
urls={
"graph": "https://www.dropbox.com/s/cf21ouuzd563cqx/BlogCatalog-dataset.zip?dl=1",
"label": "https://www.dropbox.com/s/cf21ouuzd563cqx/BlogCatalog-dataset.zip?dl=1",
"train": [], # depends on `graph`
"valid": [], # depends on `graph`
"test": [] # depends on `graph`
},
members={
"graph": "BlogCatalog-dataset/data/edges.csv",
"label": "BlogCatalog-dataset/data/group-edges.csv"
}
)
def graph_preprocess(self, raw_file, save_file):
self.csv2txt(raw_file, save_file)
def label_preprocess(self, raw_file, save_file):
self.csv2txt(raw_file, save_file)
def train_preprocess(self, train_file):
valid_file = train_file[:train_file.rfind("train.txt")] + "valid.txt"
test_file = train_file[:train_file.rfind("train.txt")] + "test.txt"
self.link_prediction_split(self.graph, [train_file, valid_file, test_file], portions=[100, 1, 1])
def valid_preprocess(self, valid_file):
train_file = valid_file[:valid_file.rfind("valid.txt")] + "train.txt"
test_file = valid_file[:valid_file.rfind("valid.txt")] + "test.txt"
self.link_prediction_split(self.graph, [train_file, valid_file, test_file], portions=[100, 1, 1])
def test_preprocess(self, test_file):
train_file = test_file[:test_file.rfind("test.txt")] + "train.txt"
valid_file = test_file[:test_file.rfind("test.txt")] + "valid.txt"
self.link_prediction_split(self.graph, [train_file, valid_file, test_file], portions=[100, 1, 1])
class Youtube(Dataset):
"""
Youtube social network dataset.
Splits:
graph, label
"""
def __init__(self):
super(Youtube, self).__init__(
"youtube",
urls={
"graph": "http://socialnetworks.mpi-sws.mpg.de/data/youtube-links.txt.gz",
"label": "http://socialnetworks.mpi-sws.mpg.de/data/youtube-groupmemberships.txt.gz"
}
)
def label_preprocess(self, raw_file, save_file):
self.top_k_label(raw_file, save_file, k=47)
class Flickr(Dataset):
"""
Flickr social network dataset.
Splits:
graph, label
"""
def __init__(self):
super(Flickr, self).__init__(
"flickr",
urls={
"graph": "http://socialnetworks.mpi-sws.mpg.de/data/flickr-links.txt.gz",
"label": "http://socialnetworks.mpi-sws.mpg.de/data/flickr-groupmemberships.txt.gz"
}
)
def label_preprocess(self, label_file, save_file):
self.top_k_label(label_file, save_file, k=5)
class Hyperlink2012(Dataset):
"""
Hyperlink 2012 graph dataset.
Splits:
pld_train, pld_test
"""
def __init__(self):
super(Hyperlink2012, self).__init__(
"hyperlink2012",
urls={
"pld_train": "http://data.dws.informatik.uni-mannheim.de/hyperlinkgraph/2012-08/pld-arc.gz",
"pld_valid": "http://data.dws.informatik.uni-mannheim.de/hyperlinkgraph/2012-08/pld-arc.gz",
"pld_test": "http://data.dws.informatik.uni-mannheim.de/hyperlinkgraph/2012-08/pld-arc.gz"
}
)
def pld_train_preprocess(self, graph_file, train_file):
valid_file = train_file[:train_file.rfind("pld_train.txt")] + "pld_valid.txt"
test_file = train_file[:train_file.rfind("pld_train.txt")] + "pld_test.txt"
self.link_prediction_split(graph_file, [train_file, valid_file, test_file], portions=[10000, 1, 1])
def pld_valid_preprocess(self, graph_file, valid_file):
train_file = valid_file[:valid_file.rfind("pld_valid.txt")] + "pld_train.txt"
test_file = valid_file[:valid_file.rfind("pld_valid.txt")] + "pld_test.txt"
self.link_prediction_split(graph_file, [train_file, valid_file, test_file], portions=[10000, 1, 1])
def pld_test_preprocess(self, graph_file, test_file):
train_file = test_file[:test_file.rfind("pld_test.txt")] + "pld_train.txt"
valid_file = test_file[:test_file.rfind("pld_test.txt")] + "pld_valid.txt"
self.link_prediction_split(graph_file, [train_file, valid_file, test_file], portions=[10000, 1, 1])
class Friendster(Dataset):
"""
Friendster social network dataset.
Splits:
graph, small_graph, label
"""
def __init__(self):
super(Friendster, self).__init__(
"friendster",
urls={
"graph": "https://snap.stanford.edu/data/bigdata/communities/com-friendster.ungraph.txt.gz",
"small_graph": ["https://snap.stanford.edu/data/bigdata/communities/com-friendster.ungraph.txt.gz",
"https://snap.stanford.edu/data/bigdata/communities/com-friendster.all.cmty.txt.gz"],
"label": "https://snap.stanford.edu/data/bigdata/communities/com-friendster.top5000.cmty.txt.gz"
}
)
def small_graph_preprocess(self, graph_file, label_file, save_file):
self.induced_graph(graph_file, label_file, save_file)
def label_preprocess(self, label_file, save_file):
self.top_k_label(label_file, save_file, k=100, format="(label)-nodes")
class Wikipedia(Dataset):
"""
Wikipedia dump for word embedding.
Splits:
graph
"""
def __init__(self):
super(Wikipedia, self).__init__(
"wikipedia",
urls={
"graph": "https://www.dropbox.com/s/q6w950e5f7g7ax8/enwiki-latest-pages-articles-sentences.txt.gz?dl=1"
}
)
class Math(Dataset):
"""
Synthetic math knowledge graph dataset.
Splits:
train, valid, test
"""
NUM_ENTITY = 1000
NUM_RELATION = 30
OPERATORS = [
("+", lambda x, y: (x + y) % Math.NUM_ENTITY),
("-", lambda x, y: (x - y) % Math.NUM_ENTITY),
("*", lambda x, y: (x * y) % Math.NUM_ENTITY),
("/", lambda x, y: x // y),
("%", lambda x, y: x % y)
]
def __init__(self):
super(Math, self).__init__(
"math",
urls={
"train": [],
"valid": [],
"test": []
}
)
def train_preprocess(self, save_file):
np.random.seed(1023)
self.generate_math(save_file, num_triplet=20000)
def valid_preprocess(self, save_file):
np.random.seed(1024)
self.generate_math(save_file, num_triplet=1000)
def test_preprocess(self, save_file):
np.random.seed(1025)
self.generate_math(save_file, num_triplet=1000)
def generate_math(self, save_file, num_triplet):
with open(save_file, "w") as fout:
for _ in range(num_triplet):
i = int(np.random.rand() * len(self.OPERATORS))
op, f = self.OPERATORS[i]
x = int(np.random.rand() * self.NUM_ENTITY)
y = int(np.random.rand() * self.NUM_RELATION) + 1
fout.write("%d\t%s%d\t%d\n" % (x, op, y, f(x, y)))
class FB15k(Dataset):
"""
FB15k knowledge graph dataset.
Splits:
train, valid, test
"""
def __init__(self):
super(FB15k, self).__init__(
"fb15k",
urls={
"train": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/FB15k/train.txt",
"valid": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/FB15k/valid.txt",
"test": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/FB15k/test.txt"
}
)
class FB15k237(Dataset):
"""
FB15k-237 knowledge graph dataset.
Splits:
train, valid, test
"""
def __init__(self):
super(FB15k237, self).__init__(
"fb15k-237",
urls={
"train": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/FB15k-237/train.txt",
"valid": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/FB15k-237/valid.txt",
"test": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/FB15k-237/test.txt"
}
)
class WN18(Dataset):
"""
WN18 knowledge graph dataset.
Splits:
train, valid, test
"""
def __init__(self):
super(WN18, self).__init__(
"wn18",
urls={
"train": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/wn18/train.txt",
"valid": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/wn18/valid.txt",
"test": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/wn18/test.txt"
}
)
class WN18RR(Dataset):
"""
WN18RR knowledge graph dataset.
Splits:
train, valid, test
"""
def __init__(self):
super(WN18RR, self).__init__(
"wn18rr",
urls={
"train": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/wn18rr/train.txt",
"valid": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/wn18rr/valid.txt",
"test": "https://github.com/DeepGraphLearning/KnowledgeGraphEmbedding/raw/master/data/wn18rr/test.txt"
}
)
class Wikidata5m(Dataset):
"""
Wikidata5m knowledge graph dataset.
Splits:
train, valid, test
"""
def __init__(self):
super(Wikidata5m, self).__init__(
"wikidata5m",
urls={
"train": "https://www.dropbox.com/s/dty6ufe1gg6keuc/wikidata5m.txt.gz?dl=1",
"valid": "https://www.dropbox.com/s/dty6ufe1gg6keuc/wikidata5m.txt.gz?dl=1",
"test": "https://www.dropbox.com/s/dty6ufe1gg6keuc/wikidata5m.txt.gz?dl=1",
"entity": "https://www.dropbox.com/s/bgmgvk8brjwpc9w/entity.txt.gz?dl=1",
"relation": "https://www.dropbox.com/s/37jxki93gguv0pp/relation.txt.gz?dl=1",
"alias2entity": [], # depends on `entity`
"alias2relation": [] # depends on `relation`
}
)
def train_preprocess(self, graph_file, train_file):
valid_file = train_file[:train_file.rfind("train.txt")] + "valid.txt"
test_file = train_file[:train_file.rfind("train.txt")] + "test.txt"
self.edge_split(graph_file, [train_file, valid_file, test_file], portions=[4000, 1, 1])
def valid_preprocess(self, graph_file, valid_file):
train_file = valid_file[:valid_file.rfind("valid.txt")] + "train.txt"
test_file = valid_file[:valid_file.rfind("valid.txt")] + "test.txt"
self.edge_split(graph_file, [train_file, valid_file, test_file], portions=[4000, 1, 1])
def test_preprocess(self, graph_file, test_file):
train_file = test_file[:test_file.rfind("valid.txt")] + "train.txt"
valid_file = test_file[:test_file.rfind("train.txt")] + "valid.txt"
self.edge_split(graph_file, [train_file, valid_file, test_file], portions=[4000, 1, 1])
def load_alias(self, alias_file):
alias2object = {}
ambiguous = set()
with open(alias_file, "r") as fin:
for line in fin:
tokens = line.strip().split("\t")
object = tokens[0]
for alias in tokens[1:]:
if alias in alias2object and alias2object[alias] != object:
ambiguous.add(alias)
alias2object[alias] = object
for alias in ambiguous:
alias2object.pop(alias)
return alias2object
def alias2entity_preprocess(self, save_file):
return self.load_alias(self.entity)
def alias2relation_preprocess(self, save_file):
return self.load_alias(self.relation)
class Freebase(Dataset):
"""
Freebase knowledge graph dataset.
Splits:
train
"""
def __init__(self):
super(Freebase, self).__init__(
"freebase",
urls={
"train": "http://commondatastorage.googleapis.com/freebase-public/rdf/freebase-rdf-latest.gz"
}
)
class MNIST(Dataset):
"""
MNIST dataset for visualization.
Splits:
train_image_data, train_label_data, test_image_data, test_label_data, image_data, label_data
"""
def __init__(self):
super(MNIST, self).__init__(
"mnist",
urls={
"train_image_data": "http://yann.lecun.com/exdb/mnist/train-images-idx3-ubyte.gz",
"train_label_data": "http://yann.lecun.com/exdb/mnist/train-labels-idx1-ubyte.gz",
"test_image_data": "http://yann.lecun.com/exdb/mnist/t10k-images-idx3-ubyte.gz",
"test_label_data": "http://yann.lecun.com/exdb/mnist/t10k-labels-idx1-ubyte.gz",
"image_data": [], # depends on `train_image_data` & `test_image_data`
"label_data": [] # depends on `train_label_data` & `test_label_data`
}
)
def train_image_data_preprocess(self, raw_file, save_file):
images = np.fromfile(raw_file, dtype=np.uint8)
return images[16:].reshape(-1, 28*28)
def train_label_data_preprocess(self, raw_file, save_file):
labels = np.fromfile(raw_file, dtype=np.uint8)
return labels[8:]
test_image_data_preprocess = train_image_data_preprocess
test_label_data_preprocess = train_label_data_preprocess
def image_data_preprocess(self, save_file):
return np.concatenate([self.train_image_data, self.test_image_data])
def label_data_preprocess(self, save_file):
return np.concatenate([self.train_label_data, self.test_label_data])
class CIFAR10(Dataset):
"""
CIFAR10 dataset for visualization.
Splits:
train_image_data, train_label_data, test_image_data, test_label_data, image_data, label_data
"""
def __init__(self):
super(CIFAR10, self).__init__(
"cifar10",
urls={
"train_image_data": "https://www.cs.toronto.edu/~kriz/cifar-10-binary.tar.gz",
"train_label_data": "https://www.cs.toronto.edu/~kriz/cifar-10-binary.tar.gz",
"test_image_data": "https://www.cs.toronto.edu/~kriz/cifar-10-binary.tar.gz",
"test_label_data": "https://www.cs.toronto.edu/~kriz/cifar-10-binary.tar.gz",
"image_data": [], # depends on `train_image_data` & `test_image_data`
"label_data": [] # depends on `train_label_data` & `test_label_data`
},
)
def load_images(self, *batch_files):
images = []
for batch_file in batch_files:
batch = np.fromfile(batch_file, dtype=np.uint8)
batch = batch.reshape(-1, 32*32*3 + 1)
images.append(batch[:, 1:])
return np.concatenate(images)
def load_labels(self, meta_file, *batch_files):
classes = []
with open(meta_file, "r") as fin:
for line in fin:
line = line.strip()
if line:
classes.append(line)
classes = np.asarray(classes)
labels = []
for batch_file in batch_files:
batch = np.fromfile(batch_file, dtype=np.uint8)
batch = batch.reshape(-1, 32*32*3 + 1)
labels.append(batch[:, 0])
return classes[np.concatenate(labels)]
def train_image_data_preprocess(self, raw_path, save_file):
batch_files = glob.glob(os.path.join(raw_path, "cifar-10-batches-bin/data_batch_*.bin"))
return self.load_images(*batch_files)
def train_label_data_preprocess(self, raw_path, save_file):
meta_file = os.path.join(raw_path, "cifar-10-batches-bin/batches.meta.txt")
batch_files = glob.glob(os.path.join(raw_path, "cifar-10-batches-bin/data_batch_*.bin"))
return self.load_labels(meta_file, *batch_files)
def test_image_data_preprocess(self, raw_path, save_file):
batch_file = os.path.join(raw_path, "cifar-10-batches-bin/test_batch.bin")
return self.load_images(batch_file)
def test_label_data_preprocess(self, raw_path, save_file):
meta_file = os.path.join(raw_path, "cifar-10-batches-bin/batches.meta.txt")
batch_file = os.path.join(raw_path, "cifar-10-batches-bin/test_batch.bin")
return self.load_labels(meta_file, batch_file)
def image_data_preprocess(self, save_file):
return np.concatenate([self.train_image_data, self.test_image_data])
def label_data_preprocess(self, save_file):
return np.concatenate([self.train_label_data, self.test_label_data])
class ImageNet(Dataset):
"""
ImageNet dataset for visualization.
Splits:
train_image, train_feature_data, train_label, train_hierarchical_label,
valid_image, valid_feature_data, valid_label, valid_hierarchical_label
"""
def __init__(self):
super(ImageNet, self).__init__(
"imagenet",
urls={
"train_image": "http://www.image-net.org/challenges/LSVRC/2012/nnoupb/ILSVRC2012_img_train.tar",
"train_feature_data": [], # depends on `train_image`
"train_label": [], # depends on `train_image`
"train_hierarchical_label": [], # depends on `train_image`
"valid_image": ["http://www.image-net.org/challenges/LSVRC/2012/nnoupb/ILSVRC2012_img_val.tar",
"http://www.image-net.org/challenges/LSVRC/2012/nnoupb/ILSVRC2012_devkit_t12.tar.gz"],
"valid_feature_data": [], # depends on `valid_image`
"valid_label": "http://www.image-net.org/challenges/LSVRC/2012/nnoupb/ILSVRC2012_devkit_t12.tar.gz",
"valid_hierarchical_label":
"http://www.image-net.org/challenges/LSVRC/2012/nnoupb/ILSVRC2012_devkit_t12.tar.gz",
"feature_data": [], # depends on `train_feature_data` & `valid_feature_data`
"label": [], # depends on `train_label` & `valid_label`
"hierarchical_label": [], # depends on `train_hierarchical_label` & `valid_hierarchical_label`
}
)
def import_wordnet(self):
import nltk
try:
nltk.data.find("corpora/wordnet")
except LookupError:
nltk.download("wordnet")
from nltk.corpus import wordnet
try:
wordnet.synset_from_pos_and_offset
except AttributeError:
wordnet.synset_from_pos_and_offset = wordnet._synset_from_pos_and_offset
return wordnet
def get_name(self, synset):
name = synset.name()
return name[:name.find(".")]
def readable_label(self, labels, save_file, hierarchy=False):
wordnet = self.import_wordnet()
if hierarchy:
logger.info("generating human-readable hierarchical labels")
else:
logger.info("generating human-readable labels")
synsets = []
for label in labels:
pos = label[0]
offset = int(label[1:])
synset = wordnet.synset_from_pos_and_offset(pos, offset)
synsets.append(synset)
depth = max([synset.max_depth() for synset in synsets])
num_sample = len(synsets)
labels = [self.get_name(synset) for synset in synsets]
num_class = len(set(labels))
hierarchies = [labels]
while hierarchy and num_class > 1:
depth -= 1
for i in range(num_sample):
if synsets[i].max_depth() > depth:
# only takes the first recall
synsets[i] = synsets[i].hypernyms()[0]
labels = [self.get_name(synset) for synset in synsets]
hierarchies.append(labels)
num_class = len(set(labels))
hierarchies = hierarchies[::-1]
with open(save_file, "w") as fout:
for hierarchy in zip(*hierarchies):
fout.write("%s\n" % "\t".join(hierarchy))
def image_feature_data(self, image_path):
""""""
import torchvision
from torchvision import transforms
augmentation = transforms.Compose([
transforms.Resize(256),
transforms.CenterCrop(224),
transforms.ToTensor(),
transforms.Normalize(mean=[0.485, 0.456, 0.406], std=[0.229, 0.224, 0.225])
])
dataset = torchvision.datasets.ImageFolder(image_path, augmentation)
features = super(self, ImageNet).image_feature_data(dataset)
return features
def train_image_preprocess(self, image_path, save_file):
tar_files = glob.glob(os.path.join(image_path, "*.tar"))
if len(tar_files) == 0:
return image_path
for tar_file in tar_files:
self.extract(tar_file)
os.remove(tar_file)
return image_path
def train_feature_data_preprocess(self, save_file):
numpy_file = os.path.splitext(save_file)[0] + ".npy"
if os.path.exists(numpy_file):
return np.load(numpy_file)
features = self.image_feature_data(self.train_image)
np.save(numpy_file, features)
return features
def train_label_preprocess(self, save_file):
image_files = glob.glob(os.path.join(self.train_image, "*/*.JPEG"))
labels = [os.path.basename(os.path.dirname(image_file)) for image_file in image_files]
# be consistent with the order in torch.utils.data.DataLoader
labels = sorted(labels)
self.readable_label(labels, save_file)
def train_hierarchical_label_preprocess(self, save_file):
image_files = glob.glob(os.path.join(self.train_image, "*/*.JPEG"))
labels = [os.path.basename(os.path.dirname(image_file)) for image_file in image_files]
# be consistent with the order in torch.utils.data.DataLoader
labels = sorted(labels)
self.readable_label(labels, save_file, hierarchy=True)
def valid_image_preprocess(self, image_path, meta_path, save_file):
from scipy.io import loadmat
image_files = glob.glob(os.path.join(image_path, "*.JPEG"))
if len(image_files) == 0:
return image_path
logger.info("re-arranging images into sub-folders")
image_files = sorted(image_files)
meta_file = os.path.join(meta_path, "ILSVRC2012_devkit_t12/data/meta.mat")
id_file = os.path.join(meta_path, "ILSVRC2012_devkit_t12/data/ILSVRC2012_validation_ground_truth.txt")
metas = loadmat(meta_file, squeeze_me=True)["synsets"][:1000]
id2class = {meta[0]: meta[1] for meta in metas}
ids = np.loadtxt(id_file)
labels = [id2class[id] for id in ids]
for image_file, label in zip(image_files, labels):
class_path = os.path.join(image_path, label)
if not os.path.exists(class_path):
os.mkdir(class_path)
shutil.move(image_file, class_path)
return image_path
def valid_feature_data_preprocess(self, save_file):
numpy_file = os.path.splitext(save_file)[0] + ".npy"
if os.path.exists(numpy_file):
return np.load(numpy_file)
features = self.image_feature_data(self.valid_image)
np.save(numpy_file, features)
return features
def valid_label_preprocess(self, meta_path, save_file):
from scipy.io import loadmat
meta_file = os.path.join(meta_path, "ILSVRC2012_devkit_t12/data/meta.mat")
id_file = os.path.join(meta_path, "ILSVRC2012_devkit_t12/data/ILSVRC2012_validation_ground_truth.txt")
metas = loadmat(meta_file, squeeze_me=True)["synsets"][:1000]
id2class = {meta[0]: meta[1] for meta in metas}
ids = np.loadtxt(id_file, dtype=np.int32)
labels = [id2class[id] for id in ids]
# be consistent with the order in torch.utils.data.DataLoader
labels = sorted(labels)
self.readable_label(labels, save_file)
def valid_hierarchical_label_preprocess(self, meta_path, save_file):
from scipy.io import loadmat
meta_file = os.path.join(meta_path, "ILSVRC2012_devkit_t12/data/meta.mat")
id_file = os.path.join(meta_path, "ILSVRC2012_devkit_t12/data/ILSVRC2012_validation_ground_truth.txt")
metas = loadmat(meta_file, squeeze_me=True)["synsets"][:1000]
id2class = {meta[0]: meta[1] for meta in metas}
ids = np.loadtxt(id_file, dtype=np.int32)
labels = [id2class[id] for id in ids]
# be consistent with the order in torch.utils.data.DataLoader
labels = sorted(labels)
self.readable_label(labels, save_file, hierarchy=True)
def feature_data_preprocess(self, save_file):
return np.concatenate([self.train_feature_data, self.valid_feature_data])
def label_preprocess(self, save_file):
with open(save_file, "w") as fout:
with open(self.train_label, "r") as fin:
shutil.copyfileobj(fin, fout)
with open(save_file, "a") as fout:
with open(self.valid_label, "r") as fin:
shutil.copyfileobj(fin, fout)
def hierarchical_label_preprocess(self, save_file):
with open(save_file, "w") as fout:
with open(self.train_hierarchical_label, "r") as fin:
shutil.copyfileobj(fin, fout)
with open(self.valid_hierarchical_label, "r") as fin:
shutil.copyfileobj(fin, fout)
blogcatalog = BlogCatalog()
youtube = Youtube()
flickr = Flickr()
hyperlink2012 = Hyperlink2012()
friendster = Friendster()
wikipedia = Wikipedia()
math = Math()
fb15k = FB15k()
fb15k237 = FB15k237()
wn18 = WN18()
wn18rr = WN18RR()
wikidata5m = Wikidata5m()
freebase = Freebase()
mnist = MNIST()
cifar10 = CIFAR10()
imagenet = ImageNet()
__all__ = [
"Dataset",
"BlogCatalog", "Youtube", "Flickr", "Hyperlink2012", "Friendster", "Wikipedia",
"Math", "FB15k", "FB15k237", "WN18", "WN18RR", "Wikidata5m", "Freebase",
"MNIST", "CIFAR10", "ImageNet"
] |
Turkey and EU’s Visa-Free Travel Deal is on the Verge of Breaking Down
Leonid Bershidsky, Bloomberg
- May 29, 2016 11:00 am
Skift Take
The EU needs to become more liberalized in its view of visa-free travel and consider which countries actually pose a risk to its universal culture and values.
— Dan Peltier
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The spat between the European Union and Turkey over visa-free travel is heating up. President Recep Tayyip Erdogan of Turkey is demanding the abolition of visas for his citizens, or else he’ll renege on a deal that has reduced the flood of refugees to the EU to a trickle. European Commission President Jean-Claude Juncker told Erdogan that won’t get him anywhere.
This public fight is futile. Europe could safely cancel visas for Turkey and many other countries: The benefits would far outweigh the costs.
QuickTake Europe’s Migrant Crisis
The EU struck its deal with Turkey in March. Erdogan agreed that his country would take back undocumented immigrants who arrive in Europe by the Balkan route, which was used by more than 1 million people last year. In return, he demanded 6 billion euros ($6.7 billion) in aid and an end to short-term Schengen zone visas for Turks by the end of June. The Europeans promised the money and agreed to expedite visa liberalization “provided that all benchmarks have been met.”
Erdogan appears to have missed that caveat. On Wednesday, he said the immigrant readmission agreement wouldn’t pass the Turkish parliament if visa-free travel wasn’t granted. “Turkey is supposed to fulfill criteria? What criteria are these I ask you?” he fumed.
Juncker’s reply was prompt and equally sharp. “We do expect that Turkey will stick to its commitments — and threats are not the best diplomatic instrument you can use,” he said. “So one should stop to use them, because they will produce no effect whatsoever.”
There are 72 criteria that Turkey is supposed to meet, and further work is needed on only five of them, according to a May 4 document from the European Commission. These are, however, the hardest to implement: They concern anti-corruption legislation, police and judicial cooperation with the EU, personal data protection to EU standards and, most importantly to Erdogan, changes to legislation that now allows him to persecute journalists and academics for “terrorist propaganda.”
Erdogan’s repression of dissent is deplorable. One might wonder, however, what this has to do with 90-day tourist visas to the EU. After all, if someone needs to escape persecution, the need to get a visa is a serious barrier.
In practical terms, the EU’s “black list” of countries whose citizens require visas is meant to keep out undocumented immigrants. It’s a blunt tool for that purpose, though. There is a correlation of about 0.6 between the number of a country’s citizens apprehended in Europe for being there illegally in a given year and the share of rejected visa applications from that country. Officials have a highly approximate idea of the propensity of citizens from specific countries to overstay their visas — but in many cases, they don’t act on the information.
In 2014, Schengen area countries issued 5.7 million visas to Russians, and less than 0.01 percent of that number of Russians were caught that year for being in Europe illegally. For Turkey, the ratio is about the same. Chinese citizens received 1.7 million visas, and only 0.5 percent of that number were apprehended. The number of undocumented immigrants from these three countries is small — slightly more than 27,000, compared with Europe’s population of more than 500 million. And it isn’t small because the EU countries are doing a good job of filtering out risky applications: Visa refusal rates are quite small — 1 percent for Russia, 3 percent for China, 4 percent for Turkey.
The risk of letting Turkish, Chinese and Russian citizens travel to Europe visa-free — for tourism, not work purposes — would therefore be negligible. Letting them travel freely would only give Europe an economic boost given their huge potential for tourist spending.
Yet other countries, which supply more undocumented immigrants, are closer to visa liberalization than these safe ones — or even are exempted from the need for short-term visas.
In 2014, 14,120 Serbs — who don’t have to apply for short-term visas — were apprehended for being in the EU illegally, almost as many as Turkish and Chinese nationals combined. The number of Georgians caught reached eight percent of the number of visas issued in that country, and Georgia is likely to be granted visa-free status this year — along with Ukraine, which supplied 60 percent more undocumented immigrants to the EU in 2014 than Russia.
The logic behind this has nothing to do with curbing irregular migration. It’s purely political. Many of Europe’s criteria for a visa-free regime with a non-member country have to do with the Europeanization of those countries’ domestic rules: They demand, for example, strong anti-discrimination and anti-corruption laws. It’s a mechanism of European “soft power”: If a government wants to offer its citizens hassle-free travel to Paris and Rome, it needs to adopt certain European values.
Russia and China either won’t comply with these requirements or will only pay lip service to them, so they’re not likely to have the visa requirement waived. Georgia, Serbia and Moldova are more likely to attempt to meet the political demands, the latter two countries’ citizens can already travel visa-free, and Georgians will soon get to do so, too.
The political logic is deeply flawed. It’s the citizens of the least European countries who most need exposure to Europe, its ways and values. The more they see of the free world, the more they are likely to want similar rules at home. Turks who can go freely to Europe and back may soon be unwilling to tolerate Erdogan’s authoritarianism, and his illiberal laws may be struck down. Erecting barriers for them, on the contrary, alienates them and makes Europeans look surly and unwelcoming.
The refugee deal with Turkey, which has already forced European bureaucrats to move faster than intended on vise liberalization, should prompt the EU to abandon visa liberalization as a political tool and only maintain the visa requirement for countries whose citizens present a serious risk of overstaying, such as Afghanistan or Eritrea. Everybody else should be free to visit, Turks included.
This column does not necessarily reflect the opinion of the editorial board or Bloomberg LP and its owners.
To contact the author of this story: Leonid Bershidsky at [email protected].
To contact the editor responsible for this story: Max Berley at [email protected]. |
The effect of acupuncture therapy on pain perception and coping strategies: a preliminary report.
The objective of the present study was to examine the effect of acupuncture on the perception of pain and coping strategies, thus focusing on the psychological aspects of pain. The study was conducted in two complementary and alternative medicine clinics of public hospitals. Forty-one patients scheduled for routine acupuncture therapy because of chronic musculoskeletal pain were recruited for the study to receive eight acupuncture treatments. Twenty-four patients completed the treatment schedule and filled two self-reported questionnaires before and after therapy: (1) Illness Perception Questionnaire-Revised (IPQ-R); and (2) Coping Strategies questionnaire (Brief COPE). A significant improvement was found in the following measures related to pain perception: timeline (chronic versus acute), treatment control, and personal control. Additionally, significant improvement was displayed in three measures related to coping strategies: positive reframing, religion, and venting. The results indicate that acupuncture therapy might be efficient in changing patient's pain perception from chronic to acute and in enhancing their sense of personal and treatment control over their pain. In addition, acupuncture therapy partially improved coping strategies. The present study provides further validation for acupuncture therapy in pain and highlights its possible role in affecting the psychological aspects of pain. |
Solid-state 15N NMR studies of tobacco leaves.
Nitrogen-containing compounds are one important class of constituents in tobacco because of various pharmacological and biological properties. Three types of tobacco leaves (burley, bright, and oriental) were studied using solid-state (15)N NMR cross polarization with magic-angle spinning, dipolar dephasing and five pi replicated magic angle turning (FIREMAT) experiments. The results show that burley tobacco leaves contain significantly more pyridinic nitrogen than that of bright or oriental tobacco leaves. The principal values of (15)N chemical shift tensors of nitrogen functional groups were obtained from the FIREMAT data. Possible assignments of solid-state (15)N NMR resonances were made using nitrogen chemical shift tensors in some model compounds or isotropic chemical shift values from liquid NMR results. To the best of our knowledge, this is the first solid-state (15)N NMR study of tobacco plant material. |
E.J. Dionne commentary: Tea party is focused on wrong problem
Also in Opinion
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Monday October 28, 2013 5:36 AM
Here’s the mistake made by President Barack Obama and the Democrats that nobody is talking
about: They have been too fearful of confronting our country’s three-year obsession with the wrong
problem.
And here is the tea party’s greatest victory: It has made the wrong problem the center of
policymaking.
The wrong problem is the deficit. The right problem is sluggish growth and persistent
unemployment.
The paradox is that the deficit would be less challenging today if we had been less preoccupied
with it since the 2010 elections. The deep cuts in government spending since then have slowed the
very growth we need to make our way toward fiscal balance.
But relief may be on the way. More from political exhaustion than from any change of heart, we
may be about to take halting steps toward dealing with the issues we should have been grappling
with in the first place.
The president’s defenders would assert that he has been careful all along to emphasize the need
for short-term stimulus to get the economy moving and to insist that deficit reduction was his goal
only for the longer run.
That’s true enough. But there are the words, and then there is the music. Since a Republican
Party driven by tea-party thinking managed to make government spending and deficits Washington’s
paramount concerns, the administration has backed off aggressive efforts to use government to pump
much-needed energy into an economy whose tepid growth since the 2008 implosion has left 11.3
million Americans still out of work.
By putting so much effort into negotiating a failed “grand bargain” with House Speaker John
Boehner in 2011 and subsequently agreeing to the sharp, across-the-board cuts of the “sequester” to
get out of a crisis, Obama contributed to the deficit chorus. Because of the fiscal tightening, our
unemployment rate is probably a point higher than it would have been otherwise. We’ve done a heck
of a job on the deficit, reducing it from about 10 percent of the economy in 2009 to 4 percent now.
We’ve done badly by the jobless.
The administration would argue that it did a lot to avoid even more damage. It had to play the
political hand dealt it by the 2010 elections while also facing the overwhelming consensus among
political elites that deficit reduction was urgent. The commission that Obama himself appointed,
led by Erskine Bowles and Alan Simpson, spread this gospel with passion and zeal — even if both
acknowledged, usually in much softer tones, that the economy still needed a short-term boost.
Of course there should be no denying that we face fiscal challenges down the road. Over the next
three decades or so, the retirement of the baby boomers will be expensive. Most of the spending
will be in health-care expenditures under Medicare and Medicaid. In an environment free from
crisis-mongering and hyper-partisanship, passage of the Affordable Care Act could usefully have
been seen as a first step toward what ought to be our goal: guaranteeing decent health coverage to
all Americans, including the elderly, at a cost government can afford. And, by the way, no matter
how successful we are at doing this, there is no way around the need for more government revenue as
long as large numbers of baby boomers are around.
But all this should be the focus of a measured discussion over the next several years, not an
excuse for a frenzy of cuts — especially reductions right now that are only dampening the recovery.
When the house is still burning, you don’t spend your time worrying about how to cut your heating
bill in the coming decades.
The good news is that the capital is so sick of political chaos and of failed quests for big
budget deals that Congress might actually address the problem right in front of our noses. Rep.
Paul Ryan, the House Budget Committee chair, spoke last week of the futility of shooting for a “
grand bargain.” This is a positive signal.
The most helpful thing Congress can do immediately is to get rid of the sequester cuts. A
Congressional Budget Office study conducted at the request of Rep. Chris Van Hollen, the Budget
Committee’s ranking Democrat, found that if left in place, the automatic reductions could cost up
to 1.6 million jobs next year. Allowing that to happen would be folly — and heartless, too.
So let’s douse the flames of slow growth and joblessness first. Government does better when it
deals with one crisis at a time. |
import 'canvas-toBlob';
import 'whatwg-fetch';
|
Q:
Is there a problem with no-ip.com
Iv'e just managed to get a WIFI re connect script working and have been testing it by pulling the power on my router and re connecting it; sO far so good. It all seems to reconnect, but when I try and access the Apache server from my mobile phone, I get server not found!
It works from within my WIFI, but not from the net.
I haven't changed anything on my router, apart from rebooting it a few times
I found this article on the net and wondered if it's not the script but noip's DUC (dynamic update client) not working. I don't seem to be able to log in to noip.com either!
If NoIP is compromised/blocked by Microsoft, will things go back to normal, or do I have to search for an alternative free Dynamic update client.
Any ideas?
I don't think it's the script, as I can get access if I find out my external IP address, but hear it is anyway, just in case anyone can spot a reason why this may have upset my Apache server.
#!/bin/bash
LOGFILE=/var/log/wifitestlogfile.log
TESTIP=74.125.224.72
ping -c4 ${TESTIP} > /dev/null
if [ $? != 0 ]
then
message="$(date) -- WiFi seems down, restarting - message from script /usr/src/scripts/wifi_test_2.sh"
echo >$LOGFILE # empties the file so just the last log is saved
echo $message >>$LOGFILE
ifdown --force wlan0
ifup wlan0
else
message="$(date) -- WiFi seems up - message from script /usr/src/scripts/wifi_test_2.sh"
echo >$LOGFILE # empties the file so just the last log is saved
echo $message >>$LOGFILE
fi
A:
This is related to the microsoft takedown of the noip domains. If you are using noip you are probably SOL until after lawyers get involved. Probably easier to move to another free dns provider, just like the botnets will.
|
257 S.W.3d 126 (2008)
Gregory DILLMAN
v.
COMMONWEALTH of Kentucky.
No. 2007-CA-000455-MR.
Court of Appeals of Kentucky.
June 6, 2008.
*127 Donald H. Morehead, Assistant Public Morehead, Steven J. Buck, Assistant Public Advocate, Department of Public Advocacy, Frankfort, KY, for appellant.
Gregory D. Stumbo, Attorney General of Kentucky, James C. Maxson, Assistant Attorney General, Frankfort, KY, for appellee.
Before KELLER and THOMPSON, Judges; GRAVES,[1] Senior Judge.
OPINION
THOMPSON, Judge.
Gregory Dillman appeals his conviction in the Pulaski Circuit Court for two counts of trafficking in a controlled substance in the first degree. For the reasons set forth herein, we affirm.
On February 10, 2005, Beverly Morgan, a confidential informant wearing an audio recording device, purchased two methadone tablets from Dillman for eighty dollars. On March 24, 2005, Morgan, wearing an audio recording device, purchased from Dillman one-half of an oxycodone tablet for sixty dollars.
On March 22, 2006, Dillman was indicted for two counts of trafficking in a controlled substance, first-degree. Following a jury trial, Dillman was found guilty on both counts and sentenced to twelve years' imprisonment. This appeal followed.
*128 Dillman first contends his Fifth Amendment privilege against self-incrimination was violated. Specifically, he contends the trial court impermissibly ordered him to answer a question from the prosecutor regarding an unindicted crime. We disagree.
The Fifth Amendment to the United States Constitution provides that a defendant cannot be compelled to incriminate himself by his own testimonial communications. Varble v. Commonwealth, 125 S.W.3d 246, 253 (Ky.2004). However, when a defendant decides to testify in his own defense, he subjects himself to the rigors of cross-examination and must answer all questions relevant to the prosecution of the case. Lumpkins v. Commonwealth, 425 S.W.2d 535, 536 (Ky.1968).
During trial, Dillman exercised his constitutional right to testify in his own defense. Although admitting that he had obtained oxycodone for Morgan, he testified that he was merely a middleman in the transaction and sold the oxycodone to her "at cost" simply to provide drugs to a friend and fellow drug addict. During cross-examination, Dillman was asked to identify the person who supplied him with oxycodone. After Dillman invoked the Fifth Amendment, the trial court ordered him to disclose the identity of his supplier over his objection.
Dillmans privilege against compelled self-incrimination was not violated. After Dillman testified that he was merely a non-profit middleman, the trial court properly permitted the prosecutor to inquire into the nature of Dillmans middleman status, which included the identity of his supplier. Dillmans own testimony placed the prosecutors question within the scope of relevancy.
Dillman next contends that the trial court erred by admitting evidence against him of uncharged crimes and bad acts despite the Commonwealths failure to provide him with reasonable pretrial notice in violation of Kentucky Rules of Evidence (KRE) 404(b) and (c). He also alleges that the evidence was inadmissible under KRE 404(b). We disagree.
Generally, as provided in KRE 404(b) and (c), the Commonwealth cannot produce evidence of crimes and bad acts other than the crimes charged in the indictment. O'Bryan v. Commonwealth, 634 S.W.2d 153, 156 (Ky.1982). However, when a defendants testimony introduces the prior bad acts, he is precluded from claiming that the prosecutors use of the prior conduct constitutes inadmissible evidence. Thompson v. Commonwealth, 648 S.W.2d 538, 539 (Ky.App.1983). Dillmans testimony introduced the prior conduct that he now seeks to declare inadmissible. While we do not seek to discourage such a sacred right, these are the perils of testifying in ones own defense.
Dillman also contends that the Commonwealth was improperly permitted to ask him whether or not he made a statement to police in 2002 that he sold drugs for profit. He further points out that he was not provided with reasonable pre-trial notice regarding the Commonwealths intention to introduce this evidence.
During cross-examination, Dillman testified, I don't sell drugs, I just picked that up for her [Morgan]. After Dillman agreed that he had taken Morgans money in exchange for drugs, Dillman testified that he believed trafficking or selling only occurs when drugs are sold for profit. The prosecutor then asked Dillman if he was in it for the money. Dillman replied, No, I work.
After requesting a bench conference, the prosecutor informed the court that he sought to introduce Dillmans 2002 statement to police in which he stated that he *129 was acquiring particular drugs because he could make a three hundred percent profit. After Dillman voiced his objections, the trial court ruled that the evidence was admissible under two different legal theories.
First, the trial court ruled that Dillmans assertion of the entrapment defense permitted the introduction of his past statement to establish a pre-disposition to commit drug trafficking for profit. Second, the trial court ruled that the past statement was admissible to rebut Dillmans trial testimony that he does not sell drugs for profit.
We believe that the trial court incorrectly admitted the statement as evidence of Dillman's pre-disposition in regard to his entrapment defense. A defendant may assert an entrapment defense, which if successful would exonerate him from criminal liability, if he was induced by police or their agent to commit a crime for which he was not otherwise predisposed to commit. Johnson v. Commonwealth, 554 S.W.2d 401, 402 (Ky.App.1977). When a defendant has met his evidentiary burden of establishing this defense, the Commonwealth may demonstrate that a defendant originated or was otherwise disposed to engage in the criminal conduct prior to being induced by a government agent by introducing evidence of a defendants past similar criminal conduct. Wyatt v. Commonwealth, 219 S.W.3d 751, 757 (Ky.2007).
Notwithstanding its ability to introduce past criminal conduct, the Commonwealths evidence of such conduct cannot be so remote that the probative worth of the evidence is outweighed by the prejudice to the defendant. Gray v. Commonwealth, 843 S.W.2d 895, 897 (Ky.1992). Fundamental fairness requires that a jury's verdict be predicated on the particular crime charged in the indictment and not prior bad conduct dovetailed to the charged offense with the effect of emphasizing a general criminal disposition. Robey v. Commonwealth, 943 S.W.2d 616, 618 (Ky.1997).
We conclude that Dillman's assertion of an entrapment defense was not sufficient to support the introduction of his prior unsworn out-of-court statement. Dillman's prior statement was made several years prior to the dates he committed the charged offenses. The introduction of the prejudicial prior statement substantially outweighed its probative value. However, we conclude that Dillman "opened the door" for the introduction of his prior statement, and therefore, affirm the trial court.
Dillman testified that he did not sell drugs for profit. This testimony could have been interpreted to state that Dillman never sold drugs for profit at any time in his life. However, he told police something different in 2002. Thus, evidence of Dillman's prior statement could be introduced to rebut and impeach his trial testimony. Ernst v. Commonwealth, 160 S.W.3d 744, 762 (Ky.2005).
With respect to Dillman's contention that the introduction of his prior statement violated the notice requirement of KRE 404(c), we conclude that there was no error. Although the Commonwealth did not disclose its possession of evidence regarding this statement during pre-trial proceedings, it disclosed its intention to introduce the prior statement after hearing the defense's opening statement.
Under the circumstances, the Commonwealth did not violate the notice requirement of KRE 404(c). As demonstrated to the trial court, the Commonwealth acted in as prudent a manner as possible under the circumstances. The Commonwealth disclosed the prior statement at the earliest *130 feasible time in which it believed the evidence was relevant.
Dillman next contends that the trial court erred when it failed to exclude evidence of his unindicted crime and past bad act due to prejudice. Specifically, even if this evidence was otherwise admissible, Dillman contends its probative value was substantially outweighed by the danger of undue prejudice as prohibited by KRE 403. We disagree.
KRE 403 provides the following:
Although relevant, evidence may be excluded if its probative value is substantially outweighed by the danger of undue prejudice, confusion of the issues, or misleading the jury, or by considerations of undue delay, or needless presentation of cumulative evidence.
In making an evidentiary determination under KRE 403, the trial court's ruling will be reviewed for abuse of discretion. Partin v. Commonwealth, 918 S.W.2d 219, 222 (Ky.1996). "The test for abuse of discretion is whether the trial judge's decision was arbitrary, unreasonable, unfair, or unsupported by sound legal principles." Commonwealth v. English, 993 S.W.2d 941, 945 (Ky.1999).
First, as previously noted, Dillman cannot contest the introduction of his oxycodone purchase because he originated this testimony. Secondly, even though extremely prejudicial, the Commonwealths inquiry regarding Dillmans 2002 statement to police was in direct rebuttal to his denial of selling drugs for profit. The prosecution is granted latitude to prove its case with competent evidence, and defendants cannot determine the facts they do not want the jury to receive. Page v. Commonwealth, 149 S.W.3d 416, 420 (Ky.2004). Accordingly, the trial court properly admitted the evidence and Dillman was not unduly prejudiced.
Dillman next contends that the trial court erred by failing to instruct the jury on criminal facilitation to commit trafficking in a controlled substance. Based on the testimony at trial, Dillman contends that the evidence compelled an instruction on criminal facilitation because the jury could reasonably find him guilty of the offense.
A trial court must instruct the jury on the whole law of the case, which includes instructions applicable to every legal issue supported to any extent by the evidence. Holland v. Commonwealth, 114 S.W.3d 792, 802 (Ky.2003). We conclude that the trial court did not commit error by not instructing the jury on facilitation because Dillman did not present a sufficient evidentiary foundation. Unlike being a mere facilitator, he was an active participant in the commission of drug trafficking. Thompkins v. Commonwealth, 54 S.W.3d 147, 150-151 (Ky.2001); see also Commonwealth v. Day, 983 S.W.2d 505, 508 (Ky.1999)(holding that facilitation instructions were not warranted under similar facts as this case).
For the foregoing reasons, the judgment of the Pulaski Circuit Court is affirmed.
ALL CONCUR.
NOTES
[1] Senior Judge John W. Graves sitting as Special Judge by assignment of the Chief Justice pursuant to Section 110(5)(b) of the Kentucky Constitution and KRS 21.580.
|
Friday, April 11, 2008
Blogger versus skunk DAY 1
With the almost-doorframe-sized KULLEN closet slid carefully into the basement rec room, I found myself in need of some sort of challenge.... what to do...
Last year we had a skunk move in under the garbage shed. Searching online provided a solution that seemed like it could work... So off to Farm Boy I went, and came back home to chop up one yellow onion and one jalapeno pepper, and boil them in a water/cayenne pepper solution for 20 minutes. After straining the liquid into a spray bottle, I was all set.
I excessively coated the ground around the hole leading under the shed, then sprinkled a layer of flour on the wet dirt. The next morning, pawprints led out of the hole but did not return. I sprinkled more flour, waited a few days, but the skunk was gone. The hole was filled, stones were laid atop it, and the skunks never returned to the undersides of that shed.
Our other shed on the other hand.... sometime during the winter a skunk (or two?) has gone beneath our bigger shed. You know, the weatherproofed nice one that we keep all our excess stuff in. Our now skunk-scented stuff. Like stuff we were going to sell at a garage sale. Or our patio furniture. Or our strollers.
Since I have only a quarter of the anti-skunk juice left, and the amount of escape areas from beneath that shed are numerous, a new plan must be set in place.
My initial thought process went something like:1. Get one of those loud air horns.2. Shut myself into the shed3. Plug ears and honk (the horn) like mad.
That plan was abandoned when I realized "Since the skunk scent is lingering simply from it living under there, what would happen should it wake, suddenly startled, and spray... with me in a non-ventilated shed directly above?"
So, Plan B was put into action: yesterday, a small radio was placed in the shed playing talk radio loud enough that the skunk could hear, but not so loud as to violate noise bylaws... and if the skunk isn't scared away by the sound of talking upstairs by this time tomorrow, well... |
Using a vacuum sealer?
I'm buying a lot of food and everything else I can think of, I'm new at this. Family thinks I'm nuts. Going it alone. I have a vacuum bag sealer, a good one, and tons of bags, and have oxygen absorbers on the way. Can I put my own new boxed food in them with a oxy. absorber? Like powdered milk, it's good for 2/3 years new, if in a vacuum bag, with the absorber, won't it last years and years too? Then I can do small package mixes, my own sugar, and teas, does anyone have the answer to this? Also, if I bag seal batteries, do I need an axygen absorber in them too?
If your using a vacuum sealer then you don't need oxygen absorbers. It won't hurt but it is just overkill. What i do is either leave the food in the original bag with the bag opened or cut the directions from the container and put them in the bag with the food. There are a few things that you don't want to vacuum seal -one of them is brown sugar. When sealing powdery items you need to keep the powder from being sucked into the sealer.
There are a lot of threads about using a "food saver". Unfortunately they are not all under one topic so you have to search around. OTOH you will find a lot of interesting and helpful info. : )
So- while in the forum tab, in the search box try: food saver, vacuum sealer, jar attachment. You will also find Grainlady's post especially helpful.
I'm a veteran FoodSaver user -- since 1986 (I'm on my 3rd one and the next one is in the basement - new in the box). I don't think I could do home food storage without one after all these years. I dislike using buckets for food storage and have very little of my dry goods stored in them. I've successfully used this method since 1986 and didn't even know what oxygen absorbers and mylar bags were until a few years ago. So different strokes for different folks....
Oxygen-free storage will extend the shelf-life (probably double the storage time), but temperature is also important. Some foods don't taste the same after being vacuum-sealed for a prolonged time, so you may want to do some trial and error as well as making sure you rotate these foods in and out of storage on a regular basis. When you store your food reserves at the "optimum storage temperature (between 40°F to 60°F)" that temperature range ALONE can double the storage life. The shelf-life of storage foods is usually calculated on 70°F, which is considered "room temperature" and all food will degrade quicker at temperatures warmer than room temperature. Even foods like MREs will degrade quickly if stored in hot temperatures. This is the projected storage life of MREs at different temperatures based on tests by the U.S. Army:
I have a 3-year supply of milk and milk-substitute powders (4 different brands in storage at this time), but I purchase it in hermetically-sealed #10 cans and it's placed in my 3rd level of home food storage - Long-term Emergency Storage. Since I use powdered milk products for everyday use, I also buy it in a 25# bucket or I'll purchase a 50# bag and split it with a friend to keep the price per gallon of reconstituted milk low. The bulk amount in a bucket is considered a food from my 2nd layer of home food storage - which is Pantry Foods (foods used for everyday food preparation). I've been using powdered milk products exclusively since 1981 and don't ever purchase milk from the store.
If you purchase boxes of non-fat dry milk powdered from a grocery store (which is generally the most expensive and also has the shortest shelf-life, and not nearly as tasty as a couple brands I use everyday) I'd suggest storing it in canning jars and use the FoodSaver jar sealer with it to keep it "free-flowing" rather than packed tight in a bag. I will occasionally store some of my powdered milk in jars I vacuum-seal shut in order to extend the shelf-life. In fact, you will find using vacuum-sealed canning jars a real $ saver for dry goods. I check the lids of my vacuum-sealed canning jars once a month, that way if a seal fails the food was only unsealed for a month or less. I store a wide variety of dry goods in canning jars: tea bags and loose tea leaves, instant coffee crystals, chocolate chips, grains/seeds/beans, prepared pecans and almonds (they are sprouted overnight in lightly-salted water and then dehydrated until they are crispy dry which makes them easier to digest and they will keep longer than raw nuts), some pasta, homemade cocoa mix, freeze-dried foods after I open a #10 can.....
A good resource for information about using a vacuum-sealer for home food storage is Wendy DeWitt - http://allaboutfoodstorage.com/2009/...-presentation/ You can find her series of training sessions on YouTube. Be sure to download her booklet - Everything Under The Sun. Since you are just getting started, Wendy's information will be really helpful since you don't seem to have a good food storage plan as of yet. A plan will help you use your money wisely and choose foods wisely. For instance, I store and use tomato powder (which has an indefinite shelf-life) and I use it to make tomato sauce, tomato paste, pizza sauce, pasta sauce, tomato juice and can even make a fairly good bbq sauce and ketchup by adding a few pantry items. So I've eliminated all of those other cans/jars of foods from my food storage.
You need to make sure you don't vacuum-seal flour in FoodSaver bags. There is enough moisture in flour - when packed tight in the sealed bag - it can develop a musty odor. It could even develop aflatoxins which are a type of mycotoxin if stored in bags, and that's unsafe in food. If you are storing flour, store it in a jar or canister that you can vacuum-seal shut - BUT - it remains free-flowing within the jar or canister so it won't develop the musty smell. This is information I have in one of my FoodSaver User-Manuals, so it's the suggested storage from the company. I only store whole grains - no flour - since wheat has a much longer shelf-life than flour. Flour, even vacuum-sealed and/or frozen only stores for 1-2 years (at best) and old flour is often the reason for failed breads and baked goods. Plus, I try to store as much nutrient-dense foods as possible, and bleached and unbleached flour, as well as commercial whole wheat flour are "dead" food.
If you store packaged foods - things like Pasta Roni or seasoned pasta or rice dinners, you can put the contents of the box in a canning jar and vacuum-seal the jars shut. If the packages are small enough you can place the contents of several boxes/packages in one jar (place them in a plastic storage bag and stack in the jar). Tape the cooking instructions (nutrition information, or anything else you need to know from the package) on the outside of the jar. I put white sugar, bag and all, in a FoodSaver bag and seal shut. HOWEVER, you need to avoid vacuum-sealing brown sugar as kathya mentioned. There is enough moisture in brown sugar to potentially develop bacteria growth in the oxygen-free environment.
I tend to store ingredients instead of processed foods and make my own "convenience" foods from those ingredients (Saving Money with Homemade Convenience Mixes - http://umaine.edu/publications/4029e/). Whole foods and ingredients are generally less expensive to purchase than prepared and processed foods. I don't even store much pasta because I can make my own from grains I keep in storage. I make some "In-A-Jar" type recipes and vacuum-seal them in jars, but they are "time sensitive" even vacuum-sealed and need to be rotated as Pantry Foods. There are lots of recipes in the book "Dinner Is In The Jar" by Kathy Clark - http://dinnerisinthejar.com/. I have some of these in my pantry, but overall they tend to be too high in sodium and use too many processed foods for me.
My food storage plan...
-Level 1- 72-Hour Emergency Foods: These are foods that don't require heating or refrigeration. We've used this during winter storms when we were without utilities for a prolonged period of time.
-Level 2- Pantry Foods: Foods I use for everyday food preparation. I started with 6-months worth and eventually built it into 12-months.
-Level 3- Long-term Emergency Foods: Foods that keep longer than 1-year and I have 1-years worth. Most are freeze-dried or dried.
I also have 3-years worth of the "Seven Survival Foods" - grains, legumes, seeds for sprouting, salt, sweeteners, fats (I store coconut oil because it has a longer shelf-life than other fats, as well as health benefits) and powdered milk (or milk substitute/s). These are the foods I use the most in our diet as well.
BTW, I never use oxygen absorbers - it's just another expense the way I see it - but you can add them if you'd like.
Batteries need to be stored where it is cool and dry. Some "experts" suggest in the refrigerator (which has very low humidity due to the frost-free feature). The only benefit to vacuum-sealing them would be to assure they stay dry, and that can be done in an air-tight container if they are stored where humidity is high. From what I've read, oxygen-free storage doesn't seem to be a benefit.
I’m also somewhat new to vacuum sealing and have been trying to find out if I should vacuum seal sprouting seeds? Some sites say yes and some say no I know that temperature is important so should they be stored in the refrigerator or just a cool cabinet? Also should dried fruit, berries, raisons, be vacuum sealed. I put some marshmallows in a jar and vacuumed them are they safe or do they have enough moisture in them to get toxic? Oh so many questions I’m just glad I found this site.
Hello Jane, I am new here too, and have learned a lot.
I just want to see if this will post, my last one did not.
I have learned a lot from GrainLady and Kathryn.
I have my sealer, waiting for the jar top sealer for jars, gonna start with dried beans in them.
I’m also somewhat new to vacuum sealing and have been trying to find out if I should vacuum seal sprouting seeds? Some sites say yes and some say no I know that temperature is important so should they be stored in the refrigerator or just a cool cabinet? Also should dried fruit, berries, raisons, be vacuum sealed. I put some marshmallows in a jar and vacuumed them are they safe or do they have enough moisture in them to get toxic? Oh so many questions I’m just glad I found this site.
On a personal note, I'm sprouting wheat on a daily basis (for growing into wheatgrass) I vacuum-sealed in FoodSaver bags in 2007 and I don't have any problems getting it to sprout. I sprout a wide variety of grains/seeds/beans I have vacuum-sealed in storage on a regular basis. It's perfectly fine to place seeds destined for sprouting in air-tight containers as an option (a jar with a tight-fitting lid is a better option than a zip-lock bag since pantry pests can chew through plastic bags). The biggest benefit from vacuum-sealing them means you are assured you won't have an insect infestation because they won't live without oxygen if the food happens to have pests or their eggs in them. Most pantry pests are either already in the food or the box or bag, or they are often found in dry pet food which is often kept in the house.
My food storage is in a room in our basement, which is the coolest place in our home. "Room temperature" is considered 70°F and that's what most food storage charts are based on. Optimum storage is between 40°F to 60°F. Refrigerator temperature should be 40°F or colder to prevent premature food spoilage and the increased potential for bacteria growth.
Your home-dehydrated or commercially dried foods (like apricots, raisins, prunes, dried blueberries, dried cranberries, etc.) will keep fine in the package they come in, or a jar with a lid on it, but you should consider them pantry foods (enough for 6-12-months worth) and rotate them on a regular basis - not long-term emergency foods. In fact, home-dehydrated foods aren't the best keepers. Fruits keep longer than vegetables because of the fruit sugar. I try to use all home-dehydrated foods within 3-12-months of preparation. I DO vacuum-seal my home-dehydrated apple slices in 1/2-gallon canning jars because I make so many of them -- but I make sure they are dried until they are brittle, not rubbery, for vacuum-sealed storage. I'll vacuum-seal zucchini "chips" as well (we use them instead of potato chips), another food that I dry crispy dry. If you can find a copy of the book "How To Dry Foods" by Deanna DeLong (check your local library) - she explains how you can check the percentage of moisture left in foods you dehydrate at home.
You should contact the FoodSaver help line for more information. I have some problems with some of the so-called "experts" when it comes to food safety and vacuum-sealing. I think some of them either don't know, or disregard food-safety concerning storing foods with moisture over 10-percent. "It ain't killed me yet." isn't a good plan! We're contending with more types of bacteria, and more deadly bacteria than even existed 20-years ago.
For long-term storage (stored longer than a year) I have freeze-dried raisins and other fruits/vegetables/cheese/meat which are packed hermetically sealed in #10 cans. When I open them I'll transfer them to canning jars (user-friendly amounts) and vacuum-seal them to keep them fresh longer. Even home-canned foods should be considered pantry foods and used within a year of processing.
Marshmallows are interesting when you vacuum-seal them and need to be vacuum-sealed in a canister or jar in order to keep them free-flowing. They puff-up as the air is taken out of the container, but they are safe to vacuum-seal, but I would NEVER consider them a long-term storage food. A better idea is to learn how to make homemade marshmallows and to store the ingredients with which to make them. How to: http://smittenkitchen.com/2009/06/sp...-marshmallows/ The same ingredients you use to make homemade marshmallows are useful for making all kinds of things, and that's why we store INGREDIENTS instead of specific-use specialty foods (I store the ingredients to make pancakes/waffles - not pancake/waffle mix - because I can make hundreds of things from those same simple ingredients).
The more things you can make from scratch using INGREDIENTS you have in storage, the more versatile your food storage will be. For instance, I store tomato powder - a great storage item that has an indefinite shelf-life. With water and simple pantry ingredients (seasonings, spices, herbs, vinegar, sweetener, oil, etc.) I make tomato sauce, tomato paste, pizza sauce, spaghetti sauce, tomato juice, and even a reasonable facsimile of a quick version of ketchup and bbq sauce. So I don't have shelves lined with cans/jars of tomato-related products other than tomato powder. With tomato powder, home-grown dehydrated tomatoes, and some home-grown tomatoes in the freezer, that's about all the tomato things I have. I store wheat, which has a really long storage life, and with the simple ingredients of whole wheat flour, water and some seasonings I can make whole wheat "CHIPS"/"CRACKERS". Add a little sweetener and some cinnamon to the flour and water and you can make "cereal" flakes. It's easy, and a lot less expensive to make your own snack foods using storage ingredients.
I vacuum-seal nuts after I've soaked them in lightly-salted water and dehydrated them until they are crispy dry (per information found in the book "Nourishing Traditions"). They are now easier to digest, higher in nutrition, and will store longer than raw nuts.
Keep studying... I'm still learning all kinds of things even after using a FoodSaver for home food storage since 1986. |
A basking shark shows off its leaping skills Youen Jacob
Gliding through the ocean and feeding on tiny animals, the basking shark seems far more peaceful than its ferocious relative the great white shark. But it turns out languid basking sharks can swim as fast and jump out of the water as high as great whites if they so choose.
Great white sharks are known to jump out of the water – or breach – to capture agile seals and otters. By comparison, basking sharks eat mostly zooplankton that drift into their 1 metre wide megamouths. They are also much larger than great whites, so it’s a mystery why they would expand effort on breaching. But for some reason, they do.
In an attempt to understand the unusual behaviour, Jonathan Houghton at Queen’s University in Belfast, and his colleagues placed a monitoring device on an 8-metre-long, 2.7-tonne basking shark swimming near Ireland and captured a breaching event after 3 hours. Bren Whelan, another member of the team, also filmed the breaching behaviours of 20 basking sharks from the shore.
The footage showed giant basking sharks leaping near vertically to about 1.2 metres above the water surface. Houghton estimates the sharks must have accelerated to a speed of 18 kilometres per hour for breaching – the same speed reached by white sharks.
The entire breaching event, from bursting to recovery, would cost an 8-metre-long basking shark 45 to 51 kilocalories – a greater energy expenditure than white sharks incur when they breach. But because basking sharks are almost twice the size of great whites, the researchers concluded that the two species’ energy spent per kilogram of body weight are comparable.
“The similar energy cost between basking and white sharks is surprising to me,” says David Sims at the Marine Biology Association in Plymouth, UK. He points out that great white and basking sharks have very different cardiovascular capacities for their divergent lifestyles. Great white sharks are relatively warm-bodied and known to chase down fast-swimming tuna, whereas basking sharks have colder bodies and swim slowly.
The analysis has revealed some more details about how basking sharks breach, but why they do it still remains elusive. “At present, it’s a mystery,” says Sims.
Journal reference: Biology Letters, DOI: 10.1098/rsbl.2018.0537
We have corrected who filmed the basking sharks from the shore. |
This invention relates to a demodulator for demodulating an input signal subjected to amplitude-and-phase modulation.
With the amplitude-and-phase modulation technique, it is possible to transmit a plurality of digital signal series which are independent of one another. As will later be described with reference to a figure of the accompanying drawing, an amplitude-and-phase modulated signal includes, besides quadrature phase components spaced in the modulated signal by a 2.pi./4 radian phase interval, a plurality of additional components. In a conventional amplitude-and-phase demodulator, the amplitude-and-phase modulated signal supplied thereto as an input signal is demodulated by the use of a pair of reference carrier signals, one of which is in quadrature phase relative to the other and which are recovered from the input signal. An error component inevitably remains in the recovered reference carrier signals due to the additional components. Consequently, the conventional demodulator is defective in that jitters are inevitable in the recovered reference carrier signals although the circuitry for recovering the reference carrier signals is complicated in structure to render the demodulator expensive. As a further result, the conventional demodulator has been incapable of reproducing the digital signal series with high precision. |
Acupuncture in the prophylaxis of recurrent lower urinary tract infection in adult women.
To evaluate the effect of acupuncture in the prevention of recurrent lower urinary tract infection (UTI) in adult women. A controlled clinical trial with three arms: an acupuncture group, a sham-acupuncture group, and an untreated control group. Patients were followed for 6 months. An acupuncture clinic in Bergen, Norway. Sixty-seven adult women with a history of recurrent lower UTI. Acute lower UTIs during the 6-month observation period. Eighty-five percent were free of lower UTI during the 6-month observation period in the acupuncture group, compared with 58% in the sham group (p < 0.05), and 36% in the control group (p < 0.01). There were half as many episodes of lower UTI per person-half-year in the acupuncture group as in the sham group, and a third as many as in the control group (p < 0.05). Acupuncture seems a worthwhile alternative in the prevention of recurring lower UTI in women. |
In the modern telecommunications industry, standard communications systems are linked to each other using protocols based on the Open Systems Interconnection (hereinafter referred to as “OSI”) model. The goal of OSI is to create an open system networking environment where any vendor's computer system, connected to any network, can freely share data with any other computer system on that network. In fact, the OSI model would allow any terminal connected to any computer to access any application on any other computer provided that the computers were connected by some form of common network. In networks adopting the OSI reference model, data flow between systems is performed through the OSI environment. The OSI model for network communications defines seven layers, each of which performs specific communications operations independent of the other layers. The seven layers are divided largely into upper layers and lower layers. The upper application-oriented layers perform services related to session management, data abstraction, and applications. The upper layers provide services that handle the applications, and the structuring, and encoding of data. The lower, network-dependent, layers provide services related to the physical connections, types of links, and routing functions. The lower layers provide transparent connections over diverse network configurations and a consistent interface to the upper layers.
The upper layers comprise an application layer, a presentation layer, and a session layer. The application layer executes protocols for user and network operation management and enables communications between the users' CPUs (central processing units). This layer provides services to the user and applications, such as job control, file transfer facilities, electronic mail, virtual terminal and directory services. The presentation layer has structure for communication between function modules of the application layer and handles presentation formats of information. This layer negotiates a common syntax used to encode data for data transfer and allows data to be transferred, independent of hardware considerations. The session layer controls dialog between the application layers. This layer provides organizing functions for synchronizing dialog and session recovery from lower layer problems.
The lower layers comprise a transport layer, a network layer, a data link layer, and a physical layer. The transport layer enables correct communications between terminals even if the upper layers do not consider the quality of line or physical constitution of additional systems. This layer provides an interface between the upper layers and the lower layers, concealing the detailed functional operation of the physical network connections to provide a network-independent service to the application-oriented upper layers. The network layer provides data transfer services. This layer provides addressing and routing functions, and may also include flow control between networks. The data link layer transmits data correctly without a hitch by enhancing reliability of a physical link in a logic network. This layer takes the information provided by the physical layer and adds error detection and retransmission functions. At this stage data is treated as units of data. The physical layer defines a physical interface between physical media, and transmits and receives bits according to the transmission requirement from the data link layer.
In an open system, user program data in a system A is entered into OSI environment and the data is transferred from the application layer to the physical layer in sequence to transmission media. Here, the data is enclosed in frames used in a high-level data link control (hereinafter referred to as “HDLC”) procedure prior to transmission. The frame passes a data switching network, so-called a relay open system in the OSI model, and arrives at a receiving computer in the open system. In the receiving computer, the data is passed from the physical layer to the application layer in sequence and, finally, transmitted to an application process B, the destination in a system B in the open system.
The data flow between systems may be performed between systems or a system and a terminal connected to another system. However, communications between more than two systems with different protocols is restricted. Thus, a protocol converter is required to perform data communications between different communication networks.
As a prior art, U.S. Pat. No. 5,852,660, Lindquist et al., discloses a network protocol conversion module within a telecommunications system. The U.S. patent provides a method and apparatus for enabling telecommunications signals containing application layer data generated by a first SS7 (Signaling System No. 7) telecommunications network to be transported across a second SS7 telecommunications network, wherein the first SS7 telecommunications network and the second SS7 telecommunications network are incompatible.
Conventional protocol converters allow two different protocols to exchange data between CPUs. It means direct data exchange between applications, or data exchange using simple logic between devices. In those conventional protocol converters, time delay is generated while the CPU performs other tasks. In addition, while one CPU receives signals and exchanges responses with the inside of system, a load on the CPUs and a waste of time are caused thereby incurring a large loss in the view of performance.
Conventional protocol conversion methods for communications between various network protocols are classified into three classes.
First, there is 1 to 1 protocol conversion method. This method converts a particular layer of a particular protocol into a corresponding layer of another protocol, based on the seven-layered OSI model. In order to convert m layers, m conversion methods are required and in order to convert n protocols, nC2 methods are required. As a result, m□nC2 methods are required in total. Therefore, for data exchange between various network protocols having various protocol layers, a lot of conversion methods are required thereby causing great complexity.
Second, there is a method of converting into a particular protocol. This means to convert n network protocols into a particular network protocol selected from the n network protocols. In order to convert n network protocols into a particular protocol, (n−1) conversion methods are required and in order to convert m layers, m conversion methods are required for each protocol. As a result, m□ (n−1) methods are required in total. Although it shows less complexity in converting network protocols compared to the first method, it still requires a lot of protocol conversions.
Third, there is a method of utilizing an overlay way. For example, it is IP-over-IEEE1394, IP-over-ATM, and so on. These are structures that an internet protocol, IP, is laid on an IEEE1394 or ATM layer. They do not perform particular conversions and are not data exchange methods between different network protocols. In other words, in the IP-over-IEEE1394, an apparatus in an IEEE1394 network transmits IEEE1394 data laid on the IP and receives data through the IP. The data received through the IP is passed through the IEEE1394 layer so that the IEEE1394 apparatus can accept the data. Therefore, it is not data exchange between different network protocols.
For example, U.S. Pat. No. 5,715,250, Watanabe, discloses an ATM-LAN (asynchronous transfer mode local area network) connection apparatus capable of connecting terminals of different protocol standards. The U.S. patent provides a small-scale ATM-LAN connection apparatus which enables communications between first and second ATM terminals of different standards, namely, the first ATM terminal of a LAN emulation protocol and the second ATM terminal of an IP over ATM protocol.
However, the above-mentioned conventional protocol conversion methods have problems such as complexity in conversion methods, complexity due to different layer architectures and roles of protocols, and complexity in accessing apparatuses in different networks. In other words, the number of conversion methods increases in proportion to the number of network protocols to be converted and the number of layers in the network protocols to be converted, thereby increasing complexity. In addition, when the protocol conversion is performed, the complexity increases by times of a particular factor, because the protocol layer architectures and roles of each layer in each network protocol are very different based on the seven-layered OSI model. The particular factor may depend on the number of option fields and tasks to be treated in each protocol layer. Moreover, there is no common address hierarchy recognizable between different network apparatuses when communications between the different network apparatuses are performed. |
Sunday, June 29, 2008
Although the little robot inflicted a major flesh wound on Kung Fu Panda this weekend here in the states, KFP is doing brisk business on foreign shores:
DreamWorks Animation and Paramount's martial arts toon "Kung Fu Panda" has conquered the Asian box office in only three weeks, becoming the highest-grossing toon ever in South Korea.
That's good news for Hollywood studios looking to extend their international reach and tailor movies to a specific territory, or handful of territories. "Panda" will ultimately play everywhere, but the strength of its engagements in Korea and China is noteworthy.
"Panda," ... took in $3.76 million from 582 screens over the June 20-22 frame for a cume of $20.7 million in its third sesh.
What delights my soul is that the big, American-produced animated features continue to do exceedingly well in international markets, which bodes well for more American-produced animated features to be made.
The toon came in No. 4 overall for the frame, even though it has yet to roll out in much of Europe. "Panda" grossed $20.5 million for the weekend from 2,857 playdates for a foreign cume of $68 million. It launched with $4 million in China and $5.9 million in Mexico.
Par and DreamWorks Animation are taking a gradual approach in releasing the toon, mainly because of the ongoing Euro Cup soccer tournament.
Disney will likewise be careful with the rollout of Pixar toon "Wall-E," which opens on June 27. The gradual rollout of both "Panda" and "Wall-E" mean that the international box office could be strong for weeks.
I don't doubt for a millisecond that both of these features will make heavy coin worldwide, and that the Hollywood congloms will take note.
7
comments:
Anonymous
said...
Okay, I'm not in the animation business - I'm just an admirer and fan of the craft. So can someone with knowledge of the subject tell me: are computers the great equalizers? I mean, it seems to me that when feature toons were all 2D, Disney was THE major player because most of the quality 2D came from that studio. And the reason Disney quality was so high was because of the painstaking apprenticeship and focus on innovation Disney insisted on that most studios couldn't touch. But now that feature toons are all CG, suddenly there are studios producing toons all over the place. So I guess what I'm asking is: does computer animation require less, or a different kind of, talent than did 2D? A shorter apprenticeship? Or what?
Making an animated feature requires all different kinds of disciplines and skillsets, no matter if you are making CG or traditional.
In terms of actual animators, as a cg animator who was traditionally trained, I would certainly say that animating 2D takes greater skill, and a greater learning curve. To explain further...
In terms of what is common to both:Animating is acting. There are principles to learn, understanding characterization, performance, appeal, weight, how the body moves, story sense, and other aspects that relate to acting and physics. Truly getting a solid grasp on these aspects is often what takes the longest--usually at least a minimum of 2 to 4 years. But really, it's a lifetime of learning, continually refining what you know.
In terms of where 2D and 3D differ:Traditional hand-drawn has another whole layer of skill that takes many years of study, and that is the skill of draughtsmanship--the ability to draw anything, at any angle, purely out of imagination, with flourish. This can take years of specialized training. Obviously, some have a greater natural aptitude than others, but in general, the combination of both great draughtsmanship and solid understanding of acting and animation principles takes a minimum of roughly 4 to 7 years to get somewhat competent.
Conversely, cg animators don't need to learn drawing. While drawing can help, it isn't a requirement, and there a number of excellent cg animators who don't draw. Once the principles of animation and acting are understood, the only thing a cg animator needs to learn to get started is a computer software program like Maya. If taught by a competent instructor, you can be reasonably familiar with Maya (enough to animate with a pre-built rig) in just a couple months.
Not sure if I should leave this comment in this particular Comment Box, but I will.
Could someone please tell us how the whole Sit Down Shut Up thing ended? It seems to have been been almost a week since the ultimatum, and no one has been talking about how it ended. The story has just been dropped by everyone that started writing about it. I feel like I just watched a movie and the whole third act was missing.
While I don't disagree with Tim about his excellent response, I'd like to point out that having a reasonable drawing skill level, will help the cg animator come up with better stronger poses!Every time I bring this up, cg animators who dont draw look at me funny! But to me, someone who has spent time at life drawing classes has a better grip on the whole body language thing. Jut my opinion anyway!. |
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This story was printed from CdrInfo.com,
located at http://www.cdrinfo.com.
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Appeared on: Tuesday, November 13, 2007
Yahoo! to Expand Reach of Global Mobile Services in 2008
Yahoo! today announced nine new partnerships with mobile operators across Asia Pacific, Latin America as well as the availability of Yahoo! Go 2.0 in Chinese language for Taiwan.
Yahoo is offering consumers in Latin America's three largest markets a set of mobile Internet search services, paving the way for network carrier partners to offer Yahoo services of their own.
The company on Monday that consumers in Argentina, Brazil and Mexico can point their phone Web browsers to m.yahoo.com to download Yahoo's OneSearch mobile Internet software, which features local information in Spanish or Portuguese languages.
OneSearch offers Internet search on the first screen that users call up, in contrast to browsers designed for computer users that force phone users to navigate through several screens of links to locate the Web information they desire.
The Yahoo service, which will start out in public test mode in Latin America, was first introduced in the United States earlier this year. It makes mobile Web search faster and more relevant by providing links to local news, financial data, weather conditions, Flickr photos, and other Web sites.
Yahoo has also struck new deals to offer mobile phone Web services through nine network operators across Asia.
The Silicon Valley-based Internet company said on Tuesday that it was introducing a mobile service called Yahoo Go in traditional Chinese in Taiwan. These deals build on six earlier Asian carrier partnerships announced in June.
Yahoo is racing to attract subscribers to Internet services delivered via mobile phones rather than via computer browsers as rival Google has begun a longer-term push to offer software to create a new class of Internet-ready phones. |
//
// RedundantDefaultFieldInitializerIssue.cs
//
// Author:
// Mansheng Yang <[email protected]>
//
// Copyright (c) 2012 Mansheng Yang <[email protected]>
//
// Permission is hereby granted, free of charge, to any person obtaining a copy
// of this software and associated documentation files (the "Software"), to deal
// in the Software without restriction, including without limitation the rights
// to use, copy, modify, merge, publish, distribute, sublicense, and/or sell
// copies of the Software, and to permit persons to whom the Software is
// furnished to do so, subject to the following conditions:
//
// The above copyright notice and this permission notice shall be included in
// all copies or substantial portions of the Software.
//
// THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR
// IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY,
// FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL THE
// AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER
// LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM,
// OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN
// THE SOFTWARE.
using System;
using System.Collections.Generic;
using ICSharpCode.NRefactory.PatternMatching;
using ICSharpCode.NRefactory.TypeSystem;
using ICSharpCode.NRefactory.Refactoring;
namespace ICSharpCode.NRefactory.CSharp.Refactoring
{
[IssueDescription("Redundant field initializer",
Description = "Initializing field with default value is redundant.",
Category = IssueCategories.RedundanciesInDeclarations,
Severity = Severity.Hint,
AnalysisDisableKeyword = "RedundantDefaultFieldInitializer")]
public class RedundantDefaultFieldInitializerIssue : GatherVisitorCodeIssueProvider
{
protected override IGatherVisitor CreateVisitor(BaseRefactoringContext context)
{
return new GatherVisitor(context);
}
class GatherVisitor : GatherVisitorBase<RedundantDefaultFieldInitializerIssue>
{
public GatherVisitor(BaseRefactoringContext ctx)
: base(ctx)
{
}
public override void VisitFieldDeclaration(FieldDeclaration fieldDeclaration)
{
base.VisitFieldDeclaration(fieldDeclaration);
if (fieldDeclaration.HasModifier(Modifiers.Const) || fieldDeclaration.HasModifier(Modifiers.Readonly))
return;
var defaultValueExpr = GetDefaultValueExpression(fieldDeclaration.ReturnType);
if (defaultValueExpr == null)
return;
foreach (var variable1 in fieldDeclaration.Variables) {
var variable = variable1;
if (!defaultValueExpr.Match(variable.Initializer).Success)
continue;
AddIssue(new CodeIssue(variable.Initializer, ctx.TranslateString("Initializing field by default value is redundant"),
new CodeAction(ctx.TranslateString("Remove field initializer"),
script => script.Replace(variable, new VariableInitializer(variable.Name)),
variable.Initializer)) { IssueMarker = IssueMarker.GrayOut });
}
}
Expression GetDefaultValueExpression(AstType astType)
{
var type = ctx.ResolveType(astType);
if ((type.IsReferenceType ?? false) || type.Kind == TypeKind.Dynamic)
return new NullReferenceExpression();
var typeDefinition = type.GetDefinition();
if (typeDefinition != null) {
switch (typeDefinition.KnownTypeCode) {
case KnownTypeCode.Boolean:
return new PrimitiveExpression(false);
case KnownTypeCode.Char:
return new PrimitiveExpression('\0');
case KnownTypeCode.SByte:
case KnownTypeCode.Byte:
case KnownTypeCode.Int16:
case KnownTypeCode.UInt16:
case KnownTypeCode.Int32:
return new PrimitiveExpression(0);
case KnownTypeCode.Int64:
return new Choice { new PrimitiveExpression(0), new PrimitiveExpression(0L) };
case KnownTypeCode.UInt32:
return new Choice { new PrimitiveExpression(0), new PrimitiveExpression(0U) };
case KnownTypeCode.UInt64:
return new Choice {
new PrimitiveExpression(0), new PrimitiveExpression(0U), new PrimitiveExpression(0UL)
};
case KnownTypeCode.Single:
return new Choice { new PrimitiveExpression(0), new PrimitiveExpression(0F) };
case KnownTypeCode.Double:
return new Choice {
new PrimitiveExpression(0), new PrimitiveExpression(0F), new PrimitiveExpression(0D)
};
case KnownTypeCode.Decimal:
return new Choice { new PrimitiveExpression(0), new PrimitiveExpression(0M) };
case KnownTypeCode.NullableOfT:
return new NullReferenceExpression();
}
if (type.Kind == TypeKind.Struct)
return new ObjectCreateExpression(astType.Clone());
}
return new DefaultValueExpression(astType.Clone());
}
}
}
}
|
Search form
R.D. Offutt and Farm Fresh Direct form potato marketing company
R.D. Offutt Co., Fargo, is combining two of its operations — in O’Neill, Neb., and Winnemucca, Nev. — with Farm Fresh Direct LLC, Monte Vista, Colo., to create a national sales and marketing company.
The company, Farm Fresh of America, says the deal makes it the largest grower-owned fresh potato shipper in the U.S.
The two new operations from Offutt add 300 million pounds to Farm Fresh. The company now offers russets, reds, golds, organics, fingerlings, and value-added products like PotatOH microwavable potatoes.
Offutt currently farms 190,000 acres in the U.S., including 60,000 acres of potatoes. Farm Fresh Direct operates six packing operations in Colorado.
The release said Farm Fresh plans to expand its operations and product portfolio, including more PotatOH products. |
Q:
Removing Puncuation Marks off a text file and then calculating odd and even length words
So far, i have done a lot in the code.. i replaced the punctuation marks from the text file but i do not know how to find the words with even and odd lengths and add them to their count. So: My wordcount for this file is 114 words but this program returns 50 even words and 55 odd words which doesn't add up to my wordcount of 114 so there is obviously something wrong.
A:
BufferedReader file3 = new BufferedReader(new FileReader("sonnet1-b.txt"));
int even = 0;
int odd = 0;
String lines;
String processedLine = "";
//It's unclear if this variable will have a bigger purpose in the future
ArrayList<String> words = new ArrayList<>();
while ((lines = file3.readLine()) != null) {
processedLine = lines.replaceAll("'", "").replaceAll("[^a-zA-Z]", " ").replaceAll("( )+", " ");
//I removed words here and changed the split to split on the space. When I ran your original code, the whole text came in as one line. I think your original problem may have been in this area. You need to get the length of the words. You're original split param only put spaces into each.
String[] each = processedLine.split(" ");
for (String str1 : each) {
//Based on your description, you need to check the length of str1, not each.
if (!(str1.length() % 2 == 0)) {
odd++;
} else {
even++;
}
}
}
System.out.println("There were " + even + " even words, and " + odd + " odd words");
There were 58 even words, and 56 odd words
|
Queen Elsa Portrait Gift Bag - Large x 1pc
Product Details
Gift bags are great to add the finishing touches to all your lovely presents! Making it a quick and easy way to show just how much effort you've made!! And lets's be honest, what better way to present an item than in a gift bag with their FAVOURITE Disney Character!!
Luxury Matt Laminated Gift Bag
Glitter / Flitter Detail
Navy Blue Rope Handle
Queen Elsa Portrait
Size: 265mm x 330mm + 140mm
Everyone loves Disney, and this year we've introduced all of your favourite characters! From Minnie Mouse & Mickey Mouse, everyones favourite couple! To all you favourite Disney Princess' including the new addition of Queen Elsa from Frozen! Not only have we have got the main characters, we've got the friends too! There's the Mickey Mouse Clubhouse Characters; Daisy Duck, Donald Duck and Goofy! And not forgetting Princess Anna, who is every little girls dream sister!
You worry about the gift, and leave the presentation to us!
You can save money on this item when you purchase several at a time. The table below shows the minimum quantities required to benefit from this offer, and how much they'll cost. |
<?xml version="1.0" encoding="utf-8"?>
<LinearLayout xmlns:android="http://schemas.android.com/apk/res/android"
xmlns:tools="http://schemas.android.com/tools"
android:id="@+id/newlinear"
android:layout_width="match_parent"
android:layout_height="match_parent"
android:orientation="vertical" >
<!-- Ignored via attribute, should be hidden -->
<Button
android:id="@+id/button1"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:text="Button1"
tools:ignore="HardcodedText" >
</Button>
<!-- Inherited ignore from parent -->
<LinearLayout
android:id="@+id/parent"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
tools:ignore="HardcodedText" >
<Button
android:id="@+id/button2"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:text="Button2" >
</Button>
</LinearLayout>
<!-- Hardcoded text warning ignored through "all" -->
<Button
android:id="@+id/button3"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:text="Button3"
tools:ignore="all" >
</Button>
<!-- Ignored through item in ignore list -->
<Button
android:id="@+id/button4"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:text="Hardcoded"
tools:ignore="NewApi,HardcodedText" >
</Button>
<!-- Not ignored: should show up as a warning -->
<Button
android:id="@+id/button5"
android:layout_width="wrap_content"
android:layout_height="wrap_content"
android:text="Hardcoded"
tools:ignore="Other" >
</Button>
</LinearLayout>
|
GENTRIFUCKATION – GENTRIFICATION IN BERLIN
If you feel like contributing, please send a message to: [email protected]
Gentrification is slowly attacking Berlin after being almost done with London and Paris. In the German capital, it’s an army descending from Kreuzberg to Neukölln stealing leather sofas and expresso machines on the way. An English philosophy teacher explains how this process triggers a circle of poverty and hate in the city centre.
They took over Prenzlauer Berg. They took over Kreuzberg. Mitte fell into their purse a long time ago. Who are they? What do they want? Why are they taking over? Those questions are tough ones to answer. I perceive gentrification as a process of giving an area a face-lift – just without any previous warning. A neighbourhood that was socially deprived and nearly abandoned has in a few short years, filled with trendy bars and clubs, and now a coffee or a beer costs twice as much as it used to. Good for business you say?
Of course it is and that’s the main issue. The gentrification phenomenon is pushing workers out of the central city to give way for international students, artists and so on. The first step in the process is the broke student searching for a cheap rent. He or she will turn towards those former crappy districts in order to be able to live sparingly. One student attracts another; soon a district will be overflowing with people who want to move there. Here is the tricky part. Soon as the rentiers and other building owners realize this, they will increase their prices out of the blue to make the area “good to live in” again. By that expression, I mean good for the people with money, which is the goal of the investors. Their dream, as usual is to make the much money as possible.
The fall of the wall, Berlin becoming capital of Germany again, the nightlife of this city are well known all around Europe; those facts triggered this phenomenon nearly finished in Paris or London. The speculative investments along with the people taking advantage of prices is turning Berlin’s town centre into a museum of itself, a museum not even affordable for the people who live there. The only victims are the silent ones without any weapons to fight against the process. The workers are being squeezed between increasing rents and prices and their salaries do not increase in a similar fashion.
Landlords have, for example in Neukölln, flats and apartments that are uninhabitable, yet they still rent these for three of four hundreds euros a month – because they can. I witnessed this when trying to sublet a room in that very neighbourhood. The room I was in was small and dirty, and the subletter made ample profit to pay rent and his holidays through what I was paying. A lot of people are searching for accommodation so I had no choice but rent it.
Gentrification could be a healthy process, triggering a melting pot, a jambalaya of workers, students, families and artists from every part of the world. They could share their background and their culture but the opposite process is underway. Take Neukölln as an example, the Turkish community does not have the same lifestyle as the new trendy people coming into Berlin. A place for tea and shisha does not have the same customers as the new cool bar with Lou Reed and Jim Morrison hanging in the toilets. The time schedule does not match either, as can be seen in Neukölln, often you can witness a half-drunk western kid yelling at the Turkish späti (Late night shop in Berlin) because he does not have any alcohol.
This has resulted in two communities containing themselves, not sharing and not remotely interested in what the other has to offer, there is a split in the habits of consumption and a split in how the other is perceived. To make things worse, one community is being pushed out because of the increasing rents, whilst the other is gently settling in the city for short, middle or long term. It’s a real tragedy. This process encourages reactionary ghettoization and animosity is triggered towards the other community.
Is the mayor supposed to do something? Yes of course, but his only answer is “be happy that the money is flowing in your neighbourhood”, well the money is not for everybody, but then again, sometimes the authorities must be reminded that when you leave everything according to the invisible hand, the workers just get a couple of fingers up their arses.
The only solution that I see for the future would be to put a cap-on the rent, which seems almost impossible in today’s world, in a system where everything is economically connected, everything has a value and can be speculated on. Disconnecting the housing market in Berlin from the rest of the world would be difficult to achieve – but I say let’s change the system. For all those that want to come to Berlin and want to rent here – refuse the high prices, refuse to go in gentrified bars and areas, the power is in our hands. Let’s take it back!
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your view is skewed, simplistic, superficial and idiotic at best. how many turkish friends do you have? but also, have you asked yourself, how many ‘original neukölln’ people want to be friends with you?
respecting different parts of the community doesn’t mean having to be friends with them or sharing shishas’ and “splitting the habits of consumption”. we can all share a city, respect each other, not be friends, and still form a thriving and functional community. for every ‘western kid’ abusing a spätie seller, (have lived here in NK for 3+ years and never witnessed one of these incidents, but anyways…) you’ll have an arab man hissing at a girl jogging in shorts. things like this happen, because ignorants come in a variety of colors. we mustn’t be naive, a big city will invariably host a lot of them.
also, i take it you’re as new as the evil gentrifiers you so much disdain. or maybe you came here 10 years ago, and have the ‘first immigrant’ complex. get rid of it. playing the ‘i was were here first’ puts you on the same level of nationalistic and xenophobic that you probably go to protests against.
Mieterhöhung is a problem which can be efficiently and systematically solved in only one way: by changing the laws, and regulating the ways people can speculate on the housing market. our grandfathers (or mine at least) have fought to give us a political system which can be changed from the inside, and it’s not as closed as we think.
and here’s another provocation: refusing to go in ‘gentrified bars and areas’ will just achieve one thing, you’ll gentrify the new havens you go to.
in the system you confusedly describe, you’re part of the problem.
Borja
First of all, I think that you missed the point that is NOT the opinion of the journalist, is the “English philosophy teacher” the one who is giving his point of view.
On the other hand I think he’s trying to to explain a concept that EXISTS, even if we like it or not, so the line “your view is skewed, simplistic, superficial and idiotic at best” it’s a very disrespectful and misinformed way to answer (I really think that this is not your case but somehow you felt attacked and it looks like your leading by anger sometimes).
My point is, correct me if I’m wrong, that you’re taking this as a personal attack to a group in particular when the concept is based on the social behaviour and not the invidual one. He’s talking about the richness of cultures that this city is offering and how sad is not to inmerse on them and the FACT that money crush society and culture everyday.
Last thing is about the way to change the law. I used to think that jurisdictional framework is something that easily evolves with human development but it’s not…and makes me wonder if this would have embarrassed our grandfathers that fought for them. In Spain we watch people on the news commiting suicide because they couldn’t afford to paid their mortages, being forced to loose their houses and keep on paying to the banks…..what the goverment is doing to change this abusive law, is still being a mistery…
ali
i didnt read the comments but i liked the article. but the last words “refuse to go in gentrified bars and areas, the power is in our hands. Let’s take it back!” are very ridicolous i think. i mean isnt you and i think moste of the readers hear doing most of the stuff what you describe in all the rest of the article.
Grepache Trucidant
I think what the journalist wanted to say with that conclusion is some bars are taking advantage of the situation and are performing prices that do not correspond to the wages of the city. They expect people to pay for the “coolness” of it. The point is clear, money destroys everything, try to avoid it as you much as you can. |
Chatting breeds creative ideas or thats what it looks like if one walks into the LEGO offices. Designed by architectural firm Bosch & Fjord, the place looks and feels vibrant.
If you think that they may have one meeting room too many there, here is their explanation: The idea of having 13 meeting rooms (yes, 13!) is based on the thought process that majority of the ideas are realized while people are moving around and indulging into conversations. Observe the workspaces and you will see a sense of freedom which transcends across the office making it one cool place to hatch ideas.
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(Probably the only office in the world which shares a common table for reception and cafe!) |
#include <assert.h>
void test1(int a) {
int b = 0;
__asm__ (
"mov $5, %%eax \n"
"mov %%eax, %0 \n /* Ignore comment. */"
"mov $3, %%ebx \n"
"add %%ebx, %1 \n"
: "=m" (a), "=m" (b)
:
);
assert(a == 5);
assert(b == 3);
}
void test2(int a) {
int *p = &a;
int b = 2;
__asm__ (
"movl $5, %0 \n"
"movl $6, %1 \n"
: "=m" (*p), "=m" (b)
:
);
assert(a == 5);
assert(b == 6);
}
void test3(void) {
int a = 1;
int b = 2;
__asm__ (
"add $2, %1 \n\t"
"mov %1, %0 \n\t"
: "=r" (a)
: "r" (b)
);
assert(b == 2);
assert(a == 4);
__asm__ (
"add $2, %1 \n\t"
"mov %1, %0 \n\t"
: "=r" (a), "+r" (b)
:
);
assert(b == 4);
assert(a == 4);
}
void test4(void) {
int a[] = {1, 2, 3, 4};
int b = 0;
__asm__ (
"leaq %1, %%r10 \n\t"
"mov %2, %%r15d \n\t"
"leaq (, %%r15, 4), %%rax \n\t"
"mov (%%r10, %%rax, 1), %0 \n\t"
: "=r" (b)
: "m" (a[0]), "r" (a[1])
: "rax", "r10", "r15"
);
assert(b == a[2]);
}
void test5(void) {
int a = 1;
__asm__ (
"add $1, %0 \n"
: "+rm" (a)
);
assert(a == 2);
__asm__ (
"add $1, %0 \n"
: "+rm" (a)
:
);
assert(a == 3);
}
void test6(void) {
static unsigned char data[4] = { "\xFF\xFF\xFF\xFF" };
unsigned int a = 0;
__asm__ volatile (
"mov (%1), %0 \n"
: "=r" (a)
: "r" (data)
);
assert(a == 0xffffffff);
}
int main(void) {
test1(42);
test2(42);
test3();
test4();
test5();
test6();
return 0;
}
|
George Zimmerman Libel Suit Against NBC Dismissed
A Florida judge has ruled in favor of NBC and dismissed George Zimmerman‘s defamation lawsuit in connection with the shooting death of 17-year-old Trayvon Martin.
Zimmerman had filed the suit in December 2012 alleging NBC portrayed him as racist in a series of news reports about Martin’s death in February 2012.
Circuit Judge Debra S. Nelson made the ruling Monday. She had written that Zimmerman was a “public figure” and he had to prove “actual malice.”
“NBC News is gratified by the court’s dismissal of this lawsuit, which we have always believed to be without merit,” the network said in a statement.
Nelson had placed Zimmerman’s suit on hold pending his criminal trial. He was acquitted in 2013 of second-degree murder and manslaughter in Martin’s shooting at a gated community in Florida.
Zimmerman had accused NBC News of defaming him by broadcasting edited clips of a 911 call he made. Those clips made it appear as if Zimmerman volunteered that the teenager was black and had been racially profiled when Zimmmerman had actually said “he looks black” in response to 911 dispatcher asking, “Is he black, white or Hispanic?” |
Q:
In php, how can I make a library of functions more cohesive?
I find php's Object Orientation somewhat verbose and unsavory. I love working with the cleanliness of functions, and my ideal is to code in php from as close to Clojure's excellent approach to Functional Programming as can be done & still make sense in php.
As I move towards F.P., I've found that it's hard to keep a group of related functions cohesive. In OO, that would be done with shared state and methods that exist as part of the same class. Is there some aspect of F.P. that can be used to help with that?
A:
maybe namespaces in php 5.3 ?
|
Unresectable pancreatic cancer: arterial embolization to achieve a single blood supply for intraarterial infusion of 5-fluorouracil and full-dose IV gemcitabine.
Response rates to systemic chemotherapy for unresectable pancreatic cancer are low. The purposes of this phases 1 and 2 study of intraarterial therapy were to ascertain the recommended dose of intraarterial chemoinfusion and to evaluate the efficacy and safety of this therapy. Pancreatic arteries originating from the superior mesenteric artery (the anterior and posterior inferior pancreaticoduodenal and the dorsal pancreatic) were embolized to achieve a single blood supply from the celiac artery to manage pancreatic cancer, and a catheter-port system was placed. Intraarterial 5-fluorouracil (5-FU) and IV gemcitabine (fixed dose of 1000 mg/m(2)) were administered. In phase 1, doses of 5-FU were increased from 750 to 1000 mg/m(2). In phase 2, tumor response, toxicity, and survival time were assessed. A total of 20 patients were enrolled. In 19 patients (95%), the technique to unify the pancreatic blood supply was successful. No severe toxicity was observed with escalation of the 5-FU dose. The tumor response rate was 68.8%. The median overall survival time was 9.8 months and the progression-free survival time, 6.0 months. The grade 3 toxicities neutropenia (15.8%) and thrombocytopenia (5.3%) occurred. In intraarterial administration of 5-FU at a dose of 1000 mg/m(2) combined with full-dose systemic gemcitabine for unresectable pancreatic cancer, the toxicity rate was acceptable, and response rate and survival time improved over those for treatment with gemcitabine alone. |
The influence of genetic changes in body weight, egg production, and body conformation on organ growth of turkeys.
Measurements were made on the breast with bone (BWB), a demand organ, and various supply organs in mature turkeys (approximately 40 wk of age) from various lines of turkeys to determine the influence of selection for increased egg production, BW, and body conformation on resource allocation. Comparisons made were: 1) a line (E) selected long-term for increased egg production and its randombred control (RBC1); 2) a line (F) selected long-term for increased 16-wk BW and its control (RBC2); 3) the F line with a commercial sire line (C); and 4) the RBC1 line and a randombred control (RBC3) that was formed from the F and C lines. Data were analyzed on an absolute basis and after adjustment to a common BW by covariance analysis. The only major change in organ sizes that occurred that could not be accounted for by differences in BW was in the E line. The actual and relative weights of total supply organs decreased and the relative weight of the BWB increased in the E line when compared with its randombred control. Selection for increased BW in the F line did not result in a relative change in BWB. The BWB weight was relatively heavier in the C line than in the F line. The relative amount of BWB was slightly but significantly different in the two randombreds (RBC1 and RBC3) formed 29 yr apart. Weight of the gizzard did not increase at the same rate as BW in two large-bodied lines (F and RBC3). |
‘Toe’ was always the goal: Browns’ Dawson closing in on Groza’s field goal mark
Before he beat out Chris Boniol and Danny Kight for his first NFL job …
Before he outlasted three coaches and hundreds of teammates …
Before Phil Dawson became Phil Dawson, he looked up the Browns record for most field goals in a career and told his wife, Shannon, he would one day own that mark.
With 233 field goals, he’s one off Hall of Famer Lou “The Toe” Groza’s career mark. Dawson hopes Sunday against the Falcons is when he becomes No. 1 in Browns history.
“It’s a goal I’ve had since the day I got here,” said Dawson, who was signed as a free agent by the expansion Browns in 1999 without ever kicking in an NFL regular-season game. “Had I announced that back then, I probably would’ve gotten laughed out of town. It’s heresy, you know.
“You might as well try to be the best. I’ve never been a guy just happy to be here, happy to have a job. I remember telling my wife way back then, ‘Someday that’s going to happen.’ So it’ll definitely be a special moment for her and I ’cause there’s been a lot of ups and downs between then and now and for it to finally be here is pretty neat.”
Dawson smiled, flashing his big dimples, when first asked Friday about the big day ahead.
“What’re you talking about?” he said.
He was only kidding and couldn’t keep up the gag.
“Uncharacteristically, I found myself reflecting a lot this week,” he said. “That’s not something I usually do. It’s going to be a challenge to zero in and make sure I approach everything the same way.”
Dawson, 35, has been the only player left from the expansion team since 2006, when cornerback Daylon McCutcheon went on injured reserve. He’s the franchise’s all-time leader in field-goal percentage (82.9), third in points (986) and entered the season in the top eight in NFL history in accuracy.
The field-goal record is the one he’s always chased. He can’t control the number of extra points he kicks – that’s up to the offense, which has been among the league’s worst for most of his tenure.
Dawson knew of Groza growing up in Texas, but didn’t grasp his stature until meeting him at training camp in 1999. Groza died in 2000. The Browns headquarters is at 76 Lou Groza Blvd.
“Mr. Groza pulled me into the tents right over here and I sat down at a round table with him,” Dawson said. “That’s when it really hit me.
“That was the first Hall of Famer I had ever had the pleasure of sitting down with. Just to share that moment kinda added fuel to that motivation way back then. So the amount of respect I have for him and what he was able to do here, every day I come down this road and I see his name on the street. You mix all that together, it’s going to be pretty neat.”
Dawson loves to talk about his family, which includes sons Dru and Beau and daughter Sophiann.
“I yanked Shannon out of Texas, took her all the way across the world to this strange, foreign land of Ohio and told her I’m gonna get that,” he said of the record. “She said, ‘You better. You made me go through all this.’
“It’s been a family deal. To think this all started before I ever had kids and now my two boys will be there Sunday. That’s just gonna be a neat thing.”
If Dawson doesn’t make two 3-pointers, the next two games are at Pittsburgh and New Orleans.
“When the schedule came out, my wife and I sat down and tried to figure out when it would happen,” Dawson said. “Obviously wanted that to be in Cleveland, in front of the fans and have my own family there. Hopefully it’ll happen and lead to a victory.”
Dawson has made plenty of memorable kicks in his 11-plus years. He hit a winner in Pittsburgh’s Three Rivers Stadium in 1999, the overtime-forcing kick off the goalpost extension in Baltimore and the two kicks in a blizzard against Buffalo. He said the record-breaker would likely surpass them all.
“I just wished more of them would’ve resulted in victories because that’s kind of the whole point of what we’re doing here,” he said. The Browns are 60-120 since 1999.
Dawson missed his first two kicks this year, but has rebounded to hit four straight.
“It’s always enjoyable for me as a coach to see a good guy who works hard have success at what he does,” special teams coordinator Brad Seely said. “Obviously, Phil’s had a lot of success and will continue to have a lot of success in this league because of his work ethic, his attitude and because of the type of person that he is.”
Dawson said setting the lofty goal of passing Groza was important at the time because he didn’t have the support group he was used to having. All the coaches and alumni in high school and college weren’t with him in Cleveland. He had coach Chris Palmer, who made no promises beyond Week 1.
“I felt like that whole season, I miss a kick, I’m out of a job,” Dawson said. “It wasn’t necessarily fun or enjoyable. So I needed something to shoot for.”
Dawson is trying to prepare himself for the emotions he will feel Sunday, because he’ll have to quickly put them aside so he can kick off. Unless, of course, he hits the winner as time expires. |
Nancy Drew: Treasure in the Royal Tower
After Nancy writes the letter to George, it goes into your inventory
and Nancy says something about needing a mailbox. Explore Nancy's room.
First, read an article in the magazine on the table about using
fingerprints to discover keypad access codes. Grab Nancy's passkey off
of the desk. Your room is number 205. Note your locker number and
combination on the paper in the desk drawer (310 with combo 3-1-7). You
might want to write this down (it is a good idea to have paper and
pencil in this game). Take the hotel menu from the top drawer of your
dresser. Read the interesting brochure about the castle in your
suitcase. Then walk to the radiator by your bed-it is broken! *** if
you need advice at any time in the game, call Bess and George or Ned by
using the phone by your bed, and if you want to change the time so that
you can get to the ski rental office or whatever, set the alarm clock
by your bed.
Exit Nancy's room. Go down to the hotel lobby and talk with Dexter
Egan, the caretaker. Exhaust all the conversations. He will ask you to go
down to the ski rental office to pick up Professor Hotchkiss' boots and
bring them up to her room, 214. (If you forget to give the letter to
Dexter, do not worry, because it doesn't affect the game). The ski
rental office is open 9 A.M. to 12 P.M. and 2 P.M. to 5 P.M. Check your
watch to see if you can catch Jacques in the office. If not, then set
the alarm clock by your bed to a time when the office is open. On your
way down the spiral stairs to the basement, you will pass through the
lounge next to the lobby. Read the 2 French Revolution books in the
bookcase in the lounge. They will help a *lot.* You should also exhaust
all the conversations with Lisa Ostrum, in the lounge. She'll tell you
that Dexter keeps a spare key to the library in his desk.
Go down the spiral stairs to the basement (through the doorway in the
lounge, then make a left). Use the sign that says "Ski Rental" to help
you find the ski rental office. Chat to Jacques and exhaust all the
conversations. He will give you Prof. Hotchkiss' boots. Then go to the
locker room and test your locker combo. Your locker is 310, remember?
Turn the dial to the right until you reach the number five, then click
on the green triangle above it. Then turn the dial to the left until
you reach 1, and click on the triangle again. Turn the dial back to the
right until you are on 7, then click on the green triangle one last
time. Uh-oh! The lock must be broken.
If Jacques is still in his office, chat to him about the broken lock
and he'll tell you to try number 311. If he's not in his office, pick
up the little paintbrush on the ledge and go set your alarm clock for a
time when the office is open, then chat to him. Then open locker 311
using 5-1-7. Oops! Looks like the locker is already occupied. Read
everything that you can in the locker. Now, if you haven't already got
the paintbrush on the ledge of the door of the ski rental office, do
that. If the office is open, go set your alarm for a time when it is
closed and then get the brush.
*Use the elevator* to go up to room number 214, knock on the door, and
return Prof. Hotchkiss' boots to her by clicking the down arrow near
the bottom of the screen when the conversations are exhausted, clicking
on the boots in your inventory, and clicking on the ground by the door.
Go into the elevator to tell Dexter you returned the boots. The
elevator gets stuck! The emergency button doesn't work! Look up to see
the trapdoor thing in the ceiling. Go through it and explore until you
see the box thing. Look up to find a door and JUMP up to the 2nd
floor.
Go down the main stairs to the lobby to tell Dexter that the elevator
got stuck and pester him to fix your radiator. He will ask you to fix the
circuit breaker so that the light works on the back stairwell. Find the
circuit breaker in the basement and move the top 3 right-hand
single switches to the right. Move the double-switch below them to the
right as well. Move the top left-hand triple switch to the left. Pull
the elevator-reset switch next to the circuit breaker box. Go up the
back stairwell (the lights are on).
Go ask Dexter once more (in vain) to fix your radiator. He will ask you
to ask Prof. Hotchkiss what she wants for dinner. Go up to her room and
she tells you she's developing a powerful craving for couscous. When
you tell Dexter this he tells you to tell her to order something off
the menu. Do this, then slip the menu from your dresser under her door.
She orders 50 chicken drumsticks! Tell Dexter this. Your last errand is
to tell Jacques to defrost that bag of chicken legs. If the ski rental
office isn't open, set your alarm to a time when it is. Go chat to
Jacques. Go back up the spiral stairs up to your room. On your way to
your room, exhaust all the conversations with Lisa. Your radiator is
fixed! Grab the oil can by the radiator. Now set your alarm for 8 P.M.
Time to get into that library! Take the elevator down to the basement.
Go through the trapdoor thing you went through when you were stuck in
the elevator. Turn around and look down and Nancy will say that that
there is a strange noise coming from below. Climb up the metal ladder
until you notice the open grate. Go through the ventilation duct until
you see the grate leading into the library. Open it, then start to go
down the stairs. You will hear a doorknob jiggling. Quickly open the
grate back up and run into the ventilation duct. Watch the scene that
follows. Once the coast is clear, go back into the library. Read the
book called "An Atlas of the United States." The longitude of Wisconsin
is 90 degrees, right? Write that down. Read the Diary of Hans Axel von
Fersen, Marie Antoinette's friend. Read "Purple-Hearted Queen." It's on
the floor. You HAVE to read the "True Stories Behind Famous Portraits"
book in order to win the game. It's on the small table. Dip the
paintbrush into all the dust on the desk. Look at the painting of Marie
Antoinette. Go over to the alarm keypad and use the paintbrush on each
key. Remember the "Fingerprinting 101" article in Nancy's room? Test
the access code by pressing the keys. If the screen says "Approved,"
congratulations. The code is 3, *, 7, 2. On the globe, move the needle
to the longitude of Wisconsin, then click on the knob on top. Write
down the numbers that you find on the paper. Go over to the plaque
above the fireplace and click. The apparatus there is called a sextant.
Move the compass to each number from the paper. Every time you move the
compass, click on the green button on top. The secret room upstairs
opens!
Go up the stairs and enter the secret room. Pick up the lighter and use
it on the candle to get a key. Read the letter next to the candle. Make
a U-turn and read the 2 books. Exit the secret room and then the
library from the front doors (do not worry-you will not get caught).
Set your alarm to 8 P.M. Make sure the elevator is on the 1st floor.
Go down to Dexter's desk and investigate. Read the "To Do" list and
find the key to the library in a drawer. Then go through the front
doors of the library using the key. The alarm will go off. Quickly go
forward 2 steps, turn, and go to the alarm keypad. Punch in the code
(3, *, 7, 2). Then go up the stairs and into the ventilation duct.
Climb down the ladder and hear the "strange sounds from below." Turn
and find the stuck lever. Use the oil can and you can open the grill.
Go down the steps and turn left. You should find a door with 6
sliding locks. This is a randomly-chosen puzzle that changes each time
you go through the door. Click on the different locks and memorize the
ones that do not slide back into place until you have the entire
pattern. Follow the passage to the left and-SURPRISE-you should see
none other than...I'll let you see for yourself. This person is sawing
away at the gate. And boy, does he or she seem surprised to see you!
Here are the responses you should say.
"Don't you think..."
"What's your..."
"What kind of document?"
"A secret compartment?"
"What happened to the medallion?"
"So, how do you know all of this?"
"What did he think the journal contained that was so important?"
"But how do you think the medallion fits in?"
"I do not know..."
"Well, as long as you tell Christi..."
The person gives you the code to his or her locker...2-6-6-5. Turn and
get the sword tip from the knight. Go up the stairs and through the
passage. Go to the basement and open the person's locker. Read
everything that you can in the locker before getting the BLUE
MEDALLION. "OUCH" Looks like sum1 knocked you out. Answer the
phone.
*I do not know what..."
*It was the last thing..."
*I am afraid I am serious..."
Listen to your voice messages and set your alarm for 8 A.M. Go down and
talk with Dexter. Be honest with him about the red dirt from the Royal
Tower entrance. Ask him about Ezra Wickford's garden. He will tell you
there is a key in the shed. Go through the locker room in the basement
to get outside. Go inside the shed and go down the stairs and then to
your left. Go to the work benches. The key is on a peg board near the
screwdrivers. Read the newspaper clipping and the ski lift
instructions. You are beginning to freeze, though, so do all this
quickly and do not take too long. Go back into the castle before going
into the garden. Leave through the locker room again. Go to the "No
Trespassing" sign and go a little to the left of it. Go to the vine-
covered wall and open the gate. Find the sundial and the statue in the
wall. Turn the sundial to the left to move the head of the statue. Pull
the lever in the back of the statue's head. Take out the box and use
the key you found in the secret room to unlock the box. You now have
the RED MEDALLION. Go back into the castle quickly now, because you
do not want to freeze to death.
Go chat to Lisa in the lounge. She'll tell you about Dexter carrying a
green ornament thing by the shed and tell you to go check it out. Go
back out through the locker room and go by the shed. Try to get back
into the castle. Hurry inside the shed and go over to the ski lift
machine. Click on the middle lever once and the right lever twice.
Dexter will come help you back inside.
Go up to room 214 to visit Professor Hotchkiss. She will give you a
random question to answer. Some common places to find the answer are
the books in the lounge bookcase, the library, etc. If you absolutely
cannot find the answer, knock on her door again and ask her to repeat
the question. She will give you a new question (if, by some chance, she
gives you the same question or you still can not find the answer to a new
one, just ask her to repeat as many times as you like). Type in your
answer on the slip of paper she gives you and press ENTER. She will
tell you to meet her in the lounge between 3 and 6 A.M.
Go set your alarm to 3 A.M. and go down to chat to her. Exhaust all the
conversations and she will give you the spare passkey to her room and
tell you to look around-only while she is in the lounge between 3 and 6
A.M. Go up to her room and read the notes by the typewriter. Read the
letter in her briefcase. Move back the pillow on the couch and get the
BLUE MEDALLION. Watch the video on the camera. Then put the battery
pack from the camera on the recharger next to the camera.
Go set your alarm for 8 A.M. Go get the GREEN MEDALLION from the shed.
It's on the machine to the right of the ski lift machine. Don't let the
rat get you
Set your alarm for 3 A.M. Go back to Professor Hotchkiss' room and
watch the 2nd half of the video. Then leave the Professor's room and
go right to the end of the hall to find the circular room with the
painting and peep hole. Look through the hole with each medallion and
notice the location of the symbols (red is to the left, blue is to the
right, and green is below them).
Call the elevator to the 1st floor. Go through the front doors of the
library using the key. Deactivate the alarm system. Go up the stairs in
the library and into the ventilation duct. Go down the metal latter and
open the grill again. Solve the sliding lock door puzzle (it will be
different this time) and go through the iron gate using the key from
the shed. Make sure you have the spear tip from the statue of the
knight. To solve the chain puzzle, follow the pattern on the opposite
wall. The chains should end up looking like the pattern. (Pull the
chains in this order: [numbered from left to right ] 5, 5, 3, 2, 2, 1,
4, 4).
Once you have solved the chain puzzle, go across the stepping stones.
Go left down the hallway to the chessboard-like thing. What you are
trying to do here is move the 4 discs around the board until they
finally land on top of their listed squares. The order in which
they go on the squares is blue, yellow, pink, then white. It's hard to
tell you exactly how to get them to go on their squares, so just try
your best.
Go up the newly-opened stairway into the top of the tower. Go forward
until you can find and click on the golden leaf puzzle on the wall.
This is another one that is very hard to tell you how to solve.
Basically, you can turn individual pieces 90 degrees by putting the
cursor near the corner and seeing the curved arrow cursor, then
clicking. You're trying to get all of the tiles to match together. This
one is another one that can be frustrating. Remember to turn pieces and
you know that the ones with the outlines on them are on the edge.
You are now able to open the secret compartment.
Nab the journal. Look at Marie Antoinette's portrait. Put the
medallions into the little circles in the middle of the room. Red goes
to the right, blue goes to the left, and green goes below. But there is
still something missing in the middle, right?
Meet Prof. Hotchkiss in the lounge and set your alarm if necessary. Ask
about the translations through the peep holes and talk about the
journal. She says she will wrestle you for it if you do not give it to
her. Tell her that physical contact isn't necessary as long as you can
have the journal translated. She tells you that she will have it ready
by this time tomorrow night. Go up to your room and set your alarm for
3 A.M. Go down to the lounge to talk with her. She says that she has
the journal translated and as an added bonus it includes the official
decoder! Go up to the Professor's room and read the translation to the
right of the typewriter. Read the official decoder to the left of the
typewriter as well. Now go back to the room at the top of the Royal
Tower, solving puzzles and whatnot if necessary!
Make sure the medallions are placed in the middle in the correct order
(red to the left, blue to the right, green below them). You will notice
yet again that there is still something missing in the middle. Go up to
Marie Antoinette's portrait and get a close-up of the purple rose. Use
the tip of the spear from the knight to chip away at the portrait and
get a key. Place the key in the middle of the medallions on the floor.
A pedestal with the diamond will come up! But the bad news is that the
thief will also appear (I'm not revealing who the thief is). The thief
will try to make a run for it, but you know how to stop the thief,
do not you? Quickly find the square stone button on the left side of the
wall by the stairs and PUSH! The thief is trapped! Give yourself a pat
on the back for helping Nancy Drew solve another mystery
Basically, when you are walking around, if you move the magnifying glass
cursor and you see an arrow pointing forward, you can click it and
you will move forward (interesting concept, huh?)! There are also some
left- and right-pointing arrows that will take you in those directions
if you click. These arrows will also help you look around a room.
Occasionally there are up- and down-pointing arrows, as well. Clicking
when the cursor is in a U-shape near the bottom of the screen will turn
you around 180 degrees.
When the magnifying glass cursor's outline turns red, it means you are
onto something, so click! Also, when you open a suitcase or locker or
whatever, if you want to leave, you will have to click on the suitcase or
locker to shut it before you can go.
When you want to chat to a person, click on them (the magnifying glass'
outline will be red). There will be a few responses you can choose from
in white. Click on the one you want to say and the conversation will
continue. The person's responses will be in blue.
This is a complete walkthrough for the Senior Detective level, but will work for Junior Detective also. A few of the puzzles will be easier to solve
100%
This is a complete walkthrough for the Senior Detective level, but will work for Junior Detective also. A few of the puzzles will be easier to solve in the Junior level. We will not include solves for all the puzzles, but if you are having particular difficulty with a puzzle please write and we will help. We also have many saved games in case you need one. The tutorial can be helpful if you are not familiar playing Nancy Drew games.
I have enjoyed playing the Nancy Drew games since the first one, Secrets Can Kill came out, and look forward to each new Nancy Drew game. Nancy Drew 5, The Final Scene will be coming out this November!
Check the following maps to help you find your way around the castle:
Nancy is on a ski vacation staying at the Wickford Castle in Wisconsin. Christi Lane, a friend of Nancy's father, owns the castle. A blizzard swept in and closed the mountain and ended her plans for skiing. Nancy finds other ways to keep busy.
The game starts with Nancy writing a letter to George. It goes into your inventory so you can mail it when you get a stamp later. Pick up your room pass key from the desk. Rm. number 205. Look at your locker card in the desk drawer. #310 with the combination 5-1-7.
Take the menu from the top drawer of your dresser. Open magazine on the table and read how to get fingerprints. Check phone messages.
Walk over by the radiator and notice that it must be broken. Open your suitcase and read the brochure.
Exit your room and head downstairs to talk with Dexter Egan, the hotel manager. You can ask about the stamps and he will take your letter, but if you forget don't worry, it isn't crucial to the game. Talk to Dexter and exhaust all the conversations. Especially talk to him about the library and offer to help him. He will give you a chore to do. The ski rental office is open 9am - 12pm and 2pm - 5pm. You will pass by Lisa on your way down the spiral staircase to the basement. Talk to her about everything. She will tell you that Dexter keeps an extra Library key around his desk. (I wonder how she knows.) While you are in the lounge, read the 2 books in the bookcase.
Check your watch, if it is still before noon, you can catch Jacques in his office and get the boots. Talk to him twice
If the ski rental office is closed, pick up the little paint brush on the door ledge. Try out your locker and notice the combination doesn't work. To open the locker: Turn the dial to the right until you reach 5, then click on the dark triangle above the number. Turn the dial to the left until you reach 1, then click the triangle again. Turn the dial to the right until you reach 7 and click the triangle once more. Pass the time until 2 pm when the office opens again. Talk to Jacques twice. Locker 310 won't open with the 5-1-7 combination. Open locker 311. Learn about Lisa's secret identities/passports, ID's, etc. Also learn that she speaks fluent Spanish (unlike she said earlier). Go up the elevator to Professor Hotchkiss's room, #214.
Return the boots to Professor Hotchkiss then take the elevator back down to talk with Dexter. [To return the boots, place them in the hall in front of her door. As you turn and walk away you will hear her open the door and take the boots.] You will get stuck in the elevator and the emergency button doesn't work! Turn around and look up for a way out. Jumping across to the metal ladder along the wall is a little risky, perhaps you can find another way. After you get back to the hall head down the stairs to talk with Dexter and let him know the elevator is broken also. He tells you that the lights in the upper spiral staircase are out and asks you to check the circuit breakers. Move the top 3 levers on the right as shown in the picture below.
To reset the elevator, notice the elevator control box on the left side of the circuit breaker box. There is a lever to reset the elevator there. Pull it down.
Go back up the stairs and notice the lights to the upper staircase are on. Ask Dexter about your radiator again. He will tell you that you fixed the circuit breakers and then he will give you another errand. This time he wants you to run up and ask the professor what she wants for dinner. She tells you she would like cous cous. When you tell Dexter he says that she needs to order off the menu. Bring her the menu and she will order 50 chicken legs! When you give Dexter her order he will give you one last errand and that is to tell Jacques to take the bag of chicken legs out of the freezer to defrost. Now your radiator will be fixed and you are free to enjoy your vacation. Check your watch to see if you have time to meet Jacques in his office. If not you can either do some snooping around or go up to your room and set the alarm clock by your bed to a time when the ski rental office will be open. Once you relay the message to Jacques about the chicken legs, you will find an oil can next to your radiator and it will be fixed! On your way you can confront Lisa with what you learned about opening her locker by mistake. Ask her about her many identities. Talk to her about the SECRET GARDEN and TOWER ENTRANCE
After you have the oil can you can do more snooping. Set your alarm to 8pm. Take the elevator to the basement and climb out. You should hear noise that sounds like sawing. Nancy will mention something about a strange noise. Turn around and look down. Nancy will say something about a strange noise coming from down below and that there is something important down there.
To get into the Library the 1st time:
While you are down in the basement climb up the metal ladder against the wall. When you are near the top you will notice a grate that is falling off and an open vent. Swing across to the vent and crawl through it until you come to the grate leading into the library. Open it and jump down. As you start to go down the stairs you will hear the sound of someone coming. Quickly turn around and get back into the vents. Watch Dexter type in the code for the alarm and search the library. When he is gone you are safe to go back in the library.
Things to do in the Library:
Look in the desk and read An Atlas of the United States. Note the longitude of Wisconsin is 90 degrees West.
Notice the dust on the top of the desk? Use the paint brush on the dust and then use that on the alarm key pad to figure out the code. (3, * , 7, 2 ) Try it out! If it says approved you have it correct.
Find the globe and move the needle to the longitude you found in the atlas, then click on the top knob to open it. The paper inside has the clue for the compass puzzle found behind the plaque above the fireplace. (-15, 10, -5) Move the compass to each number and every time you move it click on the green top button. When you do this successfully you will hear a creaking, squeaky sound as the door to the secret room upstairs opens. Before you rush up there, take a look at some important books. One is the book on Marie Antoinette lying on the floor written by Professor Hotchkiss. The other book you MUST read is the one about Marie Antoinette's Famous Portrait that is on the small table to the RIGHT of the spiral stairs that lead up to the Secret Room and/or Vent shaft. This BOOK is what "triggers" the close up for the Purple Rose in the Portrait in the Tower.
Go up to the secret room, pick up the lighter and use it on the candle to get an ornate key. Read the letter next to the candle. Turn around and read the two books about Dexter, one good and one bad. You can now leave the library from the main doors without getting caught.
Now it is time to see where that noise is coming from beneath the elevator. Go to your room and set the alarm for 8 pm. Go back to the 1st floor Library. It is easy if you are using the elevators. Make sure the elevator is on the 1st floor and you have the oil can in your inventory. If you don't have the library key you will find it in a drawer on Dexter's desk. You will need that too! Open the door to the library and the alarm will go off. Quickly go forward two steps then turn and head to the alarm. Push the buttons 3, *, 7, 2 and the alarm will go off. Go up through the vent and climb down the ladder to the bottom of the elevator shaft. You will hear "strange sounds from below." Turn around and find the lever that is stuck. Use the oil can on the lever and open that grill. Go down the stairs and turn left toward a door with six sliding locks. The combination will change each time you want to open this door. Follow the hall around to the left where you hear the sawing noises. Confront Jacques,"don't you think I should be asking YOU that question?"
"What's your fiancée…."
"What kind of document?"
"A secret compartment?"
"What happened to the medallion?"
"So, how do you know all of this?"
"What did he think the journal contained that was so important?
"But how do you think the medallion fits in?"
"I don't know, Jacques….."
"Well as long as you tell Christi…."
Jacques gives you the code to his locker…. 2-6-6-5
Turn and get the sword tip from tin soldier. Go up the stairs, through the passage. Go back to the Basement and open Jacques locker. Look at the letter from his fiance', read the Diamond Chart and the Immigration letter, get the BLUE MEDALLION. BONK! Answer the phone in your room.
"I don't know what really happened."
"It was the last thing I saw..."
"I am afraid I am serious..."
Listen to your voice mail. Set your alarm for 8am. Go downstairs to talk with Dexter. Be truthful with him about the dirt on your shoes. Ask about the garden and the place his father used to go to think. He will tell you there is a key in the shed.
On your way out to the shed if you meet up with Lisa don't reveal too much. Be careful about giving her too much information. Go through the locker room to get outside. It is very cold and you are starting to freeze. When you enter the shed go down the stairs and then turn to your left and go toward the work benches. The key you are looking for is on the peg board near the screwdrivers. There is also a newspaper clipping and instructions for the ski lift machine. Do this quickly and then leave and go back to the castle. To find the Secret Garden leave from the locker room again, take 3 steps forward and then click on the NO Trespassing sign. Go forward just to the left of that sign. Again you are getting cold so you must not take too long. Go to the vine covered wall and open the gate. Go forward and then left toward the sundial and a statue in the wall. Turn the sundial to the left to move the head of the statue. Go to the statue and pull the lever in back of the head. Take the box out and use the ornate key to open it. Take the RED MEDALLION. Quickly turn back and leave the garden before you freeze!
Talk to Lisa. She will tell you that she saw Dexter carrying some green ornament outside by the shed and that you should check it out. You don't see anything and when you try to get back in the castle you are locked out! Hurry over to the shed and start up the ski lift machine. Set the levers according to the diagram 3.0, 2.0, and 4.0. To start the ski lift click on the middle lever once and the right lever twice. Dexter will come out to see what is wrong and help you back inside.
If you can't get Lisa to tell you about Dexter carrying something green outside by the shed go up to your room and listen to your voice mail. Her message is the last one and it will say something about wanting to be friends and to see her because she has something to tell you.
When you are back safely, go to room 214 to talk with Professor Hotchkiss. She will give you a question to answer. If you need to find the answer look at the books in the lounge bookcase. Once you answer her question correctly she will tell you to meet her in the lounge between 3 and 5:59 am. If you don't know the answer to the question, knock on her door again and ask her to repeat the question. She will give you another one.
Go to your room and set the alarm for 3 am.
Meeting Professor Hotchkiss. Talk about her theory of Marie Antoinette. She will give you a copy of her room pass key and let you know that you can inspect her room while she is in the lounge from 3am to 5:59am.
You have plenty of time now so go up to her room and check it out. Read her notes next to the typewriter. Open her briefcase and read the letter. Move the pillow on the couch and get the BLUE MEDALLION. This time you don't get BONKED. Go over to the dresser and watch the video on her recorder. Place the battery pack on the recharger and come back the next night to watch the remainder of the video.
Go back to your room and set the alarm 8am. Go out to the shed and retrieve the GREEN MEDALLIONwhich is on the machine to the right of the ski lift machine. Don't let the rat bite you!
Return to your room, call your friends and listen to your voice mail. Set your alarm for 3am so you can visit Professor's room again and watch the 2nd half of the video. After viewing the last part of the video leave her room and turn right to the very end of the hall where you will find the circular room with the peep hole. Peep through that hole with each medallion and notice the location of the symbols. Red is to the left, Blue is to the right and Green is below and center.
Time to go to the ROYAL TOWER. Take the elevator to the first floor, enter the library, deactivate the alarm system, go up the stairs, through the vent and down the shaft to the room under the Basement. Solve the door puzzle yet again, and then use the Skeleton key on the rod iron gate, but not before you get the spear tip from the Tin Soldier.
To solve the Chain Puzzle, turn around and look at the plaques on the wall opposite the chains. The chains should be in that order. By pulling each chain, it not only activates movement of that particular chain, but also one other chain. It is not very difficult, really, but I managed to solve it by: clicking on 1, 2, 3, 5, 2, 4, and 1 (from left to right).
Once you have solved the Chain puzzle, you need to move across the stepping stones. Go left down the hallway and you will come to what looks like a chess board. The idea here is to move the 4 pieces around the board until each lands on top of their corresponding square. Place the blue one first, yellow next, then pink, and finally the white one. This opens the stairway all the way to the top of the tower. [saved game titled SR.Tower 1st time] Go up the tower and open the door, walk forward several steps and click on the GOLD LEAF puzzle on the wall. You can turn each individual piece when you put your arrow cursor in the upper left corner and get a curved cursor. When you solve this puzzle you will be able to open the secret compartment.
Get the Journal. Look at Marie Antoinette's portrait. Look at the floor in the middle of the room. The medallions fit nicely but there is something missing in the middle.
Return to your room and set the alarm to meet Prof. Hotchkiss in the lounge. Ask her about the translations you saw through the peep holes. Give her the journal. She says she will wrestle you for it, but you say that is not necessary as long as you can have the translation. She agrees and says she will have it by this time tomorrow night. Time to relax a little and just set your alarm again for 3 am. Go down to the lounge and talk with her. She tells you that she translated the entire journal and as an extra bonus it includes Marie's official decoder. Go up to her room to read the translation which you will find to the right of the typewriter. Look at the decoder which is to the left of the typewriter. Time to get back to the tower!
Place the medallions with Red on left, Blue on right and Green at the bottom. Go to Marie's portrait and you should get a highlighted cursor on the purple rose.
If you come to the part where you should get a highlighted cursor and can't maybe you missed something. Here are a few common things missed:
Did you read the book about Marie Antoinette on the table near the spiral staircase in the library? Did you give Prof. Hotchkiss the diary you found in the tower and ask her to translate it. Did you later read the translation and also the coder page? The coder is to the left of the typewriter. When you look at the decoder Nancy will say, "Purple Rose holds diamond key of Queen!"
When you looked through the peep hole, did you look through with each of the medallions? Do you have the medallions in the proper order? Red left, blue right and green below.
Use the tip of the spear to chip away at the portrait and you will get a key. Place the key in the center of the medallions. The middle of the floor will open and a pedestal with the diamond will come up. The diamond thief will also appear and spray your eyes with pepper spray. [saved game: ENDING] As the thief tries to run down the stairs, quickly find the square stone button on the left side of the wall of the stair well and push it. You will trap the thief!
Ok, I have the alarm code for the library but it keeps going off because I didnt dust the keypad, I have the brush and everything but whenever I go into the secret room in the library to get dust she NEVER says its dusty, she just says Its so dark! Am I at the wrong desk? HELP ME GET DUST PLEASE! i'vee been stuck for over a week! Answers: 3
What is the meaning of Mary's message & how do you get the key?"Em" Answers: 1 |
558
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***NOTE: I am currently only accepting online math students at a rate of $35.00 per hour for summer and the 2015 fall semester.***
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LV | YMF BLOG
On March 4th, eight Las Vegas ASCE YMF members departed Las Vegas with the ultimate destination of touring the latest and largest seawater desalination facility in the Western Hemisphere. The Carlsbad Desalination plant cost $1 Billion to construct and ceremoniously began operations in December 2015. The plant has a current capacity of 56,000 acre-feet/year (50 million gallons/day) with the capability to expand in the future.
Upon arriving in Carlsbad, California, the Las Vegas YMF caravan rendezvoused with David Swallow, Director of Engineering at the Regional Transportation Commission of Southern Nevada, and Kristina Swallow, Las Vegas’s own 2017 ASCE President Elect official nominee. The group was soon joined by over twenty Southern California YMF members. Upon checking in with the security team at Poseidon Water and being provided with the essential Personal Protective Equipment, the large group of curious engineers was split up into two groups to allow for a more manageable tour.
The tour groups were shown around the facility and presented with a ton of important background information. Some of the sights that were shown included the intake/outfall structures and the massive network of nanofiltration and reverse osmosis filters. The one-hour tour finished in the most appropriate manner by having a taste test of the final product - pure H2O. There was something to be said standing a mere half mile from the Pacific Ocean and consuming crystal clear water – a true testament to human ingenuity and the determination to maintain sustainable development with consideration and respect for the greater environment.
Following the technical tour, the Las Vegas YMF group met with the Southern California YMF members over pizza and beverages at a local craft beer facility. At the social get-together, the mixed group of YMF members socialized and discussed the role of YMF through different perspectives. The social get-together was very enjoyable and resulted in new professional contacts and opened the door for a future visit from the Southern California YMF to Las Vegas.
The trip was an overall success! Following a relaxing day at the beach on Saturday, the group of eight Las Vegas YMF members headed home Sunday morning with new beach tans and dreams of a more sustainable desert southwest.
Who We Are
The Las Vegas Younger Member Forum (LV YMF) of the American Society of Civil Engineers (ASCE) promotes and enhances the civil engineering profession within the public community, by providing younger members and students with opportunities for professional and leadership development, networking, and community service in a social environment that allows "engineers" to express themselves. |
Q:
ImageProjectiveTransformV2 error in loading meta graph by import_meta_graph
I am trying to load meta graph of trained networks "name.ckpt-1.meta" using tf.train.import_meta_graph("./name.ckpt-1.meta")
but the following error appears:
Traceback (most recent call last):
File "/home/rapsodo/.local/lib/python3.6/site-packages/IPython/core/interactiveshell.py", line 3265, in run_code
exec(code_obj, self.user_global_ns, self.user_ns)
File "<ipython-input-7-634d5d15ac05>", line 1, in <module>
saver = tf.train.import_meta_graph(input_checkpoint + '.meta', clear_devices=False)
File "/home/rapsodo/workspace_mike3352/anaconda2/envs/mike_tfpy36/lib/python3.6/site-packages/tensorflow/python/training/saver.py", line 1960, in import_meta_graph
**kwargs)
File "/home/rapsodo/workspace_mike3352/anaconda2/envs/mike_tfpy36/lib/python3.6/site-packages/tensorflow/python/framework/meta_graph.py", line 744, in import_scoped_meta_graph
producer_op_list=producer_op_list)
File "/home/rapsodo/workspace_mike3352/anaconda2/envs/mike_tfpy36/lib/python3.6/site-packages/tensorflow/python/util/deprecation.py", line 432, in new_func
return func(*args, **kwargs)
File "/home/rapsodo/workspace_mike3352/anaconda2/envs/mike_tfpy36/lib/python3.6/site-packages/tensorflow/python/framework/importer.py", line 391, in import_graph_def
_RemoveDefaultAttrs(op_dict, producer_op_list, graph_def)
File "/home/rapsodo/workspace_mike3352/anaconda2/envs/mike_tfpy36/lib/python3.6/site-packages/tensorflow/python/framework/importer.py", line 158, in _RemoveDefaultAttrs
op_def = op_dict[node.op]
KeyError: 'ImageProjectiveTransformV2'
I did not understand the reason and did not saw same thing somewhere else, Im not sure because of the tensorflow version or something else.
A:
I found the solution; It is because of version mismatch. Newer version of tensorflow does not match with older versions in terms of saving graph etc.
If we saved checkpoints with older version, we should use proper version (same version is preferred) to load meta graph or frozen graph.
|
Q:
How to fix Angular 2 `Uncaught (in promise): TypeError: Cannot read property 'query' of null`?
I've been using the Heroes tutorial in the Angular 2 docs to experiment. However, I've come to a point that I don't understand what's happening with this error:
Uncaught (in promise): TypeError: Cannot read property 'query' of null in browser_adapter.ts:88.
The two pieces involved are the HeroDetailComponent and the HeroService.
import { Component, OnInit } from '@angular/core';
import { RouteParams } from '@angular/router-deprecated';
import { Hero, HeroService } from '../index';
@Component({
selector: 'my-hero-detail',
templateUrl: ...
styleUrls: [...]
})
export class HeroDetailComponent implements OnInit {
hero: Hero;
// TEMPORARY FIX:
_heroService = new HeroService(); // Avoids injection
// constructor(private _heroService: HeroService,
// private _routeParams: RouteParams) {}
constructor(private _routeParams: RouteParams) {}
ngOnInit() {
let id = +this._routeParams.get('id');
console.log(id);
}
}
When the I use this code, it works. But when I switch the constructors, and use the one with the HeroService injection, then I get the error I mentioned earlier.
@Injectable()
export class HeroService {
getHeroes() {
return HEROES;
}
getHero(id: number) {
return new Hero(1, 'Name', 'Power', 'AlterEgo');
}
}
While I was trying to figure out what's going on I removed all the promise-related code. However, I still get the same error. Everything is compiling fine, it's a runtime error. The HeroService and RouteParams are provided in a parent component.
Two questions:
How to solve this issue?
How to debug this kind of problems?
I'm inclined to think it's a bug in Angular 2, but I'm not sure how make sure that it's not an error on my part. Thanks in advance.
UPDATES:
I've added the the temporary fix code (which avoids injection and thus is not a solution to this question as I would like to have injection working properly).
This is a Plunker with an approximate version of the code I'm trying. I couldn't get it to run properly, but it may be helpful to diagnose the problem by looking into the code.
A:
I see the following problem: HeroComponent depends on HeroDetailsComponent, but HeroDetailsComponent is exported afterwards in the app/heroes/index.ts file.
Someone reported a problem with this kind of set up here
A:
In the "tsconfig.json" set "emitDecoratorMetadata" parameter of the "compilerOptions" section to the "true" value.
|
RECOMMENDED FOR FULL-TEXT PUBLICATION
Pursuant to Sixth Circuit I.O.P. 32.1(b)
File Name: 19a0149p.06
UNITED STATES COURT OF APPEALS
FOR THE SIXTH CIRCUIT
ERICKSON TRUCKING SERVICE, INC., ┐
Petitioner/Cross-Respondent, │
│
> Nos. 18-2283/2380
v. │
│
│
NATIONAL LABOR RELATIONS BOARD, │
Respondent/Cross-Petitioner. │
┘
On Petition for Review and Cross-Application for Enforcement
of an Order of the National Labor Relations Board;
No. 07-CA-178824.
Argued: June 25, 2019
Decided and Filed: July 10, 2019
Before: SUTTON, BUSH, and LARSEN, Circuit Judges.
_________________
COUNSEL
ARGUED: Matthew M. O’Rourke, MILLER JOHNSON, Grand Rapids, Michigan, for
Petitioner/Cross-Respondent. Ruth E. Burdick, NATIONAL LABOR RELATIONS BOARD,
Washington, D.C., for Respondent/Cross-Petitioner. ON BRIEF: Matthew M. O’Rourke, Keith
E. Eastland, MILLER JOHNSON, Grand Rapids, Michigan, for Petitioner/Cross-Respondent.
Ruth E. Burdick, David A. Seid, David Habenstreit, NATIONAL LABOR RELATIONS
BOARD, Washington, D.C., for Respondent/Cross-Petitioner.
_________________
OPINION
_________________
SUTTON, Circuit Judge. What’s down in the well, it’s said, comes up in the bucket.
The National Labor Relations Board concluded that Erickson Trucking Service, a unionized
Nos. 18-2283/2380 Erickson Trucking Serv., Inc. v. NLRB Page 2
crane-rental company in western Michigan, unlawfully fired several employees due to a labor
union’s activities on their behalf. We agree, most notably because that’s how the company
explained the matter to the discharged workers.
I.
Erickson Trucking Service, founded in the 1920s and headquartered in Grand Rapids,
Michigan, offers cranes for rent. It owns 36 cranes, with lift capacities ranging from 18 to 900
tons. The company sends cranes and crane operators to construction sites across the country,
renting its larger, more specialized cranes to projects as far away as Texas and Florida.
Erickson Trucking has used union labor since 1923. It employs 20 members of Local
324, International Union of Operating Engineers, to operate forklifts and cranes. The company
is the only unionized company of its kind in western Michigan. According to Steven Erickson,
the owner and sole officer since the 1980s, that reality leads to “additional costs that . . . other
contractors d[o] not have.” J.A. at 146. The company has been “struggling” with declining
demand for smaller cranes for a couple of decades, Erickson testified, partly because western
Michigan “is being taken over by the non-union sector.” J.A. at 116. Erickson wants to invest in
larger, specialized cranes with higher rental fees and wider demand.
The company’s strong relationship with Local 324 soured in 2015. For the first time, the
Local insisted on jurisdictional rigidity—that only members of the Local, not the company’s
other unions, perform crane-operator work. Then the Local’s new business representative,
Brandon Popps, requested a mid-term change in their contract. The change would increase
wages by 30 to 40%, corresponding to the rate recently negotiated by another area union. The
company is contractually bound to pay another union’s rates when operators work in its
jurisdiction, but Erickson refused Popps’ proposal to extend the higher rate to the Local’s
jurisdiction. In response, the Local threatened to stop referring union members for the
company’s regular temporary-labor needs.
One other thing happened in 2015. Operators began seeking Popps’ help with payroll
mix-ups rather than resolving them with Erickson. Wage issues are common at Erickson
Trucking due to its payroll’s complexity. Under the company’s contract with the Local, up to
Nos. 18-2283/2380 Erickson Trucking Serv., Inc. v. NLRB Page 3
seven agreements govern crane operators’ wages, varying with the location of the jobsite. Each
contains six to ten pay scales. Erickson did not take kindly to Popps’ sudden involvement in
frequent payroll adjustments. When he refused to discuss them with Popps in late 2015—and
told employees to “quit talking to Brandon because he’s going to get you in trouble”—the Local
filed its first-ever grievance and unfair labor practice charge against the company. J.A. at 89.
Erickson eventually agreed to allow workers to seek the Local’s help with wages, and
they settled the charge in late March 2016. Before that, however, Erickson accused the Local of
using “bully tactics” and interfering with payroll “as punishment for not signing a bogus
contract.” J.A. at 4048. “I would expect that our Union would be better served,” he wrote to its
leadership, “if the representatives were trying to convert non-union contractors instead of pissing
off the longstanding union contractor?” Id. Half of the company’s crane operators took payroll
issues to Popps in 2016.
In mid-2016 Erickson discovered that Popps was approaching the company’s customers
and encouraging them to hire through the Union’s referral process rather than contracting with
the company. Erickson cut off all contact with Popps.
From May to July of 2016, Erickson fired six members of the Local as they completed
projects—30% of the company’s operators. All six of them regularly operated a 40- or 60-ton
crane or performed lower-level operator work without an assigned crane. While temporary lay-
offs are common due to the seasonal nature of construction work, Erickson had never fired a
crane operator before 2016. Erickson told the fired workers about the lack of work for small
cranes and stated that he intended to sell all of his smallest cranes. The layoffs “could be
reversed,” he added, if the workers would “get the Union to back off.” J.A. at 79, 85. Erickson
put six small cranes on the market.
The Local filed an unfair labor practice charge, claiming that Erickson unlawfully
threatened employees based on the union’s advocacy, 29 U.S.C. § 158(a)(1), and unlawfully
discharged them for the same reason, id. § 158(a)(3). An administrative law judge agreed, as did
the National Labor Relations Board. The Board petitioned our court for enforcement of its order,
and Erickson petitioned for review, contesting only the unlawful discharge claim.
Nos. 18-2283/2380 Erickson Trucking Serv., Inc. v. NLRB Page 4
II.
The National Labor Relations Act bars employers from firing workers based on union
activity. 29 U.S.C. § 158(a)(3); Ctr. Constr. Co. v. NLRB, 482 F.3d 425, 435 (6th Cir. 2007). A
familiar burden-shifting framework applies to unlawful discharge claims. The Board’s General
Counsel must show that “animus, whether toward the union or an employee’s protected
conduct,” caused the discharge. NLRB v. Vemco, Inc., 989 F.2d 1468, 1476 (6th Cir. 1993); see
NLRB v. Transp. Mgmt. Corp., 462 U.S. 393, 404 (1983). Then the burden shifts to the
employer to show it would have discharged the employee regardless of animus. Vemco, 989
F.2d at 1482.
Did the General Counsel establish a threshold case? The General Counsel usually
makes its threshold case by establishing the employer’s knowledge of individual employees’
union activity. Airgas USA, LCC v. NLRB, 916 F.3d 555, 561 (6th Cir. 2019). In the alternative,
it may show that the employer fired employees to retaliate against the workforce as a whole or to
discourage union activity. Vemco, 989 F.2d at 1478; see Novato Healthcare Ctr. v. NLRB, 916
F.3d 1095, 1105 (D.C. Cir. 2019).
The ALJ concluded that the General Counsel made its threshold showing here. The
Board adopted that determination in full as well as all of the factual findings. Substantial
evidence supports its conclusion. See Ctr. Constr. Co., 482 F.3d at 433. Following an embattled
year with the Local’s new leadership, Erickson fired six union members in mid-2016. Erickson
felt cornered by a weak market and a newly aggressive Local, and, in his own words, fired the
operators to persuade the Local to be more reasonable. Each of the workers testified about
Erickson’s explanation, and the Board upheld the ALJ’s determination that their recollections
were more credible that Erickson’s. See Fluor Daniel, Inc. v. NLRB, 332 F.3d 961, 967 (6th Cir.
2003).
When Erickson fired Matthew Rowe in May, he explained that he was selling his smaller
cranes and work was “drying up,” and that he saw no reason to continue employing “unhappy
people.” J.A. at 68. When Erickson fired Keith Stephenson the same day, he said that “all this
union stuff” had “been in the works for a while” and there were “a lot of unhappy people around
Nos. 18-2283/2380 Erickson Trucking Serv., Inc. v. NLRB Page 5
here and [Stephenson] seemed unhappy.” J.A. at 90. When he fired Carlos Ocampo in July,
Erickson said he was discontinuing small cranes and that he had to “play by the union rules” and
“Brandon is relentless and no one seems to care about that.” J.A. at 63.
Another employee asked Erickson that summer if he would be the next to go. Erickson
said the 40-ton crane operators would be fired unless “this stuff stops with the Union” and he
would “keep letting guys go until I get to the guy I want unless this stuff stops.” J.A. at 84.
When Erickson fired Jason Baerman, Erin Baerman, and Nick Willer in mid-June, he explained
it this way: He was selling the small cranes because the Local was “making things difficult for
him to operate.” J.A. at 73. Erickson himself testified that Popps caused part of the slowdown in
business by “taking the work away from us.” J.A. at 154. The Baermans and Willer
remembered Erickson saying that the Local was “forcing” him to sell cranes and fire workers,
and that he would not “let the Union tell me how to run my business, so I’m going to sell these
[40- and 60-ton cranes] and let go of the guys that run them.” J.A. at 84. Erickson added “that
the new union contract they were trying to shove down his throat was going to get more people
let go; the contractors on this side of the state were not going to pay that, and that he was going
to make sure he got his contract.” J.A. at 74.
But Erickson offered a way out. “[Y]ou guys can make this stop,” he told the Baermans
and Willer. J.A. at 84. “Brandon and [the Local’s leadership] are costing you, your guys’ jobs.
I’ve tried talking to them. They won’t listen. But maybe if I get rid of you guys, you guys could
go talk to them and this could be reversed, and we can go back to doing business like we’ve done
around here for the last 40 years.” J.A. at 85.
The Board concluded that several of Erickson’s statements violated the National Labor
Relations Act’s prohibition on threatening employees with discharge due to union activity. 29
U.S.C. § 158(a)(1). The company does not appeal that conclusion. When paired with the reality
of the discharges, this finding makes it relatively straightforward to say that the General Counsel
permissibly made a threshold showing that the discharges were unlawful.
The company protests that the Baermans and Willer never engaged in union activity by
involving the Local, say, in a wage dispute. But the General Counsel need not show that each
Nos. 18-2283/2380 Erickson Trucking Serv., Inc. v. NLRB Page 6
discharged employee engaged in protected activity where the employer fired a group in order to
discourage union activity in the workforce generally. Vemco, 989 F.2d at 1478.
The company persists that this theory was not “fairly litigated” below and the ALJ
invoked it on his own. But the General Counsel’s complaint fairly alleged that Erickson fired all
six operators because they “assisted the [Local] and engaged in concerted activities,” and
because he wanted “to discourage employees from engaging in these activities.” J.A. at 3944.
The ALJ reasonably concluded that the company fired the operators “due not to any particular
union activity on their parts” but instead “to send a message to the Union.” J.A. at 16. The
parties assuredly litigated that theory before the Board, and substantial evidence supports the
Board’s conclusion.
Was Erickson Trucking’s justification pretextual? The company challenges the ALJ’s
conclusion that its explanation for the discharges—the greater profitability of large cranes, the
declining demand for small cranes, and the market-readiness of these operators’ cranes in
particular—was pretextual. We disagree. The conclusion was a reasonable one on this record.
The credited testimony of the discharged employees about Erickson’s contemporaneous
explanation undermines the company’s version of events. While Erickson told them that he had
decided to sell his smaller cranes and that business was slow, he also blamed Popps for “making
things difficult for him to operate,” and said he would not “let the Union tell me how to run my
business.” J.A. at 73, 84. Erickson told the employees to “be mad at the Union,” as “things
didn’t have to be this way” but it was “forcing” Erickson to fire people, and “trying to shove”
higher wage rates “down his throat” (in a year when his wage rates had already risen). J.A. at
74. Recall that Erickson Trucking is the only unionized crane-rental company in western
Michigan and that, according to Erickson’s own testimony, the small-crane market has been
“taken over” by non-union businesses that charge lower prices. Making matters harder to justify,
Erickson said that he would reverse his decision if the Local changed its ways. See Dayton
Newspapers, Inc. v. NLRB, 402 F.3d 651, 666 (6th Cir. 2005) (contrasting lawfully speeding up a
long-planned operational change due to union activity, with unlawfully “suddenly decid[ing] to
find a way to cut back . . . to spite the Union”). Complaints about diminished demand for small
Nos. 18-2283/2380 Erickson Trucking Serv., Inc. v. NLRB Page 7
cranes ring hollow against such candor—or at least insufficiently true to override the Board’s
decision.
We also must view this testimony against the backdrop of how the company does
business. It regularly sells aging cranes, perhaps one or two a year but sometimes as many as
nine at once. According to Erickson, he had been transitioning to larger cranes for over a decade
at the time of the discharges. Ten of the 20 cranes the company sold between 2005 and 2016
were small cranes. Yet until then he had never fired a crane operator. Not until a few months
after the Local sought a new contract, not until the Local became involved in payroll issues for
the first time, and not until the Local filed its first unfair labor practice charge did the company
fire a crane operator.
Even crediting Erickson’s testimony that he happened to decide in the spring of 2016 to
exit the small-crane market for unrelated reasons, the need to let go the operators does not
necessarily follow. Many larger cranes require a second operator, a lower-level position known
as an oiler, and two of the fired employees were oilers. The other four were certified to operate
larger cranes and, according to Erickson, simply needed more experience. The company’s
records also reveal a dramatic increase in temporary hires immediately after the discharges, often
for tasks the fired workers usually performed. In the light cast by this record, the ALJ
reasonably concluded that the company’s justification was pretextual.
In trying to fend off this conclusion, the company reiterates the economics of the crane
market and faults the ALJ’s application of the legal standard. In particular, the company claims
that the ALJ gave short shrift to its justification simply because the General Counsel showed
anti-union animus, improperly conflating consideration of the threshold case with the company’s
affirmative defense. But the ALJ properly dismissed the company’s justification as pretextual.
While he credited Erickson’s description of market trends and business goals as a general matter,
he carefully explained that he did not believe that was the reason these six employees were
discharged—in no small part due to what Erickson told the employees. The company ignores the
ALJ’s reasoning on that point. He found that Erickson had one motive, not two, for firing the
workers, and the one motive was anti-union animus. “[A]t that point, there is nothing left to
Nos. 18-2283/2380 Erickson Trucking Serv., Inc. v. NLRB Page 8
balance against the impermissible motive,” bringing matters to a close. Temp-Masters, Inc. v.
NLRB, 460 F.3d 684, 693 (6th Cir. 2006).
Was the Board’s remedy a permissible one? The Board ordered Erickson Trucking to
reinstate the employees and to compensate them for their interim expenses in searching for
work—remedies subject to considerable deference on appeal, Detroit Edison Co. v. NLRB, 440
U.S. 301, 316 (1979), and one of them (reinstatement) expressly authorized by statute, 29 U.S.C.
§ 160(c). The company claims that it has no work to offer the discharged employees. But that is
a more appropriate complaint for the Board’s compliance process than for this appeal. As to the
award of search-for-work expenses, the company disagrees with the Board’s calculation method
but offers no explanation why, merely citing a cautionary administrative memorandum that does
not bind the Board. The “rule of deference to the Board’s choice of remedy” is stricter than that.
Detroit Edison Co., 440 U.S. at 316.
We grant the Board’s petition for enforcement.
|
Bitter foods are usually good-for-you foods, which many people might find hard to swallow.
But Barb Stuckey would like people to give them a try.
After all, some bitter foods contain compounds that in small doses can stimulate you, fight colds and even help the battle against aging, said Stuckey, a food developer based in San Francisco and the author of Taste: Surprising Stories and Science About Why Food Tastes Good (Atria, $26).
“The taste of bitter is the taste of health,” she said, zeroing in on foods such as greens (think kale, radicchio, collards); coffee and tea; wine; and fruit (try citrus, pomegranates, cranberries, blueberries).
Of course, you have to be able to ingest the foods or beverages for them to have a positive effect.
“Most poisons taste bitter,” she explained. “So, if we have a choice, we will reject bitter foods. We are built to be suspicious.”
Humans sense bitterness from many things in order to avoid them at harmful levels, she added. Yet, served in the right amount, bitter foods can be both beneficial and even medicinal, Stuckey said.
Genetics play a role in whether a food tastes bitter or too bitter to you, but you can work to mitigate the bitterness, Stuckey said.
“When you scrunch up your face at bitterness, it’s likely that the bitterness is out of balance,” Stuckey writes in her book.
Hate Brussels sprouts? Balance the bitter flavor with a little salt, sugar, lemon juice or vinegar. Or mix in other vegetables, such as sweet potatoes, carrots or caramelized onions.
“The next time you make them, use fewer carrots and more sprouts,” Stuckey writes. “Eventually you’ll find yourself craving a bowlful — alone — specifically for the energizing, stimulating taste challenge that bitter provides.” |
Downtown Phoenix's ZapCon Expands to Include Retro Gaming Documentaries and a Performance By The Minibosses
ZapCon in leveling up. Organizers of the two-day classic arcade and pinball gaming event taking place next month in downtown Phoenix recently announced that they're expanding the scope of the event to include numerous game-related activities that don't involve mashing buttons.
According to Wes Cleveland, who's helping put on ZapCon along with fellow local old-school joystick-head Zack Johnson, attendees will be able to screen several documentaries devoted to retro gaming, as well as attend workshops and discussions covering repair, restoration, and maintenance of pinball machines.
Currently, plans are afoot to screen four different documentaries during ZapCon -- which goes down on Saturday, April 6, and Sunday, April 7, at the Renaissance Phoenix Hotel. The lineup includes High Score, a 2006 film by NYU grad Jeremy Mack concerning die-hard gamers who collect retro arcade games, and Tilt: The Battle to Save Pinball, about the lengthy history of said coin-operated machines, the "near-lost art of pinball design," and how its industry has vastly diminished into near-obscurity.
"[Pinball games], I would say, are not as rare as arcade games. They're still making them these days and there's only one major manufacturer making 'em, but there are a couple mom-and-pop shops out there are still putting them out," Cleveland says. "But as far as classic arcade-style [game] industry, that's done. You can't compete with the home console market, so there really isn't any incentive to make 'em like they used to."
Such subject matter is at the heart of Jeff Von Ward's 98-minute doc The Space Invaders: In Search of Lost Time, which covers the rise and fall of the arcade gaming world from a billion-dollar trade in the 1980s to a niche hobby populated by enthusiasts and collectors of quarter-munchers.
In other words, the same sort of folks that will be both attending ZapCon and bringing their games to the event.
We Recommend
I'd really like to see this event be part of the new Phoenix Music, Media, and Arts Festival which will always take place during the 11 days that end with Memorial Day each year. Comicon is in there, as well as nearly 100 other concerts and events.... would be a great draw! So, for 2014, that's May 16-26... start planning! |
Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2.
Inflammation under sterile conditions is not well understood despite its importance in trauma and autoimmune disease. To investigate this process we established mouse models of sterile injury and explored the role of hyaluronan in mediating inflammation following injury. The response of cultured monocytes to hyaluronan was different than the response to lipopolysaccharide (LPS) despite both being dependent on Toll-like receptor 4 (TLR4). Cultured cells exposed to hyaluronan showed a pattern of gene induction that mimics the response seen in mouse skin after sterile injury with an increase in molecules such as transforming growth factor-beta2 and matrix metalloproteinase-13. These factors were not induced by LPS despite the mutual dependence of both hyaluronan and LPS on TLR4. Explanation for the unique response to hyaluronan was provided by observations that a lack of TLR4 or CD44 in mice diminished the response to sterile injury, and together with MD-2, was required for responsiveness to hyaluronan in vitro. Thus, a unique complex of TLR4, MD-2, and CD44 recognizes hyaluronan. Immunoprecipitation experiments confirmed the physical association of TLR4 and CD44. Taken together, our results define a previously unknown mechanism for initiation of sterile inflammation that involves recognition of released hyaluronan fragments as an endogenous signal of tissue injury. |
Realtime KVM - signa11
http://lwn.net/Articles/656807/
======
smackfu
Kernel-Based Virtual Machine
If you were thinking of the other KVM.
|
---
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- Thu, 16 Jun 2016 16:33:30 GMT
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recorded_at: Thu, 16 Jun 2016 16:33:30 GMT
recorded_with: VCR 3.0.1
|
commit 0550486542f4c4628abf9e5cf1090c8f328f215f
Author: Dave Stevenson <[email protected]>
Date: Thu Mar 22 16:01:35 2018 +0000
v4l2_buffers: Add handling for NV21 and YUV420P
diff --git a/libavcodec/v4l2_buffers.c b/libavcodec/v4l2_buffers.c
index aef911f..0f4dbb2 100644
--- a/libavcodec/v4l2_buffers.c
+++ b/libavcodec/v4l2_buffers.c
@@ -321,11 +321,21 @@ int ff_v4l2_buffer_buf_to_avframe(AVFrame *frame, V4L2Buffer *avbuf)
/* 1.1 fixup special cases */
switch (avbuf->context->av_pix_fmt) {
case AV_PIX_FMT_NV12:
+ case AV_PIX_FMT_NV21:
if (avbuf->num_planes > 1)
break;
frame->linesize[1] = avbuf->plane_info[0].bytesperline;
frame->data[1] = frame->buf[0]->data + avbuf->plane_info[0].bytesperline * avbuf->context->format.fmt.pix_mp.height;
break;
+ case AV_PIX_FMT_YUV420P:
+ /* No YV12? support? */
+ if (avbuf->num_planes > 1)
+ break;
+ frame->linesize[1] = avbuf->plane_info[0].bytesperline >> 1;
+ frame->linesize[2] = avbuf->plane_info[0].bytesperline >> 1;
+ frame->data[1] = frame->buf[0]->data + avbuf->plane_info[0].bytesperline * avbuf->context->format.fmt.pix_mp.height;
+ frame->data[2] = frame->data[1] + ((avbuf->plane_info[0].bytesperline * avbuf->context->format.fmt.pix_mp.height) >> 2);
+ break;
default:
break;
}
@@ -468,6 +478,7 @@ int ff_v4l2_buffer_enqueue(V4L2Buffer* avbuf)
avbuf->buf.flags = avbuf->flags;
+ av_log(NULL, AV_LOG_ERROR, "ff_v4l2_buffer_enqueue: VIDIOC_QBUF : fd %d, index %u type %u\n", buf_to_m2mctx(avbuf)->fd, avbuf->buf.index, avbuf->buf.type);
ret = ioctl(buf_to_m2mctx(avbuf)->fd, VIDIOC_QBUF, &avbuf->buf);
if (ret < 0)
return AVERROR(errno);
|
Q:
Deferred deep linking in android
How can we get deferred deep linking work when the android app is installed from any third party location other than Play Store, say GDrive or S3 bucket. How to pass intent data in this case? Thanks in advance.
A:
Simple as this sounds, it's actually a bit complicated to implement. You probably already know about the InstallReferrerReceiver, but that's obviously only for the Play Store.
You basically need to come up with some way to store data outside the app before it is downloaded, and then retrieve it inside the app after installation. Branch.io (full disclosure: I'm on the team) does this by using unique link IDs, to which we can attach a data dictionary. When a user opens that link prior to downloading, we tag their device ID and then redirect them to the specified URL (e.g., GDrive or S3). We match the device ID again after the app is launched the first time. This allows us to pass an unlimited amount of data with each link, since the data isn't actually stored in the link itself
|
Q:
IBM Worklight 6.1 - Data returned in callback (in WL.NativePage.show()) is undefined
I'm trying follow the example in this Worklight Tutorial, to send data back from the native page. However, when it returns from the native page, the argument (data) in the callback function (backFromNativePage(data)) is undefined. I'm new to working with Worklight, so perhaps I'm not doing this correctly? I was hoping someone could shed some light on what I might be doing wrong. Thanks!
Here's what some of my code looks like:
Login.java:
public class Login extends Activity {
@Override
protected void onCreate(Bundle savedInstanceState) {
super.onCreate(savedInstanceState);
LoginWebViewClient client = new LoginWebViewClient(this);
webView = (WebView) findViewById(R.id.login);
webView.getSettings().setJavaScriptEnabled(true);
webView.setWebViewClient(client);
webView.loadUrl(url);
}
public void setAppDataAndReturn(HashMap<String, String> dataList) {
Intent returnData = new Intent();
for (Map.Entry<String, String> item : dataList.entrySet()) {
returnData.putExtra(item.getKey(), item.getValue());
}
setResult(RESULT_OK, returnData);
finish();
}
}
LoginWebViewClient:
public class LoginWebViewClient extends WebViewClient {
private Login webAct;
private HashMap<String, String> dataList;
public LoginWebViewClient(Login webAct) {
this.webAct = webAct;
}
@Override
public void onPageFinished(WebView view, String url) {
this.dataList = getData(); //returns a HashMap
webAct.setAppDataAndReturn(dataList);
}
AppInit.js:
var backFromNativePage = function(data) {
WL.Logger.error("backFromNativeLoginPage: data= "+ data);
};
var showNativePage = function() {
WL.NativePage.show('com.app.Login', backFromNativePage, {param: 'some value'});
};
By the way, I'm using Worklight version 6.1.0.00-20131219-1900 and I'm testing on an Android 4.3 phone.
Any help would be much appreciated!
Edit:
Following the suggestion from @IdanAdar, this is how I changed it to get it to work:
AppInit.js:
var showNativePage = function() {
WL.NativePage.show('com.app.Login', function(data) {
WL.Logger.error("backFromNativeLoginPage: data= "+ data);
}, {param: 'some value'});
};
A:
Based on the discussion in the comments: Try defining the callback function as a function instead of a variable.
function backFromNativePage(data) {
...
}
|
The integrins are xcex1/xcex2 heterodimeric cell surface receptors involved in numerous cellular processes from cell adhesion to gene regulation. Hynes, R. O., Cell, 1992, 69:11-25; HEMLEr, M. E., Annu. Rev. Immunol., 1990, 8:365-368. Several integrins have been implicated in disease processes and have generated widespread interest as potential targets for drug discovery. Sharar, S. R. et al., Springer Semin. Immunopathol., 1995, 16:359-378. In the immune system integrins are involved in leukocyte trafficking, adhesion and infiltration during inflammatory processes. Makajima, H. et al., J. Exp. Med., 1994, 179:1145-1154. Differential expression of integrins regulates the adhesive properties of cells and different integrins are involved in different inflammatory responses. Butcher, E. C. et al., Science, 1996, 272:60-66. The alpha4 integrins (i.e. alpha4beta1 (xcex14xcex21) and alpha4beta7 (xcex14xcex27)) are expressed primarily on monocytes, lymphocytes, eosinophils, basophils, and macrophages but not on neutrophils. Elices, M. J. et al., Cell, 1990, 60:577-584. The primary ligands for xcex14 integrins are the endothelial surface proteins mucosal addressin cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM) with lower affinity. Makarem, R. et al., J. Biol. Chem., 1994, 269:4005-4011. The binding of the xcex14xcex27 or xcex14xcex21 to MAdCAM and/or VCAM expressed on high endothelial venules (HEVs) at sites of inflammation results in firm adhesion of the leukocyte to the endothelium followed by extravasation into the inflamed tissue. Chuluyan, H. E. et al., Springer Semin. Immunopathol., 1995, 16:391-404. Monoclonal antibodies directed against xcex14xcex21, xcex14xcex27, MAdCAM or VCAM have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Laberge, S. et al., Am. J. Respir. Crit. Care Med., 1995, 151:822-829), Rheumatoid arthritis (RA; Barbadillo, C. et al., Springer Semin. Immunopathol., 1995, 16:375-379), colitis (Viney et al, J. Immunol., 1996, 157: 2488-2497) and inflammatory bowel diseases (IBD; Podalski, D. K., N. Eng. J. Med., 1991, 325:928-937; Powrie, F. et al., Ther. Immunol., 1995, 2:115-123).
A need exists for non-protein small molecule compounds which inhibit the interaction between the xcex14xcex27 integrin and its ligands MAdCAM and/or VCAM. These compounds are useful for treatment of chronic inflammatory diseases such as arthritis, asthma, multiple sclerosis, Crone""s disease, ulcerative colitis, and Hepatitis C.
Accordingly, the present invention relates to new compounds of the formula I, II or III:
wherein
Z is H or lower alkyl;
A has the structure:
in which
B is cyanoalkyl, a carbocycle or a heterocycle optionally substituted with one or more R1 substituents;
q is 0-3;
R1, R2, R3, R4, R5 and R6 independently are hydrogen, alkyl, amino, alkylamino, dialkylamino, nitro, urea, cyano, thio, alkylthio, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfinyl, sulfonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkanoyl, alkanoylamino, cycloalkanoylamino, aryl, arylalkyl, halogen, or alkylphosphonyl, and R1, R2, R3, R4 and R5 are substituted with 0-3 substituents selected from the group consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl, nitro, oxo, cyano, carbocycyl, heterocyclyl, heteroaryl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkanoylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, aryl, aroyl, heterocyclylcarbonyl, halogen and lower alkylphosphonyl; or two of R1 to R5 together form a carbocycle or heterocyclic ring;
Y is H, alkoxy, alkoxyalkoxy, aryloxy, alkylaminoalkoxy, dialkylaminoalkoxy, alkylamino, arylamino, heterocyclyl or heteroarylalkyl, where each of the forgoing may be substituted or unsubstituted;
X1 is H, C(O)OR, C(O)NRaRb, C(O)R, or C(O)SR wherein R, Ra and Rb, individually, is hydrogen or alkyl, alkoxy, aryl, heterocyclyl, heteroaryl, substituted with 0-4 substituents selected from the group consisting of halogen, hydroxy, amino, carboxyl, nitro, cyano, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, aralkyl, aralkyloxy, aryloxycarbonyl, aralkyloxycarbonyl, alkylenedioxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, and alkoxy lower alkyl; wherein said heterocyclyl, heteroaryl, aryl, aroyl, aryloxy, aralkyl, aralkyloxy, aryloxycarbonyl and aralkyloxycarbonyl is optionally substituted with halogen, hydroxyl, amino, carboxyl, nitro, cyano, alkyl and alkoxy; and wherein Ra and Rb together with the nitrogen to which they are attached may form a heterocyclyl or heteroaryl group substituted with 0-5 substituents R or Rd; wherein Rd has the structure
wherein
Xxe2x80x2 is a divalent linker selected from the group consisting of C(O)NRa, C(O) or a bond;
X2 and X3 are each independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro, cyano, or substituted or unsubstituted alkyl, aryl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl; and wherein X1 and X2 or X3 may be bonded together to form a heterocylic or heteroaryl ring(s); or X3 and Z together form a heterobicyclic ring;
X1xe2x80x2, X2xe2x80x2, X3xe2x80x2 and X4xe2x80x2 are each independently hydrogen, halogen, hydroxy, amino, carboxyl, nitro, cyano, or substituted or unsubstituted alkyl, alkenyl, alkynyl, arylalkyl, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkyl carbonylamino, lower alkenyl carbonylamino, aryl carbonylamino, arylalkyl carbonylamino, lower alkoxy carbonylamino, lower alkylamino carbonylamino, arylamino carbonylamino, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl;
or a pharmaceutically acceptable salt thereof.
These compounds inhibit the binding of xcex14xcex27 or xcex14xcex27 to MAdCAM and/or VCAM. The invention also relates to methods of making such compounds, compositions and medicaments containing the compounds and to methods of inhibiting the binding of xcex14xcex27 or xcex14xcex21 to MAdCAM and/or VCAM and to treating diseases associated with this binding.
A. Definitions:
The term xe2x80x9calkylxe2x80x9d, used alone or as part of another term, for example alkylamino, alkylsulfonyl, alkylthio, etc., means a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon group, having the number of carbon atoms specified, or if no number is specified, having up to and including 12 carbon atoms. xe2x80x9cAlkylxe2x80x9d when used alone or as part of another term preferably means a saturated hydrocarbon chain, however also includes unsaturated hydrocarbon carbon chains such as xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. The terms xe2x80x9clower alkylxe2x80x9d xe2x80x9cC1-C6 alkylxe2x80x9d and xe2x80x9calkyl of 1 to 6 carbon atomsxe2x80x9d are synonymous and used interchangeably. Preferred xe2x80x9cC1-C6 alkylxe2x80x9d groups are methyl, ethyl, 1-propyl, isopropyl, 1-butyl or sec-butyl.
The term xe2x80x9csubstituted alkylxe2x80x9d or xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d where m and n are integers identifying the range of carbon atoms contained in the alkyl group, denotes the above alkyl groups that are substituted by one, two, three or four halogen, trifluoromethyl, hydroxy, unsubstituted and substituted C1-C7 alkoxy, protected hydroxy, amino (including alkyl and dialkyl amino), protected amino, unsubstituted and substituted C1-C7 acyloxy, unsubstituted and substituted C3-C7 heterocyclyl, unsubstituted and substituted phenoxy, nitro, carboxy, protected carboxy, unsubstituted and substituted carboalkoxy, unsubstituted and substituted acyl, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino, unsubstituted and substituted benzyloxy, unsubstituted and substituted C3-C6 carbocyclyl or C1-C4 alkoxy groups. The substituted alkyl groups may be substituted once (preferably), twice or three times with the same or with different substituents.
Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, carboxypropyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl and the like. The alkyl gropu may also be substituted with a carbocyclyl group. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, as well as the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexyl groups, etc. A preferred group of examples within the above group includes the substituted methyl group, e.g. a methyl group substituted by the same substituent as the xe2x80x9csubstituted Cn-Cm alkylxe2x80x9d group. Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (e.g. tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl and iodomethyl.
The term xe2x80x9calkoxyxe2x80x9d denotes groups having the number of carbon atoms specified such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. The term xe2x80x9csubstituted alkylxe2x80x9d means these alkoxy group substituted by the same substituents as the xe2x80x9csubstituted alkylxe2x80x9d group.
The term xe2x80x9cacyloxyxe2x80x9d denotes carboacyloxy groups having the specified number of carbon atoms such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, and the like. The term xe2x80x9csubstituted acyloxyxe2x80x9d means these acyloxy groups substituted by the same substituents as the xe2x80x9csubstituted alkylxe2x80x9d group.
The term xe2x80x9calkylcarbonylxe2x80x9d, xe2x80x9calkanoylxe2x80x9d and xe2x80x9cacylxe2x80x9d are used interchangeably herein encompass groups having the specified number of carbon atoms such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.
The term xe2x80x9calkylsulfonylxe2x80x9d denotes the groups xe2x80x94NHxe2x80x94SO2-alkyl, xe2x80x94SO2xe2x80x94N-alkyl, xe2x80x94Nxe2x80x94(SO2-alkyl)2 and xe2x80x94SO2xe2x80x94N(alkyl)2. Preferred alkylsulfonyl groups are xe2x80x94NHxe2x80x94SO2xe2x80x94Me, xe2x80x94NOxe2x80x94SO2xe2x80x94Et, xe2x80x94NHxe2x80x94SO2xe2x80x94Pr, xe2x80x94NHxe2x80x94SO2xe2x80x94iPr, xe2x80x94Nxe2x80x94(SO2xe2x80x94Me)2 and xe2x80x94Nxe2x80x94(SO2xe2x80x94Cu)2.
The term xe2x80x9caminoxe2x80x9d denotes primary (i.e. xe2x80x94NH2), secondary (i.e. xe2x80x94RNH) and tertiary (i.e. xe2x80x94NRR) amines. Preferred secondary and tertiary amines are alkylamine and dialkyl amines such as methylamine, ethylamine, proylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine and disopropylamine.
The terms xe2x80x9ccarbocyclylxe2x80x9d, xe2x80x9ccarbocyclicxe2x80x9d and xe2x80x9ccarbocycloxe2x80x9d alone and when used as a moiety in a complex group such as a carbocycloalkyl group, refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms. Preferred carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. The terms xe2x80x9csubstituted carbocyclylxe2x80x9d and xe2x80x9ccarbocycloxe2x80x9d means these groups substituted by the same substituents as the xe2x80x9csubstituted alkylxe2x80x9d group.
A xe2x80x9ccarbocycloalkylxe2x80x9d group is a carbocyclo group as defined above covalently bonded to an alkyl group as defined above.
The term xe2x80x9calkenylxe2x80x9d means a branched or unbranched hydrocarbon group having the number of carbon atoms designated containing one or more carbon-carbon double bonds, each double bond being independently cis, trans, or a nongeometric isomer. The term xe2x80x9csubstituted alkenylxe2x80x9d means these alkenyl groups substituted by the same substituents as the xe2x80x9csubstituted alkylxe2x80x9d group.
The term xe2x80x9calkynylxe2x80x9d means a branched or unbranched hydrocarbon group having the number of carbon atoms designated containing one or more carbon-carbon triple bonds. The term xe2x80x9csubstituted alkynylxe2x80x9d means these alkynyl groups substituted by the same substituents as the xe2x80x9csubstituted alkylxe2x80x9d group.
The terms xe2x80x9calkylthioxe2x80x9d and xe2x80x9cC1-C12 substituted alkylthioxe2x80x9d denote C1-C12 alkyl and C1-C12 substituted alkyl groups, respectively, attached to a sulfur which is in turn the point of attachment for the alkylthio or substituted alkylthio group to the group or substituent designated.
An xe2x80x9calkylenedioxyxe2x80x9d group is a xe2x80x94O-alkyl-Oxe2x80x94 group, where alkyl is as defined above. Preferred alkylenedioxy groups are methylenedioxy and ethylenedioxy.
The term xe2x80x9carylxe2x80x9d when used alone or as part of another term means a homocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms. Preferred aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang""s Handbook of Chemistry (Dean, J. A., ed) 13th ed. Table 7-2 [1985]).
The term xe2x80x9caroylxe2x80x9d means an aryl group bonded to a carbonyl, such as benzoyl, etc.
The term xe2x80x9csubstituted phenylxe2x80x9d or xe2x80x9csubstituted arylxe2x80x9d denotes a phenyl group or aryl group substituted with one, two, three, four or five, preferably 1-2, 1-3 or 1-4 substituents chosen from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (preferably C1-C6 alkyl), alkoxy (preferably C1-C6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, heterocyclyl, aryl, or other groups specified. One or methyne (CH) and/or methylene (CH2) groups in these substituents may in tern be substituted with a similar group as those denoted above. Examples of the term xe2x80x9csubstituted phenylxe2x80x9d includes but is not limited to a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4-carboxyphenyl, ; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl. Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Preferred substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenyl groups. Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents phenyl groups having an aryl, phenyl or heteroaryl group fused thereto. The fused ring may also be substituted with any, preferably 1, 2 or 3, of the substituents identified above for xe2x80x9csubstituted alkylxe2x80x9d groups.
The term xe2x80x9carylalkylxe2x80x9d means one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated including but not limited to; benzyl, napthylmethyl, phenethyl, benzhydryl (diphenylmethyl), trityl, and the like. A preferred arylalkyl group is the benzyl group.
The term xe2x80x9csubstituted arylalkylxe2x80x9d denotes an alkyl group, preferably a C1-C6alkyl group, substituted at any carbon with an aryl group, preferably a C6-C10aryl group, bonded to the alkyl group though any aryl ring position and substituted on the alkyl portion with one, two or three groups chosen from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, amino, protected amino, C1-C7acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, C1-C6alkylthio, N-(methylsulfonylamino) or C1-C4alkoxy. Optionally the aryl group may be substituted with one, two, three, four or five groups chosen from halogen, hydroxy, protected hydroxy, nitro, C1-C6alkyl, C1-C6alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, or an N-(methylsulfonylamino) group. As before, when either the C1-C6 alkyl portion or the aryl portion or both are disubstituted, the substituents can be the same or different. This group may also appear as the substituted aralkyl moiety of a substituted aralkoxy group.
Examples of the term xe2x80x9csubstituted aralkylxe2x80x9d and this group when it occurs in a xe2x80x9csubstituted aralkoxyxe2x80x9d group include groups such as 2-phenyl-1-chloroethyl, 1-phenyl-1-chloromethyl, 1-phenyl-1-bromomethyl, 2-(4-methoxyphenyl)ethyl, 2,6-dihydroxy-4-phenyl(n-hexyl), 5-cyano-3-methoxy-2-phenyl(n-phenyl), 3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl, 6-(4-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4-aminomethyl phenyl)-3-(aminomethyl)(n-phenyl), and the like.
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4xe2x80x2-dimethoxybenzhydryl, 2,2xe2x80x2,4,4xe2x80x2-tetramethoxybenzhydryl, alkyl such as t-butyl or t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject a carboxy-protected molecule to strong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic acid protecting groups are the allyl and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substitutents. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd ed., John Wiley and Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, Chapter 5. The term xe2x80x9cprotected carboxyxe2x80x9d refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d as used herein refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include tetrahydropyranyloxy, acetoxy, carbamoyloxy, trifluoro, chloro, carboxy, bromo and iodo groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd ed., John Wiley and Sons, Inc., New York, N.Y., 1991, chapters 2-3; E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981. The term xe2x80x9cprotected hydroxyxe2x80x9d refers to a hydroxy group substituted with one of the above hydroxy-protecting groups.
The term xe2x80x9camino-protecting groupxe2x80x9d as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd ed., John Wiley and Sons, Inc., New York, N.Y., 1991, chapter 7; E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981. The term xe2x80x9cprotected aminoxe2x80x9d refers to an amino group substituted with one of the above amino-protecting groups.
The term xe2x80x9cinhibitorxe2x80x9d means a compound which reduces or prevents the binding of an alpha4beta1 integrin to a VCAM-1 ligand or reduces or prevents the binding of an alpha4beta7 integrin to a MAdCAM-1 ligand or which reduces or prevents the initiation of a cellular response mediated by the ligand. An xe2x80x9ceffective amountxe2x80x9d is an amount is an amount sufficient to at least partially inhibit the binding and and may be an inhibitory amount.
The terms xe2x80x9cheterocyclic groupxe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, or xe2x80x9cheterocycloxe2x80x9d alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic saturated or non-aromatically unsaturated ring having the number of atoms designated, generally from 3 to about 10 ring atoms, where the ring atoms are carbon and 1,2,3 or 4 nitrogen, sulfur or oxygen atoms. Typically, a 5-membered ring has 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. Examples include morpholinyl, pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperidinyl, and 3,4,5,6-tetrahydropiperidinyl. A preferred group is the morphilinyl group.
A xe2x80x9cheterocycloalkylxe2x80x9d or a xe2x80x9cheterocycloalkenylxe2x80x9d group is a heterocyclo group as defined above covalently bonded to an alkyl or alkenyl group as defined above.
Unless otherwise specified, xe2x80x9cheteroarylxe2x80x9d alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteratoms selected from the group nitrogen, oxygen, and sulfur, and preferably at least one heteroatom is nitrogen (Lang""s Handbook of Chemistry, supra). Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. Heteroaryls in which nitrogen or oxygen is the heteroatom are preferred.
The following ring systems are example of the heteroaryl (whether substituted or unsubstituted) groups denoted by the term xe2x80x9cheteroarylxe2x80x9d: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.
Heterocyclic 5-membered ring systems containing a sulfur or oxygen atom and one to three nitrogen atoms are also suitable for use in the instant invention. Examples of such preferred groups include thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. A group of further preferred examples of 5-membered ring systems with 2 to 4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl; triazolyl, preferably 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, preferably 1H-tetrazol-5-yl. A preferred group of examples of benzo-fused derivatives are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
Further suitable specific examples of the above heterocylic ring systems are 6-membered ring systems containing one to three nitrogen atoms and optionally a sulfur or oxygen atom. Such examples include pyridyl, such as pyrid-2-yl, pyrid-2-yl, and pyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl, preferably 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are a preferred group. The substituents for the optionally substituted heterocyclic ring systems, and further examples of the 5- and 6-membered ring systems discussed above can be found in W. Druckheimer et al., U.S. Pat. No. 4,278,793.
A particularly preferred group of xe2x80x9cheteroarylxe2x80x9d include; 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl sodiums salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl, 2-methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl sodium salt, 2-methyl-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetrazolo[1,5-b]-pyridazin-6-yl.
An alternative group of xe2x80x9cheteroarylxe2x80x9d includes; 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-dimethylamino)eth-2-yl-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl sodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl, and 8-aminotetrazolo[1,5-b]pyridazin-6-yl.
The term xe2x80x9clowerxe2x80x9d when used with a term such as alkyl to form xe2x80x9clower alkylxe2x80x9d, for example, means containing from 1 to 6 carbon atoms.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d include both acid and base addition salts. xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
xe2x80x9cPharmaceutically acceptable base addition saltsxe2x80x9d include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
The term xe2x80x9cprodrugxe2x80x9d as used herein means a derivative of a parent drug molecule that enhances pharmaceutically desirable characteristics or properties (e.g. transport, bioavailability, pharmacodynamics, etc.) and that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active parent drug.
The following definitions are used herein:
DIPC: diisopropylcarbodiimide
DMAP: dimethylaminopyridine
FMOC: fluorenylmethoxycarbonyl
DMA: dimethylacetamide
HBTU: 2-(H-benzotriazole)-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate
HOBT: N-hydroxy benzotriazole
TFA: trifluoracetic acid
HPLC: high pressure liquid chromatography
NMM: N-methylmorpholine
DIPEA: diisopropyethylamine
DCM: dichloromethane
THF: tetrahydrofuran
NMP: N-methylpyrolidone
CDI: carbonyldiimidazole
B. PREFERRED EMBODIMENTS
The compounds of the invention have the general structures I, II and III shown below.
where A, Z, Y, X1, X2, X3 and X4 are as defined above, both generally and preferably.
The compounds of the invention contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diasteriomers, enantiomers or mixtures thereof. The syntheses described above may employ racemates, diasteriomers or enantiomers as starting materials or as intermediates. Diasteriomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enatiomeric mixtures may be separated using the same techniques or other known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention. Compounds having the S configuration are preferred.
In one preferred embodiment, X1 in structure I is C(O)OR, C(O)R, or C(O)SR, more preferably C(O)NRaRb, with the remaining variables A, Z, Y, X2, X3 and X4 having any of the definitions given above. The X1 group is preferably in the para position relative to the point of ring attachment, but may also be preferably in the meta position. Ra and Rb together with the nitrogen to which they are attached may preferably form a 5-membered or 6-membered heterocyclyl or heteroaryl group substituted with 0-5 substituents R. The heterocyclyl or heteroaryl ring system will preferably contain one nitrogen atom, but may also preferably contain another nitrogen or an oxygen atom in the ring system. The hetero ring systems may contain fused heterocyclyl or heteroaryl rings or a combination of both and the rings may be substituted or unsubstituted. Representative examples of suitable specific heterocyclyl and heteroaryl groups are:
In a particular embodiment, X1 is any one of the groups shown in table 2 below which is designated as substituent R when combined with the carbonyl from which it depends.
R, Ra and Rb may also be non-cyclic, for example an hydrogen or alkyl, aryl, heterocyclyl, heteroaryl, substituted with 0-4 substituents selected from the group consisting of halogen, hydroxy, amino, carboxyl, nitro, cyano, heterocylyl, heteroaryl, aryl, aroyl, aryloxy, alkylenedioxy, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, lower alkylphosphonyl, aminosulfonyl lower alkyl, hydroxy lower alkyl, alkylsulfinyl lower alkyl, alkylsulfonyl lower alkyl, alkylthio lower alkyl, heteroarylthio lower alkyl, heteroaryloxy lower alkyl, heteroarylamino lower alkyl, halo lower alkyl, alkoxy lower alkyl; optionally substituted as described above. Preferred groups are substituted and unsubstituted lower alkyl, lower alkenyl, aryl, and aryl lower alkyl. Some representative examples of such R, Ra and Rb groups are shown below:
In a particular embodiment, A has the structure:
in which
B is cyanoalkyl, a carbocycle or a heterocycle optionally substituted with one or more R1 substituents;
q is 0-3;
R1, R2, R3, R4, R5 and R6 independently are hydrogen, alkyl, amino, alkylamino, dialkylamino, nitro, urea, cyano, thio, alkylthio, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylamino, aryloxycarbonylamino, alkylsulfinyl, sulfonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkanoyl, alkanoylamino, cycloalkanoylamino, aryl, arylalkyl, halogen, or alkylphosphonyl, and R1, R2, R3, R4 and R5 are substituted with 0-3 substituents selected from the group consisting of hydroxy, carboxyl, lower alkoxycarbonyl, lower alkyl, nitro, oxo, cyano, carbocyclyl, heterocyclyl, heteroaryl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkanoylamino, lower alkylsulfinyl, lower sulfonyl, lower alkylsulfonyl, lower alkanoyl, aryl, aroyl, heterocyclylcarbonyl, halogen and lower alkylphosphonyl; or two of R1 or R5 together form a carbocycle or heterocyclic ring. In a preferred embodiment, A is the group
where preferably R1, R5 or both R1 and R5 are not hydrogen. That is, preferred A groups are ortho-substituted benzoyl groups. Particularly preferred ortho substituents are chloro, bromo, amino and hydroxy. In addition to R1 and/or R5, the phenyl ring of the benzoyl may preferably have one or two additional substituents at R2, R3 or R4. Preferred R1, R2, R3 R4, and R5 include nitro, halogen (Cl, Br, F, I), amino, aryl, lower alkyl, lower alkylthio, lower alkoxy, lower alkylamino, lower alkyl sulfinyl, lower alkylsulfonyl, lower alkanoyl, and lower alkylphosphonyl, which may each be substituted or unsubstituted. Some representative example include:
In a particular embodiment, A is any one of the groups shown in table 2 which is designated as substituent Rxe2x80x2.
Y is preferably OH or an ester or pharmaceutically acceptable carboxylic acid salt thereof. Preferred esters are substituted or unsubstituted alkyl, alkenyl, aryl, and aryl alkyl esters.
Z is preferably hydrogen.
Preferred X2, X3 and X4 include halogen, alkyl, amino, alkylamino, and alkyl carbonylamino, the alkyl group of which may be substituted or unsubstituted. For compounds having structure I, X2 and X3 are more preferably hydrogen. For compounds having structure II, X2, X3 and X4 are more preferably hydrogen.
In another embodiment, preferred compounds have structure I, the S configuration, the OX1 group is in the 4-position on the phenyl ring, Z is hydrogen, X1 is C(O)NRaRb, and Y is OH or a salt or prodrug thereof.
In another embodiment, preferred compounds have structure I, the S configuration, the OX1 group is in the 4-position on the phenyl ring, Z is hydrogen, X1 is C(O)NRaRb, Y is OH, and R3, R5, X2, and X3 are all hydrogen or a salt or prodrug thereof.
In another embodiment, preferred compounds have structure I, the S configuration, the OX1 group is in the 4-position on the phenyl ring, Z is hydrogen, X1 is C(O)NRaRb, Y is OH, Ra and Rb together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5-membered or 6-membered heterocyclic or heteroaromatic ring; R3, R5, X2, and X3 are all hydrogen, or a salt or prodrug thereof.
In another embodiment, preferred compounds have structure I, the S configuration, the OX1 group is in the 4-position on the phenyl ring, Z is hydrogen, X1 is C(O)NRaRb, Y is OH, Ra and Rb together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5-membered or 6-membered heterocyclic ring containing up to 2 additional nitrogen atoms, oxygen atoms or a combination thereof; R2, R3 R4, R5, X2, and X3 are all hydrogen, or a salt or prodrug thereof.
In another embodiment, preferred compounds have structure I, the S configuration, the OX1 group is in the 4-position on the phenyl ring, Z is hydrogen, X1 is C(O)NRaRb, Y is OH, Ra and Rb together with the nitrogen atom to which they are attached form an unsubstituted 5-membered or 6-membered heterocyclic ring or such a ring substituted with 1-3 lower alkoxy, lower alkylamino, lower alkyl, lower alkoxycarbonyl, lower alkylenedioxy, lower alkylthio, lower alkenyl, lower cyanoalkyl, phenyl, phenoxy or halo groups; R2, R3 R4, R5, X2, and X3 are all hydrogen, or a salt or prodrug thereof.
In another embodiment, preferred compounds have structure I, the S configuration, the OX1 group is in the 4-position on the phenyl ring, Z is hydrogen, X1 is C(O)NRaRb, Y is OH Ra and Rb, are independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocylyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl; R3, R5, X2, and X3 are all hydrogen, or a salt or prodrug thereof.
In another embodiment, preferred compounds have structure I, the S configuration, the OX1 group is in the 4-position on the phenyl ring, Z is hydrogen, X1 is C(O)NRaRb, Y is OH, Ra and Rb, are independently, substituted or unsubstituted alkyl, aryl, arylalkyl, heterocylyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl; R2, R3, R4, R5, X2, and X3 are all hydrogen, or a salt or prodrug thereof.
C. USES
The compounds of the invention inhibit the binding of alpha4beta1 and alpha4beta7 on lymphocytes, eosinophiles, basophiles and monocytes to a cell expressing VCAM-1 and/or MAdCAM on the cell surface. The inhibitory compounds of the invention are useful to prevent the interaction of an epithelial cell bearing VCAM-1 and/or MAdCAM on the cell surface with a leukocyte cell bearing alpha4beta1 and/or alpha4beta7 on the surface by contacting the epithelial cell or the leukocyte with an inhibitory amount of the compound of the invention. The compounds are useful in assays to determine the inhibitory effect of a compound which antagonizes the binding of alpha4beta1 and/or alpha4beta7 integrin to VCAM-1 ligand and/or MAdCAM ligand. The inhibitory compound may be a small molecule, a protein or peptide or an antibody. In an in vitro assay, the ligand or the integrin may be directly or indirectly bound to a surface, such as microtiter plate, using known methods described for example in WO 9820110, WO 9413312, WO 9624673, WO 9806248, WO 9936393, and WO 9910312. The other member of the binding pair, e.g. the integrin or the ligand, respectively, (or a cell expressing the same on its surface) is then added to the surface bound member and the inhibitory effect of a test molecule is determined. The inhibitory activity of the compounds of the invention can also be determined with this type of assay.
The binding of the integrins to their respective ligands is known to be involved in inflammatory conditions associated with leukocyte infiltration of tissues lined with epithelial cells expressing VCAM-1 or MAdCAM. Such tissues include the gastrointestinal tract, skin, urinary tract, respiratory airways and joint synovial tissues. The compounds of the invention are useful in treating diseases in which such binding is implicated as a cause of the disease or symptoms of the disease. Undesired disease symptoms may arise from cell adhesin and/or cell activation which releases proinflammatory mediators, typically when there is an increase or upregulation in the expression of VCAM-1 and/or MAdCAM on the surface of endothelial cells. Various disease states which can be treated and for which the inflammatory symptoms can be reduced upon administration of the compounds of the invention include rheumatoid arthritis, asthma, psoriasis, multiple sclerosis, inflammatory bowel disease including ulcerative colitis, pouchitis and Chron""s disease, Celiac disease, nontropical Sprue, graft-versus-host pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, pericholangitis, chronic sinusitis, chronic bronchitis, pneumonitis, collagen disease, eczema, and systemic lupus erythematosis. The compounds of the invention are useful in treating these diseases and conditions by inhibiting the integrin/ligand binding.
The compounds of the invention can be assayed for ability to block the alpha4beta7/MAdCAM-1 or alpha4beta1/VCAM-1 binding interaction by addition of serial dilutions of the samples to plates with the receptors as follows. 96-well plates are coated with mouse anti-human alpha4 (31470D, PharMingen, San Diego, Calif.) The plates are decanted and blocked with 0.5% BSA. After washing alpha4beta7 or alpha4beta1 is added, followed by incubation for 2 h at room temperature. The plates are washed and samples of the small molecule antagonist are added to the plates with MAdCAM-1-Ig-HRP or VCAM-1-Ig-HRP for 2 h at room temperature. After an additional wash, the bound MAdCAM-1Ig-HRP or VCAM-1-Ig HRP is detected by addition of tetramethylbenzidine (TMB, Kirkegaard and Perry, Gaithersberg, Md.), followed by detection of the absorbance of the product.
Alternatively, the compounds can be assayed using any known protein-protein or cell-based assay method, such as those described, for example, in WO 99/10312 (examples 179-180) and WO 99/36393 (RPMI-CS-1 cell adhesion assay); Cardarelli et al., 1994, J. Biol. Chem, 269:18668-18673; and Viney et al., J. Immunol., 1996, 157:2488-2497 (cell adhesion assay).
For example, 96-well ELISA plates are coated overnight at 4xc2x0 C. with 2 xcexcg/ml with anti-human CD49d, (31470D, PharMingen, San Diego, Calif.) in phosphate buffered saline. The plates are decanted and blocked with assay buffer (50 mM Tris-HC1, pH 7.5, 150 mM NaCl, 1 mM MnCl2, 0.05% Tween-20 and 0.5% BSA) at room temperature for one hour, with gentle shaking. The plates are washed three times (in 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM MnCl2, 0.05% Tween-20) and 2 xcexcg/ml of the desired integrin (Genentech, Inc.) in assay buffer is added, followed by incubation at room temperature for two hours, with gentle shaking. After washing three times, 50 xcexcl of samples of the small molecule antagonists (serial dilutions from 10 mM stocks in 100% DMSO) are added to the plates with 50 xcexcl of 1 xcexcg/ml MAdCAM-1-Ig-HRP or VCAM-1-Ig-HRP (Genetech, Inc) in assay buffer. The plates are incubated two hours at room temperature, with gentle shaking, followed by washing six times. The bound MAdCAM-1-Ig-HRP or VCAM-1-Ig-HRP is detected by addition of the peroxidase substrate, 3, 3xe2x80x2, 5, 5xe2x80x2, tetramethylbenzidine (TMB, Kirkegaard and Perry, Gaithersberg, Md.), for 10 minutes, followed by addition of 1M phosphoric acid to stop the reaction. The absorbance of the solutions are read at 450 nm on a plate reader.
Suitable animal models exist for many diseases and conditions which can be treated with the compounds of the invention. Additional confirmation of the efficacy of these compounds in specific diseases and at desired doses can be assayed using these established models. For example animal models of chronic inflammatory diseases such as asthma (Laberge, S. et al., Am. J. Respir. Crit. Care Med., 1995, 151:822-829.), rheumatoid arthritis (RA; Barbadillo, C. et al., Springer Semin. Immunopathol., 1995, 16:375-379), colitis (Viney et al, J. Immunol., 1996, 157: 24488-2497) and inflammatory bowel diseases (IBD; Podalski, D. K., N. Eng. J. Med., 1991, 325:928-937; Powrie, F. et al., Ther. Immunol., 1995, 2:115-123) may be used to demonstrate the activity of the compounds of the invention and to conduct dose and efficacy studies.
The invention also includes pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. Typically, the inhibitors used in the method of this invention are formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment.
The inhibitory compound for use herein is preferably sterile. The compound ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.
The composition of the invention will be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The xe2x80x9ceffective amountxe2x80x9d of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the alpha4 mediated disorder. Such amount is preferably below the amount that is toxic to the host or renders the host significantly more susceptible to severe infection.
As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered parentally per dose will be in the range of about 0.01-100 mg/kg, preferably about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. Oral unit dosage forms, such as tablets and capsules, preferably contain from about 25 to about 1000 mg of the compound of the invention.
The compound of the invention may be administered by any suitable means, including oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local immunosuppressive treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
An example of a suitable oral dosage form is a tablet containing 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, if the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution is typically filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.
D. METHODS OF MAKING
Synthesis of Acyltyrosine Compounds (I)
I. Solid phase synthesis:
The compounds of invention are prepared from tyrosine and tyrosine derivatives using known chemical reactions and according to the method shown below.
In this method, the amino group of tyrosine or a derivative thereof is reacted with an acyl halide of the formula ZC(O)Hal, where Hal is a halogen, preferably Cl or Br, or an acyl anhydride of the formula ZC(O)OC(O)Z to acylate the amino nitrogen atom. Typically, the reaction conditions are dilute base in a suitable solvent, for example bicarbonate in water/THF. Other suitable mild bases and solvents/solvent mixtures will be readily apparent to those having ordinary skill in organic synthesis. Numerous starting tyrosine derivatives are commercially available or can be readily synthesized using standard chemical reactions. An example of the synthesis of a compound within the scope of the invention is shown below.
In this scheme, R may be any suitable group which is non-reactive under the reaction conditions. Examples of suitable R groups include substituted and unsubstituted alkyl, alkenyl, aryl, arylalkyl, etc. Additional compounds of the invention can then be prepared by acylating the phenyl hydroxy group with an activated carbonyl followed by the formation of a carbamate, carbonate or thiocarbamate as described below.
Solid phase reaction chemistry provides a convenient method for synthesizing the compounds of the invention. FMOCxe2x80x94or BOCxe2x80x94 protected amino acids and derivatives thereof are readily available and can be used as starting materials in the synthesis of the compounds of the invention. The protected amino acid is initially attached to a synthetic resin having an available coupling group, such as an available hydroxy (e.g. benzyloxy resin beads). Coupling is achieved using known chemical reactions, e.g. condensation reactions using for example DIPC or DMAP, to attach the amino acid to the solid support. Any known coupling reactions and resin surfaces may be used. The amino nitrogen is then deprotected using, for example, a weak base such as piperidine or other suitable base. The free amino group can then be reacted with an activated ester such a HBTU or HOBT ester of a suitable benzoic acid to form the desired A group. The resulting hydroxy compounds are within the scope of the invention.
Additional compounds can be prepared by further reacting the hydroxy group to form esters, carbamates, carbonates, etc. using known chemistry. For example, the hydroxy compounds can be reacted with a carbonyl synthon such as phosgene, carbonyldiimidazole or p-nitrophenylformate followed by a primary or secondary amine, including cyclic amines, to form carbamates as shown in the reaction scheme below.
In this scheme, a=DIPC cat./DMAP; b=20% piperidine/DMA or DMF; c=a substituted benzoid acid/HBTU or other amide coupling agent/TEA or other weak base; d=primary or secondary amine; e=TFA/triethylsilane, for example.
Compounds of structure I were typically synthesized manually via solid phase synthesis on p-alkoxybenzyl alcohol resin (Advanced Chemtech, USA) as shown above. Commercially available FMOC protected tyrosine or other tyrosine analogs (X2/X3) were purchased from BACHEM Calif., Advanced ChemTech U.S.A., or Calbiochem Corp. (Calif.). Typically 1 mmol of FMOC-tyrosine (or tyrosine analog) was added to 1 g of p-alkoxybenzylalcohol resin in 50 mL dichloromethane. Diisopropylcarbodiimde (DIPC, 1 mmol) was added followed by catalytic dimethylaminopyridine (DMAP, 0.1 mmol) and the resulting mixture was stirred under nitrogen at 20C. for 4 hours. The resin was then washed with dicloromethane and dimethylacetamide (DMA) and the FMOC group was removed via mixing with 20% piperidine in DMA for fifteen minutes. The resin was then washed three times with DMA to remove excess piperidine.
Ortho-Chlorobenzoic acid (2 mmol) or other substituted benzoic acid was mixed with HBTU (2 mmol) or other suitable activating agent in 20 mL of DMA and added the previously washed resin. N-methylmorpholine or triethylamine (4 mmol) was added and the mixture was sparged with nitrogen for 30 minutes. The resin was washed with dichloromethane and treated with 2 mmol of p-nitrophenylchloroformate (phosgene or carbonyldiimidazole can also be used) and 0.05 mmol DMAP in 20 mL of DMA for 1 h. Excess reagents were washed away and 2 mmol of morpholine or other substituted amine RaRb-NH in 20 mL dichloromethane was added. The mixture was sparged overnight at room temperature and washed with dichlormethane.
Treatment with RFA containing 5% triethylsilane for 1 hour afforded the crude product. The crude material was extracted from the resin by stirring with 100 mL of 2:1 H2O/CH3CN for 5 minutes followed by filtration to remove the resin. The crude filtrate was lyophilized and purified by preparative reverse phase C18 HPLC (CH3CN/H2O gradient, 0.1% TFA) to afford purified material. Pure fractions ( greater than 98% pure by analytical HPLC) were characterized by electrospray ionization mass spectrometry (Sciex API100) and proton NMR, lyophilized to dryness and resuspended in DMSO at 10 mM just prior to biological assay. Serial dilutions of peptide starting at 0.5 mM were tritrated into an ELISA format assay and the IC50 for each compound was determined.
II. Solution phase synthesis:
Alternatively, inhibitors with general structure I can be synthesized in three steps via solution phase chemistry starting with commercially available (L)-tyrosine or tyrosine analogs having substituents at X2/X3 and/or Y. A general synthesis of type I Analogs is depicted below. This type of synthesis is amenable to scale up and for introducing ester prodrugs.
Typically, 100 mmols of (L)-tyrosine or similar tyrosine analog is dissolved in 500 mL THF/H20 (1:1) and 300 mmols of sodium bicarbonate is added followed by 110 mmols (1.1 eq.) of a suitable benzoyl chloride or anhydride of general structure Z-COCI. The solution is stirred at room temperature for 1 h. The mixture is concentrated via rotary evaporation and acidified to pH less than 3 with 1 N HCL. The acidified solution is extracted with ethyl acetate and the organic layer is washed with satd. NaCl and evaporated to dryness. Crystallization of the crude material from ethylacetate/hexane affords pure compound as determined by analytical HPLC (average yield; 75 mmol or 75%).
If a suitable benzoyl chloride or anhydride is not available then the corresponding substituted benzoic acid (100 mmols) is used in combination with HBTU or other amide coupling reagent. If this route is employed, 100 mmols of (L)-tyrosine or similar tyrosine analog is dissolved in 250 Ml of dimethylformamide. In a separate vessel, the appropriate benzoic acid (110 mmols) in DMF is mixed with 110 mmols of HBTU or other amide coupling agent and 300 mmols of triethylamine or other weak base (NMM, DIPEA etc.). The mixture is allowed to stand for 10 minutes and then added to the tyrosine in one portion. After stirring for 1 hour at room temperature, the reaction mixture is concentrated under high vacuum and resuspended in ethyl acetate. The suspension is washed with 1 N HCL, water and satd. NaCl and evaporated to dryness. Crystallization affords pure compound (average yield; 66 mmol or 66%).
Purified 2 (50 mmols) is dissolved in 400 mL of THF and 100 mmols of TEA (or other base) is added followed by 50 mmol of p-nitrophenylchloroformate (phosgene or carbonyldiimidazole can also be used). The reaction is stirred for 1 hour at room temp, filtered and the filtrate is concentrated to dryness to afford crude compound which can be isolated via crystallization form ethyacetate/hexane or used directly in the next step. If phosgene or CDI is used instead of p-nitrophenylchloroformate then isolation at this stage is not an option and an appropriate amine RaRb-NH is added to the above reaction 30 minutes after the addition of p-nitrophenylchloroformate.
The p-nitrophenylcarbonate (10 mmol is dissolved in 100 ml to THF, 15 mmol of an appropriate amine RaRb-NH is added, and the reaction is stirred overnight at room temp. The solvent is evaporated and the resulting residue is tritrated with hexane to remove by products. Crystallization affords the desired O-carbamoyl-N-acyltyrosine inhibitor.
Synthesis of Biphenylalanine Compounds (II).
The biphenyl compounds of structure II can be synthesized starting from substituted or unsubstituted halo phenylalanine compounds as shown below. The protected amino acid starting material can be coupled to a resin as described above or using any known resin/coupling reaction system known in the art. The biphenyl ring system can then be prepared by reacting the halo amino acid with a substituted or unsubstituted phenyl boronic acid. If desired, a substituent on one of the phenyl rings may then be further elaborated using known chemical reactions. For example, a substituent containing a nitrogen atom can be further modified to provide amides, carbamates, etc. A substituent having a hydroxy or carboxy group can be converted to an ester, carbonate, etc.
A representative synthetic procedure for preparing the compounds of the invention is set forth below and refers to the scheme shown above.
Halo-N-FMOC-Phe 1 (10 mmol) is suspended in 80 mL of DMC along with Wang resin (8 mmol) in a peptide synthesis flask with bubbling N2 gas providing agitation. DIPC is added to a 0.25 M concentration followed by DMAP (1 mmol) and the reaction bubbled for 16 h. After washing the resin (3xc3x9780 mL with alternating DMF, methanol, and DCM) the resin is treated with 80 mL of 25% piperidine in NMP for 1 h followed by another wash cycle. A solution of 0.25M 2-Chlorobenzoic acid, HOBT, HBTU, and DIPEA in NMP is stirred for 0.5 h prior to addition to the resin 2. The reaction bubbled for 16 h and is washed as before. 100 mg portions of the resin can then be transferred to reaction vessels on the Argonaut Quest 210 parallel synthesis instrument and suspended with 0.25M boronic acid and DIPEA in 3 mL of degassed NMP that contained Pd(PPH3)2Cl2 catalyst. The reactions were stirred magnetically and heated to 80 degrees C. for 16 h. The resin 3 was washed (3xc3x975 mL with alternating DMF, methanol, and DCM). When in the previous step a formyl substituted boronic acid was used, the resin was swelled with 0.5M amine in 2 mL of 2% AcOH/NMP. After 1 h of stirring a 2 mL portion of 0.5M Na(OAc)3BH in NMP was added, followed by agitation for 16 h. After washing the resin 3 or 4 as before, 2 mL of TFA that contained 5% DCM and 2% triethylisilane was added followed by 1 h of agitation and filtration. The resin was washed with 1 mL of DCM and combined with the original filtrate. The reductive amination and TFA deblocking were also performed in polypropylene 48 well reaction blocks. The TFA was evaporated either by a vacuum centrifuge or via a stream of nitrogen gas to yield 20 mg of crude oil containing products 5 that were purified on HPLC and confirmed by Electrospray mass spectroscopy.
In cases where primary amines were used, compounds 4 can be further elaborated using standard methods to prepare sulfonamides 6, amides and carbamates 7, and disubstituted amines 8 as shown below.
The free alpha carboxylic acid may be converted to an ester or to an amide using reactions well known in the art. For example, a free carboxyl group can be reacted with a suitable alcohol in the presence of an acid to esterify the carboxyl group using well known reactions and reagents. Similarly, amides are formed by reacting the carboxylic acid with an amine with removal of the water produced by the condensation using known methods. A example of a reaction for esterification is shown below.
Also included in the scope of this invention are prodrugs of the compounds described above. Suitable prodrugs include known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the parent compound under physiologic conditions. A preferred class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (xe2x80x94COxe2x80x94W) group, an alkoxycarbonyl (xe2x80x94COxe2x80x94OW), an acyloxyalkyl-alkoxycarbonyl (xe2x80x94COxe2x80x94)xe2x80x94Wxe2x80x94Oxe2x80x94COxe2x80x94W) group where W is a monovalent or divalent group and as defined above or a group having the formula xe2x80x94C(O)xe2x80x94Oxe2x80x94CP1P2-haloalkyl, where P1 and P2 are the same or different and are H, lower alkyl, lower alkoxy, cyano, halo lower alkyl or aryl. Preferably the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention. These prodrug compounds are prepared reacting the compounds of the invention described above with an activated acyl compound to bond a nitrogen atom in the compound of the invention to the carbonyl of the activated acyl compound. Suitable activated carbonyl compounds contain a good leaving group bonded to the carbonyl carbon and include acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and defluorophenoxy acyl. The reactions are generally exothermic and are carried out in inert solvents at reduced temperatures such as xe2x88x9278 to about 50C. The reactions are usually also carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, triethylamine, etc. One manner of preparing prodrugs is described in U.S. Ser. No. 08/843,369 filed Apr. 15, 1997 the contents of which are incorporated herein by reference in their entirety. |
Lust or Must: Invitations
Engraved vs. Flat Printed Invitations
Engraving your wedding invitations gives your stationery a tactile, upscale air. But for the fraction of the price, you can select flat printed options that, with the help of new high-fidelity presses, have such vivid detail they have the luxe look of hand painting. |
Kymellian
The Kymellians are a fictional extraterrestrial race appearing in American comic books published by Marvel Comics. They were introduced in Power Pack #1 (August 1984) and were created by Louise Simonson and June Brigman.
Fictional biography
The Kymellians resemble anthropomorphic horses. Centuries ago, the Kymellians experimented with a formula to generate energy from anti-matter, but destroyed their home planet, Kymellia. Many Kymellians survived, and created a new home: a huge artificial world named Kymellia II.
Kymellians have the latent potential of superpowers. These include abilities they consider "lesser" such as teleportation and healing, and other, "major" ones. Mastering the major powers is very rare among them, and the Kymellians call those among them who succeed "Sorcerers".
A Kymellian named Aelfyre Whitemane (nicknamed "Whitey") and his "smartship" (a sentient starship, one of many used by Kymellians), called Friday after the character in Robinson Crusoe (after Aelfyre's interest in human literature), were studying Earth when a human scientist, Dr. James Power, was about to commit the same mistake that destroyed Kymellia. Whitey tries to ask his people for permission to interfere and save the Earth, but his message is intercepted by the Kymellians' enemies, the Zn'rx (anglicized "Snarks"), and they kidnap Dr. Power and his wife to gain the anti-matter formula. Whitey is mortally wounded in the process. Whitey rescues Power's four children, and grants them the powers he had mastered as a Kymellian Sorcerer: control over gravity and the abilities to fly, to change his molecular density, and to convert matter into energy. With this final act, Whitey perishes. The children use their new powers to save the world and their parents, and become the superhero group Power Pack.
Months later, Power Pack (with Kofi Whitemane and Franklin Richards) travel to Kymellia II, where they learn that most Kymellians thought poorly of Whitey's decision, and that their culture was under the influence of a ruthless Kymellian Technocrat. The Pack even had to fight the Kymellian champions, Force Four, a team of four Kymellian Sorcerers: Firemane, who had fire powers; Ghostmare, who could become intangible; Team Leader, who could invent anything, and Thunderhoof, who had super strength. (Force Four was a homage to the Fantastic Four, even having pig Latin versions of their real names.) The Pack defeated them, and then saved the Kymellians from the Snarks with Kofi's help. During these events, Ghostmare became The Matriarch, the Kymellians' spiritual leader, and established a new planet, Kymellia III. The Technocrat later tried to regain control of his race; but failed, and the Kymellians continue peacefully on Kymellia III.
The Inhumans and the Kree later form an alliance with the Kymellians and even perform the operation that would enable them to survive the Terrigen Mist. These Kymellians alongside the Badoons, the Centaurians, and the Dire Wraiths join with the Inhumans to form the Universal Inhumans. The Kymellians' procedure involves them consuming the nectar that blooms from the Antigen Tree (a mutagenic substance).
Known Kymellians
Aelfyre Whitemane -
Byrel Whitemane -
Fayrelyte Strongheart -
Force Four -
Kal Blackbane - A Kymellian Swordsman who is a member of the Universal Inhumans' Light Brigade. He operates under the alias of Midnight Blade.
Kareen - Wife to Yrik and mother to Kofi. She was murdered by a group of terrorists known as Bandersnatch.
Kofi Whitemane - Son of Kareen and Yrik Whitemane
Onomi Whitemane - The Queen of the Kymellians and member of the Universal Inhumans.
Techno-Healer -
Techno-Chief CZM-137 -
Techno-Master/Techno-Prime 6/Techtate -
Yrik Whitemane - A Kymellian diplomat and father to Kofi.
Z'oofrey Grasswind - A Kymellian waitress.
Other versions
Heroes Reborn/Counter-Earth
In the "Heroes Reborn" reality created by Franklin Richards as a haven for several of Earth's superheroes, a Kymellian ship crashed on that reality's Earth at some point, but its pilot died in the crash. Human scientists mined the ship for technology and the pilot's DNA for experimentation. In the latter case, Kymellian DNA was bonded to an unwilling teenage test subject who not only developed teleportation abilities (similar to Kofi's), but also gained the ability to assume a Kymellian form, all before escaping from his captors. The teen, born Elric Freeman, took the name Elric Whitemane in honor of his new Kymellian heritage (intimating that the unnamed Kymellian pilot was that reality's Aelfyre Whitemane), and combining his horse-like alternate form with his love of stories of the American Old West, assumed a cowboy-like costumed identity as Kid Colt to fight oppression on the rapidly deteriorating Earth counterpart. Currently, this Earth has been shifted into the "prime" Marvel reality (Earth-616) as the latest planet to be dubbed Counter-Earth, and Kid Colt is a member of that world's premiere team of young superheroes, the Young Allies.
References
External links
Kymellians at Marvel Wiki
Whitey (marveldirectory)
Force Four (marvel appendix) |
I'm raising dd mostly on my own because dp works. I cook. I clean. I do groceries and all the other household chores. Yet I am living for free?? All I want to do is cry. He makes good $$ and tells me that I shoulkd get a job on the weekends pumping gas or whatever else I can do to contribute to the family. I guess I'm not contributing?? What do I need? I guess I just needed to get that out. I feel belittled, frustrated, like I'm just a useless and weak woman. The only thing I've ever spent $ on is food and dd. Thanks for listening
Have you been staying home for long? I know that when I first started staying home my dh felt a lot of pressure being the only one making money. The total responsibility really freaked him out. Over the last 2 years we've had "the grass is greener" type conversations a few times. I think he has it easy because he goes to work with grown ups, eats out, stays in nice hotels and gets a full nights sleep. He thinks I have it easy because I don't have to do those things
Have you talked to him about how his attitude makes you feel? Has he ever had the total responsibility of taking care of your child while you were gone? Maybe he just has no idea what staying home entails. I always joke to my dh that I would be thrilled to give him a minute by minute list of what I do all day....it would make his head spin :LOL
I had a conversation with two SAH pals this morning about how frustrating it is to have people patronize our decision to stay home by assuming it's NOT work. Good luck working this out with your DP. I wish I had some words of wisdom to share, I just wanted you to know you have my empathy....
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I'm sorry-I know that is hurtful. Once and a while dh slips a little something out that is similar, and it really makes me feel badly too. I know that he doesn't really mean that/think it, but sometimes he just gets stressed and pissy when it's bill writing time, and we literally just make it...
I would definitely call him on it though-otherwise you will ocntinue to feel upset about it, and it isn't good to let it stew...trust me!
Lets see... You work from the time you get up until the time you go to bed. You are on 24 hours a day, 7 days a week. You don't get paid, there are no benefits, no vacation time or even a lunch break. And you do it all for the benefit of your family. You are an incredible person for making the decision to put your dd ahead of everything else. She will grow up secure and happy knowing that Mom is there for her!
I just got this today from a friend of mine (who doesn't even have children. so I thought it was funny that it was even on her radar):
A man came home from work and found his three children outside, still in their pyjamas, playing in the mud, with empty food boxes and wrappers strewn all around the front yard. The door of his wife's car was open, as was the front door to the house and there was no sign of the dog. Proceeding into the entry, he found an even bigger mess. A lamp had
been knocked over, and the throw rug was wadded against one wall. In the front room the TV was loudly blaring a cartoon channel, and the family room was strewn with toys and various items of clothing. In the kitchen, dishes filled the sink, breakfast food was spilled on the counter, the fridge door was open wide, dog food was spilled on the floor, a broken glass lay under the table, and a small pile of sand was
spread by the back door. He quickly headed up the stairs, stepping over toys and more piles of clothes, looking for his wife. He was worried she might be ill, or that something serious had happened. He was met with a small trickle of
water as it made its way out the bathroom door. As he peered inside he found wet towels, scummy soap and more toys strewn over the floor. Miles of toilet paper lay in a heap and toothpaste had been smeared over the mirror and walls. As he rushed to the bedroom, he found his wife still curled up in the bed in her pajamas, reading a novel. She looked up at him, smiled, and asked how his day went. He looked at her bewildered and asked, "What happened here today?"
She again smiled and answered, "You know every day when you come home from work and you ask me what in the world did I do today?"
"Yes," was his incredulous reply.
> She answered, "Well, today I didn't do it."
What is it with today's generation? 50 years ago it was unheard of for the wife and mother to work. It was an insult to the husband. Now, I know that inflation and low wages plays a large role but what happened to society believing and supporting single family incomes? I find so many men are resentful of their partners staying home, even though they know it's the best thing for their family. So many men are being raised to expect the women to do it all. I know a lot of men who feel that their wives should be earning and income and taking care of all the family and household responsibilities.
Raising children takes the work of both partners. Earning and income outside the home is no more important for the family than having a parent take care of that families needs. Sure if he didn't have a job then you would be up the creek, but if the laundry/shopping/cleaning/dinner making didn't get done you would be living in squallar.
Dh told me once I had it so easy : I was like what! when I did work,I still had to come home,do the housekeeping/childcare/billpaying/shopping
cooking dance.He NEVER has had to do that : the one time i was in the hospital for back surgery he farmed the kids out to friends and neighbors,the house looked like a bomb had hit.
I think he's the one who has it easy.When he comes home,meals are ready his house and children are clean and presentable ( never know who he's bringing home for dinner )bills are in the mail,the yards are tidy and weed free.Heck his clothes are freshly laundered and put away.Of course he can sleep in late on the weekends because he works!
No wonder I've threatened more than once to go live at the beach
And he wonders why I'm tired all the time I really do love him but GAWD THE MAN CAN BE SUCH AN IDIOT
I'd go out and get a part time job, then make his start doing 1/2 of everything around the house. I'm sure he'll be missing the good old days where he didn't have to do anything other than work real fast.
It was unusual for white, middle class wives and mothers to work outside the home 50 years ago. However, for most other women, working outside the home was the norm just as it is now.
Maybe that's where I'm going wrong? I grew up with grandparents who were middle class and so were all of their friends. Therefore I grew up with the stories about how my grandparents struggled through some hard times but that they made sure my grandma was able to SAH for my mom and her brother. They struggled through the war, the depression, through my grandmother's illness that had her bedridden for 2 years. For him it was an honor to support his family. He didn't have a fancy job and they were not wealthy. My grandfather has always been proud of the fact that his wife was a SAHM and was very proud of the decision I made to SAH with my kids. My grandfather never complained about doing housework or chores and he always commented on how important my Nana was to the family. My grandmother worked when my mom was older, but that was more for herself.
Now, my dad was the total opposite and he raised my brother to be the same. Our home was not a happy one. That's why it's so important to me to have my husband support and help with the kids and the house. It has taken dh a long time to realize that being a SAHM is a valued and important profession. I have a hard time dealing with him being gone so much because it's hard on all of us. In the earlier years of our marriage he acting as if I wasn't pulling my wieght, even though I ran a very full dayhome to help make ends meet. It was his decision to close the dayhome and his decision for me to SAHM (well both of ours, but mostly his). I have been offered jobs and when his company offered me a job it was 3 months before I heard about it because dh said "no, we need her at home". Whenever I talk about getting a job to help out he's very supportive but I think that's because he knows it would be too difficult on our family and I will realize that soon enough.
Sometimes he drives me crazy but he really does try. He puts the laundry away and does the dishes. Baths the kids and helps them with their homework. It's a little harder to get him to do things outside the house with the kids like PTA and soccer, but that's because he misses "his time". I am lucky and it takes me hearing about other husbands that belittle their wives value as a SAHM to realize how lucky I am.
Jasmyn's Mum ((hugs)) to you. I know how hard it is to do it all by yourself. When dh is gone I get totally burt out. I also know that if you do work to "support yourself" your workload will double and that's not fair. Perhaps you can sit down with him and let him know how his comment hurt you? Then ask him what he will contribute to the family and household chores if you were to get a job. I hope things work out for you.
It was unusual for white, middle class wives and mothers to work outside the home 50 years ago. However, for most other women, working outside the home was the norm just as it is now.
The good old days weren't. Try reading "The Way We Never Were: American Families and the Nostalgia Trap" by Stephanie Coontz to bust a few of those myths.
yea, I read somewhere that 40% of women in the 50s worked outside the home. My grandmothers didn't ever (they were white middleclass) my dh's grandmothers both did their entire life (working class).
More, sahms got a lot of disrespect even though it was then expected of middleclass wives to stay home. Read cartoons (like in teh New Yorker) and magazines from the period - suburaban wives are portayed as shopoholics who as gossip with other suburburban wives mothers all day - in other words men work to support women who don't work. So this dismissal of what sahm does is not new.
But that is beside the point. These stories break my heart. What these dhs are saying and doing is absolultely unacceptable. Think about your daughter and how you want her to be treated in her own future partnership. You are modeling what is acceptable. My dad was pretty disrespectful of my mom. I am watching my brother begin to be that same way towards his wife. He knows better, but these things are what we grew up with, and it is very hard to get away from it. This isn't just about what is right for YOU, it is about what is right for your children because they are watching what is going on and learning what is accpetable and what is not from what they see your dh do and say.
This is a man I'd walk out the door on next Saturday and spend the ENTIRE day away from home while DH is home alone with your child. Make sure you leave him a list of chores that need to be done: dishes, laundry, healthy meals for your DD and himself, etc. and go have a good time!! :LOL
secular classical-ish mama to an incredible 5 year old DS and an amazing 6 year old DD.
I use to be married to a guy like that for 10 yrs and the verbal belittling just kept escalating until I started seeing a councelor who told me I was being abused so I stopped taking his abuse he got mad divorced me and I found my self and found my smile again.Four years later I met Mr.Right he cooks cleans changes diapers and works fulltime and I stay home and take care of our 1 yr old and he always uplifts me plus we go to counceling once a week to make sure we are communicating well and Iam very happy and we now have another child on the way because he is such a Mr. mom I wanted to give him kids.If someone really loves and respects you they value you as a human being obviously someone has his ideals all out of order.You are a very valuable person dont forget it just because he has issues within himself.(You Go Girl!!!)
He makes good $$ and tells me that I shoulkd get a job on the weekends pumping gas or whatever else I can do to contribute to the family. I guess I'm not contributing??
:
It is a shame that he can not appreciate your contribution and be proud of himself for supporting the family . Does he spend any time alone with the babe? That would go a long way to show "what you do all day", lol. Childcare and homecare are major work, and, if he doesn't appreciate that, it is probably because he doesn't ever *do* that work!
Personally, I do have a part-time job (I teach 6 hours a week--two evenings when dh is home). I've found it to be helpful for all of us: a bit of extra $$ without dh working extra hours, a bit of "adult" time for me (makes me a better mama), a bit of "daddy and dd" time (makes dh a better dad, and a more appreciative husband! LOL!). So, I am not actually against the idea of getting a pt job. It can be win/win! But that is not really the point in your situation. Ironically, however, it might be a good solution--find a very pt job that you love, and leave dd with dh for that time. And make sure that he knows he has to keep up the housekeeping while you are gone! |
Chinese hospital ship starts medical services
KARACHI: Chinese hospital ship ‘Peace Ark’ has started its medical services to Pakistani patients. More than 800 patients have been treated by the medical teams of Chinese Navy hospital ship ‘Peace Ark’, in which around 500 were treated onboard and almost 300 on matters of surgical, orthopedic, dental and gynecology problems were reported at the medical camp established at PNS Shifa.
Chief of the Naval Staff Admiral Mohammad Asif Sandila also visited the ship along with other dignitaries. Upon his arrival onboard the Naval chief was received by the mission commander Shen Hao and the commanding officer of the ship. The Naval Chief visited different departments of the hospital and was also briefed on ‘Mission Harmony’.
Civil and Military dignitaries from Pakistan, diplomatic missions and Chinese dignitaries at Karachi also visited the ship. |
The governments set the price rates for water, and we respect and comply with all regulations, wherever we operate.
In British Columbia, we fully support the new Water Sustainability Act and have for many years been promoting groundwater management, including licensure for large groundwater users in B.C.
We are pleased the Act intends to take a science-based approach to monitoring and measuring groundwater resources, and will include mapping of provincial watersheds over time to better manage the water resources. In addition the Act requires licensed groundwater users to report water withdrawals annually—something Nestlé Waters Canada has been doing in B.C. since 2000. We will follow the new rates when they come into effect in 2016.
In Ontario, we currently pay $503.71 per million litres extracted. In 2014, we paid $1,027,450 in taxes in total to the County of Wellington/Township of Puslinch/Town of Erin and both school boards. We are the largest commercial taxpayer in Wellington County.
Still have a question? Please get in touch |
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#"${data.terraform_remote_state.ssm_parameter_store.lambda_bot_verification_token_arn}",
#"${data.terraform_remote_state.ssm_parameter_store.lambda_bot_verification_token_arn}/*"
"*"
]
}
statement {
sid = "1"
effect = "Allow"
actions = [
"logs:*"
]
resources = [
"*"
]
}
statement {
sid = "2"
effect = "Allow"
actions = [
"es:*"
]
resources = [
"${data.terraform_remote_state.elasticsearch.elasticsearch_domain_arn}/*"
]
}
}
resource "aws_iam_policy" "lambdabot_iam_policy" {
name = "${var.lambda_bot_name}_bot_policy"
policy = "${data.aws_iam_policy_document.lambdabot_iam_policy_doc.json}"
}
data "aws_iam_policy_document" "lambdabot_assume_role_policy_doc" {
statement {
effect = "Allow"
actions = [
"sts:AssumeRole"
]
principals = {
type = "Service"
identifiers = [
"lambda.amazonaws.com"
]
}
}
}
resource "aws_iam_role" "lambdabot_iam_role" {
name = "${var.lambda_bot_name}_iam_role"
assume_role_policy = "${data.aws_iam_policy_document.lambdabot_assume_role_policy_doc.json}"
}
resource "aws_iam_role_policy" "lambdabot_iam_role_policy" {
name = "${var.lambda_bot_name}_iam_role_policy"
policy = "${data.aws_iam_policy_document.lambdabot_iam_policy_doc.json}"
role = "${aws_iam_role.lambdabot_iam_role.id}"
}
data "archive_file" "lambdabot_zip" {
type = "zip"
output_path = "../../../intelbot/lambda.zip"
source_dir = "../../../intelbot"
}
resource "aws_lambda_function" "lambdabot" {
filename = "../../../intelbot/lambda.zip"
source_code_hash = "${base64sha256(file("../../../intelbot/lambda.zip"))}"
function_name = "${var.lambda_bot_name}"
handler = "lambda_function.handler"
role = "${aws_iam_role.lambdabot_iam_role.arn}"
environment {
variables {
"BOT_NAME" = "${var.lambda_bot_name}"
"ES_HOST" = "${data.terraform_remote_state.elasticsearch.elasticsearch_domain_endpoint}",
}
}
runtime = "python3.6"
timeout = 120
}
|
Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin.
Mitotic arrest-deficient 2 (MAD2) is one of the essential mitotic spindle checkpoint regulators, and it can protect cells from aberrant chromosome segregation. The Mad2 gene is very rarely mutated in many kinds of human cancer, but aberrantly reduced expression of MAD2 has been correlated with defective mitotic checkpoints in several human cancers. We have previously found that the MAD2 expression level is also shown to be associated with the multidrug resistance of tumour cells. In this study, we constructed a small interfering RNA (siRNA) eukaryotic expression vector of MAD2 and downregulated MAD2 expression in the gastric cancer cell line SGC7901 by transfection of MAD2-siRNA. SGC7901 cells stably transfected with the MAD2-siRNA exhibited significantly increased expression of phosphorylated survivin protein and enhanced drug resistance. Furthermore, MAD2-siRNA suppressed the proliferation of SGC7901 cells and inhibited tumour formation in athymic nude mice. This study clearly reveals that downregulation of MAD2 could regulate the cell cycle, increase proliferation, and improve the drug resistance of gastric cancer cells by regulating the activation of phosphorylated survivin. It also suggests both that MAD2 might play an important role in the development of human gastric cancer and that silencing the MAD2 gene may help to deal with the multidrug resistance of gastric cancer cells. |
At a public library, Wallace Wong proudly described his children-only ‘gender therapy’ practice, noting that his youngest client is not yet three and that he has 501 foster kids in his practice.
Last month, Justice Gregory Bowden of the Supreme Court of British Columbia, Canada ruled that a 14-year-old girl may begin receiving testosterone injections without parental consent. Bowden’s ruling, hailed as a “massive legal win” by the American LGBTQNation, ensured treatment would proceed without parental influence by declaring that if either of the girl’s parents refer to their daughter as a girl, they will be considered guilty of family violence under the Canadian Family Law Act.
In a text exchange with her father, Clark*, 14-year-old Maxine* indicated that she felt good about her injections and “will stay on it.” But Maxine’s father, alarmed by the negative physical consequences of cross-sex hormones on children and the dubious grounds on which his own daughter was persuaded to pursue them, is desperately seeking a reversal of Bowden’s decision in the BC Court of Appeal.
“[These injections] will completely disrupt her puberty,” he said. “Her bones will stop growing, her brain will stop developing… and she’s not gonna be a boy. She won’t even have the bone-strength left to be a girl anymore.”
“I will give up everything to try and save her…. I don’t think they understand how much a father can care about his daughter and fight for her,” he said. This means lawyers, affidavits, endless stalling from respondents, and the sometimes mind-boggling prospect of trying to convince judges that your physically healthy 14-year-old daughter should not be loaded up with puberty blockers and testosterone.
A month out from Bowden’s ruling, Clark is yet to get a definite date on which to make his case before the BC Court of Appeal.
Last Monday, however, new information surfaced that may favor Clark’s chances before the bench. Dr. Wallace Wong, the psychologist who labeled Maxine transgender, is facing calls for an inquiry into the conduct of his practice.
On February 28, the day after Bowden’s decision was released, Wong spoke at an event hosted by Vancouver Public Library. In a tape of the event obtained by Canadian pro-family group Culture Guard, Wong is heard proudly describing the scope of his children-only “gender therapy” practice, noting that his youngest client is not yet three years old and that he has 501 orphans and foster kids in his local practice.
If true, this indicates Wong has likely used his relationship with the BC Ministry of Children and Family to diagnose more than 10 to 20 percent of local children in government care as needing his “gender therapy,” according to Culture Guard President Kari Simpson.
In Wong’s own words, his practice began in 2010 with just “four clients at the ministry” but in the course of nine years, there was such an enormous surge of need within that population that he now has “more than 500 kids, [with] just the Ministry alone…. So we can imagine the demand of service is soaring…. The phenomenon is happening a lot faster than – than we expected.”
Simpson expressed outrage at this “soaring” demand, claiming Wong was “gender-jacking” vulnerable children from the Ministry and “profiting” handsomely into the bargain.
Wong also had some startling advice for a parent seeking to get a child referred to his program. Although the questioner had not indicated any particular urgency, Wong explained that parents should exaggerate the severity of their child’s condition to their local health offices.
Wong said a suicide threat was an effective means of accomplishing this goal. While Wong framed the matter as the government’s fault and explained to his audience that it is “up to us as advocates” to change the situation, his message could not have been lost on anyone present.
“So what you need is, you know what? Pull a stunt. Suicide, every time, [then] they will give you what you need,” Wong said, adding that gender-dysphoric kids “learn that. They learn it very fast.”
These words take on a particular significance for Maxine’s case, in which Bowden relied heavily on the opinion of Wong and his colleagues that “continued delay in hormone treatment” was placing Maxine “at risk of suicide.” In fact, Bowden references Wong as claiming that Maxine had already experienced a suicide attempt “linked to [her] gender dysphoria.”
Wong’s freewheeling comments the day after this decision was released may call into question the validity of his assessment, a favorable point for Clark’s case. But Wong was not the only doctor involved, and Bowden’s legal argument still rests crucially on the opinion of experts at BC Children’s Hospital that testosterone injections are “not a neutral option” for Maxine, but a safe and certain means of curing the “ongoing and unnecessary suffering” of her “gender dysphoria.”
Of course, such an opinion would be hotly contested among experts. Pediatric endocrinologist Dr. Quentin Van Meter of Atlanta, Georgia, told the court it was “sheer conjecture,” noting in an affidavit that while, in the short run, patients do experience “a post-treatment period of relative happiness,” available evidence indicates that for most people that happiness dissipates and is replaced, within a few years, with “life-long psychological trauma and increased suicide.”
Whether this opinion or the opinions of Wong’s colleagues at BC children’s hospital will prevail with the Court of Appeal remains a matter of conjecture. In the meantime, Maxine is taking testosterone regularly, and Clark feels that time is running against him.
“[I want] to save my daughter,” Clark stated. “I think a small window still exists to let that happen,” but a few more months of legal wrangling—a year, at most—and that window will have shut. A courtroom victory, then, even if it might benefit others from the standpoint of precedent, would be but cold comfort to a father’s heart.
*Clark and Maxine are not the real names of the father and daughter involved. Their identities have been concealed by court order. Court documents use the initials CD and AB, respectively, and media refers to Maxine as simply “Max.” |
1984–85 Kansas Jayhawks men's basketball team
The 1984–85 Kansas Jayhawks men's basketball team represented the University of Kansas during the 1984–85 NCAA Division I men's basketball season.
Roster
Ron Kellogg
Danny Manning
Calvin Thompson
Greg Dreiling
Cedric Hunter
Milt Newton
Mark Turgeon
Tad Boyle
Mark Pellock
Altonio Campbell
Chris Piper
Rodney Hull
Jeff Johnson
Don Kennedy
Jim Pelton
Schedule
References
Category:Kansas Jayhawks men's basketball seasons
Kansas
Kansas
Kansas Jay
Kansas Jay |
[Efficacy of gemcitabine combined with erlotinib in patients with advanced pancreatic cancer].
To evaluate the efficacy,clinical benefits and toxicities of gemcitabine combined with erlotinib for advanced pancreatic cancer. Clinical data of 20 patients with advanced pancreatic cancer treated with gemcitabine 1000 mg/m2 on day 1 and day 8 (repeated every 21 days) plus erlotinib 100-150 mg/d at Peking Union Medical College Hospital was reviewed retrospectively. No patient achieved complete remission or partial remission, 11 patients (55%) had stable disease, and 9 patients (45%) experienced disease progression. The disease control rate was 55%, and clinical benefit rate was 30%. The median progression free survival was 4.0 months, and the median overall survival was 8 months. The total incidence of hematologic toxicity was 70%, including 15% of grade 3-4 leucopenia and 5% of grade 3-4 thrombocytopenia. Eleven patients (55%) had rash, which were all grade 1-2. One patient had grade 2 diarrhea and five had grade 1 transaminase elevation. No chemotherapy-related death occurred. Gemcitabine combined with erlotinib is an effective regimen for pancreatic cancer with good clinical tolerance. The most common adverse events are hematologic toxicities and rash. |
Many different types of filter have been demonstrated. These include various types of absorption filtering, dielectric single or multilayer filtering, interferometric filtering (Fabry-Perot, Michelson, Mach-Zehnder, Sagnac etc) and grating filtering.
A conventional (prior art) Mach-Zehnder filter consists of a beam splitter (or coupler) which splits the input light into two paths and a beam combiner (or coupler) to combine the light again. If the two paths have different lengths, the Mach-Zehnder filter has a wavelength dependent transmission characteristic.
The split-beam Fourier filter (SBFF) described in this document is a special type of filter which can give the same characteristic transmission as a Mach-Zehnder filter as well as more complex characteristics by simply splitting the beam of a fibre beam expander with an appropriate transparent element or elements so that different parts of the beam travel different optical path lengths. This gives highly stable performance and is ideally suited to incorporation in a single mode fibre beam expander. |
Pulmonary Textures Classification via a Multi-Scale Attention Network.
Precise classification of pulmonary textures is crucial to develop a computer aided diagnosis (CAD) system of diffuse lung diseases (DLDs). Although deep learning techniques have been applied to this task, the classification performance is not satisfied for clinical requirements due to that commonly-used deep networks built by stacking convolutional blocks are not able to learn discriminative feature representation to distinguish complex pulmonary textures. For addressing this problem, we design a multi-scale attention network (MSAN) architecture comprised by several stacked residual attention modules followed by a multi-scale fusion module. Our deep network can not only exploit powerful information on different scales but also automatically select optimal features for more discriminative feature representation. Besides, we develop visualization techniques to make the proposed deep model transparent for humans. The proposed method is evaluated by using a large dataset. Experimental results show that our method has achieved the average classification accuracy of 94.78 and the average f-value of 0.9475 in the classification of 7 categories of pulmonary textures. Besides, visualization results intuitively explain the working behavior of the deep network. The proposed method has achieved the state-of-the-art performance to classify pulmonary textures on high resolution CT images. |
U.S. President Donald Trump prepares to board Marine One en route to his Mar-a-Lago estate in West Palm Beach, Florida following the release of the Mueller report at the White House in Washington, U.S., April 18, 2019. REUTERS/Carlos Barria
WASHINGTON (Reuters) - U.S. President Donald Trump will travel to Japan on May 25-28 for meetings with Japanese Prime Minister Shinzo, the White House said in a statement on Thursday.
The two leaders will discuss North Korea, “including efforts to achieve final, fully verified denuclearization,” the statement said.
“The two leaders will also explore ways to advance their shared vision of a free and open Indo-Pacific region, including steps that will strengthen our bilateral trade and investment relationship,” it said. |
Q:
Can I make the 'new' keyword optional with classes in CoffeeScript?
In JavaScript, there's a little trick you can use to make the new keyword optional:
function Frob(args) {
if (!(this instanceof Frob)) {
return new Frob(args);
}
// Normal initialization logic
}
This way, you can instantiate a Frob with or without the new keyword:
new Frob('foo'); // a Frob instance
Frob('bar'); // also a Frob instance
Is there a way to do this with the class keyword in CoffeeScript?
A:
Just define a constructor:
class Frob
constructor: (args) ->
return new Frob(args) unless this instanceof Frob
### Rest of your init code ###
Output:
var Frob;
Frob = (function() {
function Frob(args) {
if (!(this instanceof Frob)) {
return new Frob(args);
}
}
return Frob;
})();
|
FROM biocontainers/biocontainers:debian-stretch-backports
MAINTAINER biocontainers <[email protected]>
LABEL software="reprof" \
container="reprof" \
about.summary="protein secondary structure and accessibility predictor" \
about.home="http://rostlab.org/" \
software.version="1.0.1-4-deb" \
version="1" \
extra.identifiers.biotools="reprof" \
about.copyright="" \
about.license="GPL-3" \
about.license_file="/usr/share/doc/reprof/copyright" \
extra.binaries="/usr/bin/reprof" \
about.tags=""
ENV DEBIAN_FRONTEND noninteractive
RUN apt-get update && apt-get install -y reprof && apt-get clean && apt-get purge && rm -rf /var/lib/apt/lists/* /tmp/*
USER biodocker
|
In the highly personal video, the Raleigh native, 35, describes a childhood filled with domestic violence, poverty and a protective mother who shaped his life.
"I was 1 year old," says Aiken, standing in the doorway of a small home, "and my mother knocked on that door with only a diaper bag, the clothes on our back and me in her arms."
Aiken describes how he and his mother stayed with a friend on the living room floor in order to "escape from my father … a violent man who would get drunk and angry. I saw later, when I was older, pictures of her bruised face and blackened eyes in police photographs."
Aiken, whose mother distracted him with music, said it was those early experiences that made him want to become a special education teacher and a voice for the powerless, and now a member of Congress.
The singer-turned-politician hopes to bridge the political divide in Washington for the people of North Carolina.
"For most Americans, there are no golden tickets," Aiken says. "At least not like the kind you see on TV. More families are struggling today than at any time in our history. And here in North Carolina, we've suffered more than our share of pain."
Aiken is seeking the Democratic nomination to challenge Republican Rep. Renee Ellmers in North Carolina's highly Republican second congressional district located in the central and eastern parts of North Carolina. |
11/05/2009 (8:03 pm)
A major shooting spree occurred at Ft. Hood in Killeen, Tx today that may have stunning repercussions throughout the nation. Twelve people were killed, including the main shooter, and another 31 were injured.
The main shooter was Major Nidal Malik Hasan, an army psychiatrist at Walter Reed Army Medical Center for six years before his transfer to Ft. Hood in July. Major Hasan was apparently about to be deployed to either Iraq or Afghanistan. In addition to Major Hasan, who was killed, two men are in custody. Fort Hood remains locked down at this time; it looks like the police are trying to verify that all shooters have been cleared from the base.
In the video below, Fox News reports that Hasan was a convert to Islam. If true, and if the two other men in custody were connected with him, then this could be an embedded terror cell attacking a military base on US soil. The main shooter had two weapons, there may have been additional shooters, and the police are keeping the base locked down even though the main shooter is dead; it looks like the police suspect a coordinated, planned event.
Yes, the series actually has cut into the spare time, and sadly it did not end up the way I and a few million Phillies fans hoped it would. Yankees had an excellent team, so, that is the way things go. Only so much time for blogging, etc., and the Phils blog I follow ends up taking more time post season.
I tend to be a day or so late following this and a couple other blogs, and by the time I read the entry and decide a comment might be appropriate, the moment has really passed.
From what I am hearing, it sounds like the shooter survived. This means that after first rate medical care, years of legal wasted effort, he will be paroled to the Bahamas to live in luxury at the expense of the US taxpayer (if there are any left).
Izlam is fundamentally a political-religious organization that is out to conquer the world. It is completely at odds with our Western way of life, and we accept muzlims in our midst only as a matter of willful blindness. Most of us know some nice, peaceful muzlims that seem like they would not hurt a fly. But if they are muzlims, then they are subscribed to this organization that is our to overthrow our government, and we simply cannot have them in our midst. We must ban muzlims from America, every last one of them. We should give them the option to publiclly repudiate izlam or to leave. There should be no mosques, not izlamic organizations, etc. We once banned the communist party, and we can ban izlam in exactly the same way as a subversive organization out to overthrow the government.
If we continue to hug the snake to our breast, insisting that all religions are alike and that izlam is just another religion, we have no reason to be surprised with it bites us and we wake up dead.
Admittedly, I have not been all over this as I should, but I have not yet heard anything about the other people in custody. Don’t know if this has been ruled out yet, or if this is something they are investigating but keeping as quiet as possible.
One other thing that is a burr in my side is that this person obtained his education at the expense of the military, knowing full well what his side of the bargain would be. He was not a child sold into conscription in the Army.
After he has completed his education and becomes a doctor with specialized training, and a decision is made to deploy him (gee, how shocking, that wasn’t supposed to happen to ME), he decides he does not personally agree with that part of the compact and does not want to go (although there is some objective danger it’s not like he would be sleeping in a sand foxhole on the front lines with mortars zeroing in on him).
Instead of manning up and fulfilling his responsibility, which tens of millions of other American citizens do, he seethes inside, and this is the result.
Sorry if I don’t feel a lot of sympathy for his internal struggles and the fact that some of the other soldiers might be a little rough on him for his viewpoints. Although he is an officer, and I’m not quite sure how he would be subjected to constant harrassment, although I’m sure we’ll be hearing much, much more from the MSM about how Bush’s war and military made his life and that of many others a living hell. I see this whole thing slithering like a sidewinder, but inevitably, toward a politically correct template.
Getting a little irate as I write, need to go back to work.to decompress…
The media at the behest of the administration of the current resident in the White House have determined they can’t call this a “terrorist incident” because they have already said we aren’t at war with terrorism anymore. Sheesh. Need to get him out of there.
>>Instead of manning up and fulfilling his responsibility, which tens of millions of other American citizens do, he seethes inside, and this is the result.>>
The chances are that it would not have been a problem had we not been engaged in a war with muslims. Apparently, it’s ok for them to kill each other, and it’s ok to be in the military as long as the national army they’re in is not in conflict with other muslims, but if they’re in a non-islamic army in conflict with other muslims and are killed, then they die as kafir – infidels.
Interesting religion, islam. They do cover all the bases.
Convert or die. Sure sound like the Borg, don’t they!
Charles Gibson of ABC News was interviewing General George Casey Jr. and his wife on Friday about the shooting at Ft. Hood the day before. And I happened to have it on tape so the quotes here are accurate.
In the midst of the interview Gibson asked, “What have you learned about stress from this?”
Casey answered the question to talk about the stress the soldiers and first responders involved in the shooting were experiencing.
That wasn’t what Gibson wanted so he asked the question more pointedly: “Is your army, you have a relatively small number of troops, and they have an awful lot to do with two wars going on, are they over stressed in general?”
Casey answered but he shifted the key term. He made reference to the army being “over stretched” (instead of ‘over stressed’) and proceeded from there.
Gibson gave up and moved on.
I’m sure he would defend his questions by saying the public deserves to hear about the role of stress in the military. All the while maintaining radio silence when it comes to that ‘elephant’ of Nidal Malik Hasan’s Muslim faith as a possible, even probable, motivational force in the shooting. I was some proud of Casey for the expert way he handled the questions. And some disgusted with Gibson, both for what he asked and for what he refuses to ask.
There’s war; there’s terror; and then there’s the MSM reporters. Not sure which is the most frustrating to do battle with.
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o letters picked without replacement from jjxxjxjxxjxxjj.
7/13
What is prob of picking 3 a when three letters picked without replacement from {a: 5, q: 3}?
5/28
Two letters picked without replacement from ayaaaayaaaaaaaayaaai. What is prob of picking 2 a?
12/19
Calculate prob of picking 2 m when two letters picked without replacement from {s: 9, m: 11}.
11/38
Two letters picked without replacement from {g: 1, t: 2, i: 2}. Give prob of picking 1 i and 1 g.
1/5
Two letters picked without replacement from mzpzmmpsmzhpmmpzmmmz. Give prob of picking 2 m.
18/95
Four letters picked without replacement from {v: 1, w: 4, c: 1, a: 4, m: 1, j: 9}. Give prob of picking 1 m, 2 a, and 1 w.
8/1615
What is prob of picking 3 y when three letters picked without replacement from efeyeyyfe?
1/84
Calculate prob of picking 2 v and 2 l when four letters picked without replacement from llllvllkkvvvvl.
30/143
What is prob of picking 1 i, 2 b, and 1 c when four letters picked without replacement from {i: 3, c: 4, b: 2}?
2/21
Calculate prob of picking 2 x when two letters picked without replacement from xzwwxzznwxwwzhz.
1/35
Two letters picked without replacement from {w: 1, q: 8, p: 1, a: 6, h: 2}. Give prob of picking 1 a and 1 w.
2/51
Two letters picked without replacement from {w: 1, f: 2, m: 3, y: 6}. What is prob of picking 1 y and 1 f?
2/11
Four letters picked without replacement from {j: 8, o: 1, y: 1, a: 2, g: 7, q: 1}. What is prob of picking 1 y, 2 g, and 1 a?
14/1615
Four letters picked without replacement from wwwkwwwwwwwkwwwwwwww. What is prob of picking 2 k and 2 w?
3/95
Three letters picked without replacement from {n: 4, w: 5, y: 1}. What is prob of picking 2 n and 1 y?
1/20
What is prob of picking 1 z and 1 r when two letters picked without replacement from rrrzrrzr?
3/7
Calculate prob of picking 1 v and 1 r when two letters picked without replacement from {b: 3, v: 3, r: 1}.
1/7
Calculate prob of picking 1 q and 3 h when four letters picked without replacement from uuqbhhbqhquwqh.
16/1001
Calculate prob of picking 2 y when two letters picked without replacement from {h: 7, y: 6}.
5/26
Calculate prob of picking 1 s and 1 p when two letters picked without replacement from {m: 2, p: 1, v: 2, s: 1, r: 2, b: 1}.
1/36
What is prob of picking 2 z and 1 t when three letters picked without replacement from czczctczzz?
1/12
What is prob of picking 2 m and 1 s when three letters picked without replacement from smmmmmaasmmmss?
4/13
Calculate prob of picking 2 m when two letters picked without replacement from mpmppp.
1/15
Two letters picked without replacement from heeehyaeeaeaaeehey. What is prob of picking 1 h and 1 a?
4/51
Calculate prob of picking 1 r and 1 l when two letters picked without replacement from xrlrr.
3/10
Calculate prob of picking 1 p, 2 s, and 1 w when four letters picked without replacement from {p: 1, s: 3, x: 2, w: 1}.
3/35
Two letters picked without replacement from {o: 1, v: 4, m: 7, h: 1, c: 4, w: 2}. Give prob of picking 1 v and 1 c.
16/171
Four letters picked without replacement from {t: 2, j: 3, i: 3}. Give prob of picking 1 t and 3 j.
1/35
Two letters picked without replacement from asa. Give prob of picking 2 a.
1/3
Three letters picked without replacement from olljoojjo. Give prob of picking 1 o and 2 j.
1/7
Two letters picked without replacement from ecnuuccnxucc. Give prob of picking 1 c and 1 u.
5/22
Calculate prob of picking 1 h and 1 r when two letters picked without replacement from wlhrhlx.
2/21
Calculate prob of picking 2 q and 2 y when four letters picked without replacement from qqyqqqy.
2/7
What is prob of picking 2 c, 1 s, and 1 g when four letters picked without replacement from scmwmkwwkmcgwkw?
1/1365
Two letters picked without replacement from {q: 1, g: 8, i: 1, r: 7}. What is prob of picking 1 g and 1 r?
7/17
What is prob of picking 4 g when four letters picked without replacement from gffgfgggfffg?
1/33
Two letters picked without replacement from jllllllljjlllll. What is prob of picking 1 l and 1 j?
12/35
Two letters picked without replacement from {r: 5, m: 5}. What is prob of picking 1 m and 1 r?
5/9
Three letters picked without replacement from {t: 1, h: 2, i: 1, j: 1, b: 1, k: 1}. What is prob of picking 1 k, 1 j, and 1 b?
1/35
Four letters picked without replacement from yeyyyyyyyyyyyyyyyyee. Give prob of picking 3 y and 1 e.
8/19
Calculate prob of picking 3 j and 1 r when four letters picked without replacement from rejjjjujj.
10/63
What is prob of picking 1 r, 1 u, and 1 a when three letters picked without replacement from {a: 1, u: 2, i: 9, r: 1, d: 1, x: 1}?
2/455
Four letters picked without replacement from {a: 3, g: 17}. What is prob of picking 3 g and 1 a?
8/19
Two letters picked without replacement from rrrfrffrfr. What is prob of picking 1 f and 1 r?
8/15
Four letters picked without replacement from abaababbbbba. Give prob of picking 1 a and 3 b.
35/99
What is prob of picking 4 e when four letters picked without replacement from ettteetttettttte?
1/364
What is prob of picking 1 j and 2 r when three letters picked without replacement from {r: 4, j: 1, i: 2}?
6/35
Three letters picked without replacement from {r: 3}. Give prob of picking 3 r.
1
Three letters picked without replacement from {x: 5, m: 3}. What is prob of picking 3 m?
1/56
What is prob of picking 1 f and 1 n when two letters picked without replacement from {f: 3, r: 2, n: 5}?
1/3
Two letters picked without replacement from {d: 5, p: 2, v: 7, k: 2, e: 2}. Give prob of picking 1 d and 1 v.
35/153
What is prob of picking 2 e and 2 x when four letters picked without replacement from xggexgxgggge?
1/165
Two letters picked without replacement from hoxhxmyyhoihhhx. Give prob of picking 1 y and 1 x.
2/35
What is prob of picking 1 c, 1 p, and 1 g when three letters picked without replacement from yrpcypykkgk?
2/165
Calculate prob of picking 3 m when three letters picked without replacement from lmlmmlmmlm.
1/6
Four letters picked without replacement from ljpljjlllpzy. What is prob of picking 1 j, 1 l, 1 z, and 1 p?
2/33
Calculate prob of picking 1 c and 1 h when two letters picked without replacement from {w: 2, p: 1, m: 1, c: 1, t: 2, h: 1}.
1/28
Calculate prob of picking 3 i when three letters picked without replacement from {r: 7, i: 4}.
4/165
Four letters picked without replacement from wwffwfffwfl. Give prob of picking 3 w and 1 f.
4/55
Calculate prob of picking 1 o and 1 j when two letters picked without replacement from {x: 2, o: 1, j: 1, b: 1}.
1/10
Two letters picked without replacement from rrsk. Give prob of picking 2 r.
1/6
Three letters picked without replacement from {i: 3, r: 17}. What is prob of picking 3 i?
1/1140
Two letters picked without replacement from {k: 2, m: 7, u: 1, a: 3, e: 1}. Give prob of picking 2 m.
3/13
Two letters picked without replacement from rfrfffwwrrwrf. What is prob of picking 1 r and 1 w?
5/26
Three letters picked without replacement from {m: 4, e: 2, s: 5}. Give prob of picking 3 s.
2/33
Three letters picked without replacement from {c: 3, i: 2, k: 3, p: 10}. Give prob of picking 2 k and 1 p.
5/136
What is prob of picking 3 t and 1 c when four letters picked without replacement from tctttc?
8/15
Three letters picked without replacement from rooosrrrsrrorosoor. What is prob of picking 1 o and 2 s?
7/272
What is prob of picking 1 m and 1 a when two letters picked without replacement from vlajm?
1/10
What is prob of picking 1 z and 1 q when two letters picked without replacement from {z: 3, l: 2, q: 7}?
7/22
Two letters picked without replacement from {p: 2, k: 1, m: 1}. What is prob of picking 1 m and 1 p?
1/3
Two letters picked without replacement from nephnpppupnuuhpn. Give prob of picking 1 u and 1 n.
1/10
Two letters picked without replacement from {j: 3, q: 5, u: 3, r: 2, i: 3}. Give prob of picking 1 u and 1 j.
3/40
Three letters picked without replacement from {o: 3, z: 4, a: 7}. Give prob of picking 3 z.
1/91
What is prob of picking 2 i when two letters picked without replacement from {n: 1, i: 2, a: 5, j: 1, z: 3}?
1/66
Four letters picked without replacement from lafsfltlfllaffbflbta. Give prob of picking 1 a, 1 b, 1 l, and 1 f.
72/1615
Four letters picked without replacement from {k: 2, x: 3}. |
Lawsuit likely against Hopkins following accused doctor’s suicide
Johns Hopkins Hospital is likely to face a lawsuit in connection with the actions of Dr. Nikita Levy, 54, a former gynecologist at the hospital who committed suicide in the midst of an investigation into allegations that he recorded photos and video images of his patients. |
NOT PRECEDENTIAL
UNITED STATES COURT OF APPEALS
FOR THE THIRD CIRCUIT
No. 10-1581
ANTONIOS STAMOS,
Appellant
v.
STATE OF NEW JERSEY;
Office of the County Prosecutor, County of Bergen;
JOHN L. MOLINELLI, as Bergen County Prosecutor
On Appeal from the United States District Court
for the District of New Jersey
(D.C. Civil Action No. 2-09-cv-05828)
District Judge: Honorable Peter G. Sheridan
Submitted Pursuant to Third Circuit LAR 34.1(a)
October 7, 2010
Before: SMITH, FISHER and GARTH, Circuit Judges
(Opinion filed: October 7, 2010)
OPINION
PER CURIAM
Antonios Stamos filed in the District Court an action under 42 U.S.C. § 1983,
which the District Court dismissed with prejudice. Stamos, proceeding pro se, appeals
that decision. For the reasons that follow, we will affirm the judgment of the District
Court.
I
In 1996, Stamos was cited in New Jersey for a traffic violation. He appeared in
Municipal Court, Borough of Tenafly, and pleaded guilty; the court imposed a $55 fine
and $30 in court costs. Over the next four years, the Municipal Court sent Stamos at least
seven payment requests, but he never complied. As a result, the court issued a warrant
for Stamos’ arrest in 2000.
In 2007, Stamos appeared before the Municipal Court and sought permission to
withdraw his 1996 guilty plea. The court agreed and ordered a new trial, after which
Stamos was again convicted. He was sentenced to pay a $150 fine and $33 in court costs.
Stamos then initiated the first of several unsuccessful appeals challenging his 2007
conviction on the ground that it violated the Fifth Amendment’s prohibition on double
jeopardy.
After the United States Supreme Court denied his petition for certiorari in 2009,
Stamos filed in the District Court a complaint under 42 U.S.C. § 1983, raising the same
double jeopardy claim and seeking declaratory and injunctive relief. The District Court
dismissed the action under 28 U.S.C. § 1915(e)(2), reasoning that the complaint failed to
state a cognizable claim for relief because it was barred as res judicata and, in the
alternative, because the court lacked subject matter jurisdiction. Stamos filed a timely
appeal.
2
II
We have jurisdiction pursuant to 28 U.S.C. § 1291. We exercise plenary review
over a District Court decision to dismiss a complaint under § 1915(e)(2). See Tourscher
v. McCullough, 184 F.3d 236, 240 (3d Cir. 1999). Under that standard, which is the same
standard we apply to a dismissal under Federal Rule of Civil Procedure 12(b)(6), “[w]e
accept all well-pleaded allegations in the complaint as true and draw all reasonable
inferences in [Stamos’] favor.” Capogrosso v. Sup. Ct. of New Jersey, 588 F.3d 180, 184
(3d Cir. 2009) (quoting McGovern v. Philadelphia, 554 F.3d 114, 115 (3d Cir. 2009)).
“The District Court’s judgment is proper only if, accepting all factual allegations as true
and construing the complaint in the light most favorable to [Stamos], we determine that
[he] is not entitled to relief under any reasonable reading of the complaint.” McGovern,
554 F.3d at 115. Further, we may affirm on any grounds supported by the record. See
Hughes v. Long, 242 F.3d 121, 122 n.1 (3d Cir. 2001).
We will not reach the reasons given by the District Court for dismissing Stamos’
complaint because it is plain that the District Court lacked jurisdiction under the Rooker-
Feldman doctrine. See Dist. of Columbia Ct. App. v. Feldman, 460 U.S. 462 (1983);
Rooker v. Fidelity Trust Co., 263 U.S. 413 (1923). “In certain circumstances, where a
federal suit follows a state suit, the Rooker-Feldman doctrine prohibits the district court
from exercising jurisdiction.” Great W. Mining & Mineral Co. v. Fox Rothschild LLP,
__ F.3d __, 2010 WL 3035466, *4 (3d Cir. August 5, 2010). There are four requirements
that must be met for the Rooker-Feldman doctrine to apply: “(1) the federal plaintiff lost
3
in state court; (2) the plaintiff ‘complain[s] of injuries caused by [the] state-court
judgments’; (3) those judgments were rendered before the federal suit was filed; and
(4) the plaintiff is inviting the district court to review and reject the state judgments.” Id.
at *6 (quoting Exxon Mobil Corp. v. Saudi Basic Indus. Corp., 544 U.S. 280, 284
(2005)). Here, there is no question that these requirements are met. Stamos lost in state
court before filing his § 1983 suit, the injuries of which he complains were caused
exclusively by the state court judgments in question, and his request for relief specifically
included invalidation of the state courts’ rulings as to that claim. Accord Erlandson v.
Northglenn Mun. Ct., 528 F.3d 785, 788-90 (10th Cir. 2008) (holding that Rooker-
Feldman barred challenge in federal district court to municipal court conviction and fine
for littering).
Thus, dismissal under 28 U.S.C. § 1915(e)(2) was appropriate, and we will affirm
the judgment of the District Court.
4
|
Pulmonary thromboembolism secondary to left spermatic vein thrombosis: a case report.
Spermatic vein thrombosis is a particularly rare entity which can be difficult to diagnose. Pulmonary embolism associated with spermatic vein thrombosis is rarely seen. We report the diagnosis and management of a case at our institution and recommend spermatic vein ligation as the definite treatment for thrombosed spermatic veins associated with pulmonary thromboembolism. We prefer laparoscopy as a minimally invasive approach because of its clear advantages over open surgery. |
Monrovia - Mr. Sebastian Muah, Managing Director of the Liberia Telecommunication Corporation (Libtelco) has told members of the Senate Committee on Post and Telecommunication that political pressure led to the cancellation of the purchase deal between Novafone and Libtelco.
Mr. Muah made the disclosure Thursday when he appeared before the senate committee on Post and Telecommunication Committee chaired by Senator Nyonblee Karngar-Lawrence of Grand Bassa County. His appearance is a result of a mandate given by the plenary of the Senate.
The Senate reached a unanimous decision in early May to halt ongoing discussions by Libtelco to purchase cellular company, Novafone.
The Senate’s decision, according to a motion; is aimed at giving the Committee on Post and Telecommunications, chaired by Senator Nyonblee Karnga-Lawrence (Liberty Party, Grand Bassa) the chance to gather the needed information relating to discussions surrounding the alleged US$10M purchase of Novafone by Libtelco.
The probe came as a result of a communication written by Maryland County Senator, Dan Morias, who informed plenary that the Senate has been left out of the discussion surrounding the alleged purchase of the cellular company.
Senator Morias’ communication stated: “Moreover, Liberia, being a Republic, practices free market economic principles.
It beats our imagination that we will get involve; not in failed government institutions, but rather join the free market of purchasing failed institutions as Novafone GSM and thereby transferring its liability to the people of Liberia.”
Muah Admits Mistake
“Doing it again will be done differently because there is a dimension that when I look at the pure business side of it, there is this dimension side of it that I pretty much overlooked and that was my decision and leadership.
No one asked me to do it. What we forgot in the process is that; we did not involve the legislature; even if law did not say so,” he said.
During Thursday’s appearance Mr. Muah said, the mandate he took when he took over Libtelco remains viable and it will take a longer time. He added that he may not be at the entity up to that time.
“My job is also a political appointment job, even though I don’t get confirm by the Senate, it is still a political job the board; and the President make decisions around it.
Mr. Muah explained that his mandate has been to create value for Libtelco and the Liberian People and be able to make Libtelco competitive by generating income not as the same as Ghana and Ivory Coast got when they got their incumbent out of their hands for 70%; but to get resources that can come to the development of Liberia and we are still committed to that,” he said.
FrontPageAfrica in April of 2016 reported from multiple sources that the President has rejected the deal in its entirety, declaring to aides that it is not in Liberia’s best interest and has killed plans by Libtelco to sanction a sale.
One source stated that the President through a communication instructed Acting Finance Minister James Kollie to immediately terminate all negotiations regarding the Novafone deal.
The source fell short of revealing what prompted the decision by the President but did say that the President instructed the Minister to revoke any instruction that has already been given or approval of the deal immediately.
In early May the Liberia Revenue Authority (LRA), in its vigorous drive to collect lawful taxes due the government and people of Liberia, Thursday sealed the doors of five major businesses after they failed to settle tax obligations since 2009.
Businesses shutdown includes Novafone GSM Company in Congo Town, Shenny Trading Inc., on Broad Street, Continental General & Life Insurance, Medicare Insurance Corporation, and Liberty Investment (producers of AquaLife Water), all in Monrovia.
Court and LRA officials delivered closure orders and requested employees out of the premises before sealing the doors of each of the businesses.
The five companies owed a total of US$1.36 million and a little over LD$30 million, including penalties and interest for the last six years. |
Granzyme B, a new player in activation-induced cell death, is down-regulated by vasoactive intestinal peptide in Th2 but not Th1 effectors.
Following antigenic stimulation and differentiation, Th1 and Th2 effector cells contribute differently to cellular and humoral immunity. Vasoactive intestinal peptide (VIP) induces Th2 responses by promoting Th2 differentiation and survival. In this study, we investigate the mechanisms for the protective effect of VIP against activation-induced cell death (AICD) of Th2 effectors. Surprisingly, microarray and protein data indicate that VIP prevents the up-regulation of granzyme B (GrB) in Th2 but not Th1 effectors. This is the first report of GrB expression in Th cells and of its involvement in activation-induced apoptosis. The enhanced responsiveness of Th2 cells to VIP is probably due to the higher expression of VIP receptors. The effect of VIP on Th2 survival and GrB expression is mediated through the VIP receptors 1 and 2 and cAMP signaling through exchange protein activated by cAMP and, to a lesser degree, protein kinase A. In addition to effects on GrB, VIP also down-regulates Fas ligand (FasL) and perforin (Pfr) expression. The extrinsic Fas/FasL pathway and the intrinsic GrB-dependent pathway act independently in inducing AICD. The mechanisms by which GrB induces cell death in Th1/Th2 effectors include both fratricide and suicide. Fratricide killing, prevalent in wild-type cells, is calcium and Pfr dependent, whereas the cell death of Pfr-deficient Th cells involves Fas and GrB but is calcium independent. This study identifies GrB as a new significant player in Th1/Th2 AICD and characterizes two mechanisms for the protective effect of VIP on Th2 survival, i.e., the down-regulation of GrB and FasL expression. |
Reporting guidelines in health research: A review.
Contemporary health research has come under close scrutiny, exposing alarming flaws in the reporting of research. The reporting guidelines can aid in identification of poorly reported studies and can bring transparency to health research. The guidelines also help journal editors, peer reviewers, funding agencies, and readers to better discern health research. Reporting guidelines encourage accurate and thorough reporting of fundamental aspects of health research so that the results of studies can be replicated by others. Reporting guidelines are potent tools to improve the practice of research and in reducing reporting bias. For the present review, both electronic and manual literature search was carried out. Electronic databases like PubMed, MEDLINE, EBSCO host, and Science Direct were searched for extracting relevant articles. Various key words and their combinations were used for literature search like reporting guidelines, checklist, research, publishing standards, study design, medicine, and dentistry. The search results were scrutinized for relevance to the topic and only full text articles in English were incorporated. Various reporting guidelines were identified and grouped under headings based on study design. This review article attempts to highlight the various reporting guidelines in literature relating to health research, its potential applications, and its limitations. |
Discrimination and Exclusion
Both the Chinese and Japanese immigrants, Buddhist or not, encountered anti-Asian ordinances and general hostility at the local level. Anti-Chinese rhetoric and violence erupted repeatedly throughout the 1850s and 1860s. The first major anti-Chinese riot in San Francisco was in 1866. In the early 1870s the city of San Francisco passed ordinances prohibiting the use of firecrackers and Chinese ceremonial gongs, both of which played important roles in Buddhist and Daoist ceremonies. The campaign intensified in the late 1870s, culminating in the federal Chinese Exclusion Act of 1882, which suspended immigration of Chinese workers for ten years and made the Chinese ineligible for naturalization as citizens. Not only were workers prohibited, but Chinese women who might have enabled the workers already here to settle down to a family life were also barred. The Chinese population of the United States dwindled, though many workers who could not afford to return to China found themselves stranded thousands of miles from their families.
The exclusion policy was reaffirmed and expanded to include other “Asiatics” by the end of the century. Despite the concerted efforts of the Japanese to assimilate, there was an anti-Japanese movement. By 1924, a new wave of anti-immigrant and anti-Asian sentiment set quotas on all immigration and prohibited the entry of all people not eligible for citizenship, which included Chinese and Japanese. The general hostility toward East Asians was exhibited not only because of their race, but because of their “alien” customs and religious practices. Second and third generation Chinese and Japanese, wishing to assimilate more fully into American life, gradually abandoned the temples. It was, however, in terms of their “nonwhite” race that the exclusion from citizenship was cast. |
Typical upper range of mortgage:
Be aware that your credit score also has a big impact – read MSE's Credit Rating guide for further details. Also note that this calculation is mainly for people who are employed – sadly, for the self-employed, it's more difficult.
Likely range of mortgage
The nitty gritty on lenders
Lenders typically cap the loan-to-income ratio at around four-and-a-half times your annual salary, which is the upper limit in the red on the bar chart below.
Assuming you don't have existing debts and a clear credit rating you should have no difficulty in securing a mortgage in green.
Important! Remember, lenders will also assess your outgoings, including any loan agreements and credit card repayments, child maintenance payments, school fees and other bills to work out how much they'll lend. If you're a few months away from applying, try to budget as if you’re already paying mortgage payments, as lenders will want evidence from your outgoings that you can afford to repay. If you haven't already, do a budget.
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Assumptions
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3) If you selected 'Interest only', we assume your standard monthly payment doesn't decrease even if you pay off some of the balance.
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This info does not constitute financial advice, always do your own research on top to ensure it's right for your specific circumstances and remember we focus on rates not service.
We don't as a general policy investigate the solvency of companies mentioned (how likely they are to go bust), but there is a risk any company can struggle and it's rarely made public until it's too late (see the section 75 guide for protection tips).
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Always remember anyone can post on the MSE forums, so it can be very different from our opinion.
MoneySavingExpert.com is part of the MoneySupermarket Group, but is entirely editorially independent. Its stance of putting consumers first is protected and enshrined in the legally-binding MSE Editorial Code. |
Background {#Sec1}
==========
*Nutrition surveillance* means "to watch over nutrition in order to make decisions that lead to improvements in nutrition in populations" \[[@CR1]\]. Nutrition surveillance refers to a continuous process and focuses on monitoring trends over time, rather than providing one-time estimates of (e.g.) absolute levels of the prevalence of malnutrition, in order to identify and respond to crises in a timely manner \[[@CR2]\].
Although they have been recognized as an important component in fighting malnutrition, nutritional surveillance systems remain weak in most developing countries \[[@CR3]\]. Reasons for this include (1) no common agreement on the best methods to implement nutrition surveillance, (2) a lack of confidence in surveillance data, and (3) little comparable data on the costs of different potentially effective systems that would justify investments in such a system \[[@CR2], [@CR4]\]. It is, therefore, essential for practitioners to share experiences regarding nutritional surveillance in order to provide insights into what works and what does not work in the field.
Nutritional surveillance data tend to come from two main sources: administrative (e.g. health facility/feeding centre caseloads and schools health services reports) and repeated probability sample household surveys \[[@CR2], [@CR5]\]. Limitations of administrative data are well known. There may be a selection bias due to incomplete distribution of facilities and populations that are covered by programs contributing data \[[@CR6]\]. Even when the facilities are well running, only people with better access may attend clinics or nutrition program sites, thus underestimating the true prevalence/incidence of the condition of interest. Furthermore, unless active case-finding is used, beneficiaries may tend to come to the facilities only when the disease is severe. This means that indicators may lag behind incidence, making surveillance data inappropriate for an early warning system. The second data source, repeated probability sample household surveys, is the most commonly used approach to nutrition surveillance \[[@CR5], [@CR7], [@CR8]\]. Surveys provide a representative picture of the situation at a given time and allow comparisons over time and between geographical areas. However, unless they are repeated frequently enough, surveys may miss seasonal effect and cannot provide timely information on changes over time \[[@CR9]\].
Less attention has been given to the community-based sentinel sites approach to nutrition surveillance. These surveillance systems are characterised by the selection of a small sample of communities from which a set of information is collected regularly. There are two main criticisms to the sentinel approach. First, the purposive sampling of selected sites according to predefined criteria (e.g. the most "vulnerable" settlements) results into non-representative estimates (likely overestimates) \[[@CR4]\]. Second, an observational effect that acts to reduce prevalence over time as the selected sites tend to be progressively positively affected by the inputs of the survey teams (e.g. giving education, advice and counselling, referral of cases for treatment, and treating illness) \[[@CR10]\]. It is not clear, however, that a statistically representative sample, as might be used in a population survey, is an essential attribute of a surveillance system. It may, for example, be more useful to select and watch over communities that are vulnerable to shocks so as to detect potential crises early in their development. Experiences of sentinel sites nutrition surveillance have been reported from Sudan \[[@CR11]\] and the Central African Republic \[[@CR12]\].
This paper presents the experience of the international non-governmental organization Action Contre la Faim (ACF) with nutrition surveillance using a community-based sentinel sites approach, known as the Listening Posts (LP) project. We established a surveillance system in order to estimate nutritional and food security needs and to identify when and where these needs were highest. The system was set up to describe patterns over time, and also to provide accurate estimates of the point prevalence of acute undernutrition and to provide predictions of the caseloads. In this paper, we report and examine our experience in Burkina Faso in order to assess the reliability and validity of the LP method compared to repeated cross-sectional surveys in terms of selection and observation biases.
Methods {#Sec2}
=======
Selection of livelihood zones {#Sec3}
-----------------------------
Criteria for selecting the setting were as follow: existence of a programme implemented by ACF; availability of sufficient capacity to conduct surveillance; nationally and locally weak nutrition information systems in the government sector; no other sentinel surveillance system in place in the government sector; involvement of the government in the selection of the livelihood zone (LHZ); and "vulnerability" of LHZ on the basis of an Household Economy Approach (HEA) food security assessment \[[@CR13]\]. The LHZ was defined as a geographical area where people share broadly the same patterns of access to food and income, and have the same access to local markets.
Based on our selection criteria, we piloted our methodology in Tapoa province (Burkina Faso). In 2011, Tapoa province had a population of about 400,000 people, 17.4 % of which were children under the age of five \[[@CR14]\]. Prevalence of Global Acute Malnutrition (GAM) (defined as weight-for-height Z-score \<−2) was estimated to be 12.3 % (9.5--15.9 %) in children aged between 6 and 59 months \[[@CR15]\]. This is one of the highest GAM prevalence in the country. Surveillance started in January 2011 in 3 LHZ (Fig. [1](#Fig1){ref-type="fig"}): (1) agro-pastoral (north) (2) subsistence farming (centre) (3) cash farming and hunting (south).Fig. 1Zones selected for surveillance, Tapoa province, Burkina Faso. Sentinel sites are shown with *filled triangle*
Sample size calculation {#Sec4}
-----------------------
The sample size was calculated taking both accuracy and costs into account, keeping in mind that low cost is an important factor for the sustainability of surveillance systems. The following aspects were included in the calculation of the sample size: (1) age range was reduced to 6--24 months. Besides the fact that this reduced the size of the universe (small population), this age group is most vulnerable to acute malnutrition; (2) semi-longitudinal design: the use of an "open cohort" (see "top-up replacement and referral" below) decreased the required sample size through reduction of between round sampling variation compared to taking a new sample at each round; (3) estimation of GAM was done using a Bayesian normal--normal conjugate analysis with an objective prior followed by a PROBIT analysis \[[@CR16]--[@CR19]\]. The Bayesian conjugate analysis was used because the prior contains information that contributes "pseudo-observations" to the conjugate analysis. This means that the Bayesian conjugate analysis will have a larger effective sample size than a frequentist analysis of similar sample size provided that there is no gross conflict between the prior and the likelihood (i.e. observed) data. A larger effective sample size translates to improved precision of estimates \[[@CR19], [@CR20]\]. The Bayesian normal--normal conjugate analysis yields posterior estimates of the mean and standard deviation (SD) which are the inputs required by the inverse cumulative distribution function used in the PROBIT estimator. The PROBIT estimator retains information about scale and variability that is lost by the classical approach when the data are coded to a case/not case binary variable. This retained information allows the PROBIT approach to return estimates with improved precision compared to the classical (i.e. case counting) approach \[[@CR17], [@CR18]\], making the method well suited to work with small samples. With these conditions, and using computer-based simulations using data derived from cross-sectional surveys, we calculated that a sample size of *n* = 96 from each LHZ could be expected to yield a 95 % credible interval (CI) of ±10 % or better at any level of prevalence. A sample size of *n* = 132 children was selected in order to ensure that useful precision is achieved.
Sampling and eligibility criteria {#Sec5}
---------------------------------
A two-stage cluster sample of children was taken from each selected LHZ. Six primary sampling units (PSUs), also called "Listening Posts", were selected using the centric systematic area sampling (CSAS) methodology, by which the sample selected was reasonably evenly distributed across the survey area. This type of sample provides implicit stratification by spreading the sample properly among sub-groups of the population such as rural, urban, peri-urban populations, administrative areas, ethnic sub-populations, religious sub-populations, and socio-economic groups \[[@CR21]--[@CR25]\]. This tends to improve precision of survey estimates from survey data. In the second sampling stage, we selected 22 children from each Listening Post (PSUs) using the Expanded Program on Immunization (EPI) household sampling scheme: the first household was selected by choosing a random direction from the centre of the community, counting the houses along that route, and picking one at random, and the sampling was continued by choosing the household nearest to the preceding one that included an eligible child \[[@CR26]\]. All children aged between 6 and 24 months in selected households were included in the sample. Since a child falling into such a narrow age range would not be found in every household, the sample was spread widely across the PSU community \[[@CR26]\]. This procedure provided the same advantage as implicit stratification by ensuring that all parts of the PSU were sampled.
Top-up replacement and referral {#Sec6}
-------------------------------
When a child reached his or her second birthday, they were replaced by another child aged between 6 and 9 months not already in the cohort (the "top-up sample") from the nearest household with an eligible child. Before being replaced, nutritional measurements were done and the survey questionnaire administered. A dead or lost-to-follow up (e.g. moved away) child was replaced by another child not already in the cohort and of similar age from the nearest household with an eligible child. These procedures ensured that the age structure of the cohort remained constant between surveillance rounds so that prevalence estimates would not be influenced by aging of the surveillance cohort. All children with a mid-upper arm circumference (MUAC) below 125 mm, as well as sick children, were referred to the nearest health centre.
Data collection {#Sec7}
---------------
Two interviewers for the three LHZ were trained to perform the sampling protocol, the required anthropometric measurements, and apply the survey questionnaire. Regular supervisions were conducted to ensure anthropometric measurements were done correctly. Each interviewer visited one Listening Post (PSU) per day, and performed interviews of mothers and measurements (weight and MUAC) of 22 children and top-up sampling when this was required. Data were collected during the first 2 weeks of each month. In order to avoid an interviewer bias, monthly rotations were organized in the visited LP between the two interviewers. 36 monthly rounds of data collection were performed and are included in the analysis presented here. Anthropometric measurement (weight and MUAC), morbidity (prevalence of diarrhoea in the last 15 days), infant and young child feeding (IYCF) practices, food security, and water, sanitation and hygiene (WASH) indicators were collected using a paper based questionnaire. In this article, we will concentrate on the prevalence of global acute malnutrition (GAM), defined as MUAC \<125 mm, which is recognized as a sensible indicator to capture variations of the nutrition status at community level \[[@CR27]\]. One supervisor prepared the planning of the interviewer, the questionnaires, checked for missing data and validated the data for analysis. Data was entered into an Excel spread sheet, together with quality assurance mechanisms such as cross-field consistency checks, legal value, and range checks.
Data analysis {#Sec8}
-------------
Design effect was calculated by dividing the standard error (SE) with clustering by the SE without clustering. For continuous variables, median and Inter-Quartile-Range (IQR) were calculated for the entire study period. The prevalence of GAM was estimated by MUAC with a case-defining threshold of 125 mm using a Bayesian normal--normal conjugate analysis followed by a PROBIT estimation approach. In the work reported, an objective prior was specified using the sex-combined median MUAC-for-age and the square of the sex-combined median negative z-score for children aged between 6 and 24 months taken from the WHO's World Growth Standard (MGRS) reference population \[[@CR28]\]. We used the population mean and variance parameter of the MGRS reference populations (i.e. 145 mm and 121 mm^2^, respectively). Using these parameters, the equation used to estimate the mean MUAC was:$$\documentclass[12pt]{minimal}
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\begin{document}$$\mu |survey\;data\sim\,N\left( {\frac{{145 + n\bar{x}}}{n + 1},\frac{121}{n + 1}} \right)$$\end{document}$$where *n* is the number of children in the sample and $\documentclass[12pt]{minimal}
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\begin{document}$$\bar{x}$$\end{document}$ is the mean MUAC observed in the survey.
We used these values (i.e. the posterior mean and variance) to find the 95 % credible interval for the posterior mean using the inverse cumulative normal distribution (NORMINV) function in Microsoft Excel. We translated the posterior mean and the associated 95 % credible interval into a proportion (i.e. prevalence) using the cumulative normal distribution (NORMDIST) function in Microsoft Excel using a threshold value of 125 mm. By using this function, we estimated the probability that a child selected at random from the monitored population would have a MUAC below 125 mm (which equates to prevalence).
Data were analysed by the program manager and validated by the ACF Department for Food and Livelihoods. For the purpose of surveillance, data were analysed on a monthly basis using means and estimated proportions of the different collected variables. When plotting the results as a time series, the effect of sampling variation was reduced by applying a simple low-pass filter (i.e. smoothing using a 3 months moving average).
Comparison between LP and cross-sectional surveys {#Sec9}
-------------------------------------------------
The external validity of the estimates from the LP survey was assessed by comparing the time trend and variability of LP data with that from other data sources. In Burkina Faso, available data included nutritional cross-sectional surveys using the Standardized Monitoring and Assessment of Relief and Transitions (SMART) methodology \[[@CR29]\], conducted by ACF in Tapoa Province in March 2011, May 2012, December 2012, May 2013 and October 2013 (data not published but available upon request). In order to have the same age group as used for the LP surveillance system, only 6--24 months aged children were kept from the cross-sectional surveys.
First, the individual data of LP surveys from all the three LHZ were pooled. We modelled the time trends of continuous MUAC for both LP and cross-sectional data through forward stepwise curvilinear regression weighted by the population in each LHZ. Time (*T*), squared time (*T* ^2^) and cubed time (*T* ^3^) were entered into the model as independent variables. This led to the following polynomial model:$$\documentclass[12pt]{minimal}
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\begin{document}$$Y = \beta_{0} + \beta_{1} {\text{T}} + \beta_{2} {\text{T}}^{2} + \beta_{3} {\text{T}}^{3}$$\end{document}$$where *Y* is the continuous MUAC of the individuals assessed at time *T*, *β* ~0~ is the intercept of the model, *β* ~1~, *β* ~2~ and *β* ~3~ are the coefficients of respective terms *T*, *T* ^2^ and *T* ^3^.
Second, in order to compare estimates from the LP and cross-sectional surveys, we built a regression model by pooling data from both the LP and cross-sectional surveys sources and adding a new binary variable (*W*) with the value one when the corresponding data were from LP survey and zero when from cross-sectional survey. This led to the following model:$$\documentclass[12pt]{minimal}
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\begin{document}$$Y = \beta_{0}^{\prime } + \beta_{1}^{\prime } {\text{T}} + \beta_{2}^{\prime } {\text{T}}^{2} + \beta_{3}^{\prime } {\text{T}}^{3} + \beta_{4}^{\prime } {\text{W}}$$\end{document}$$where *Y* is the continuous MUAC of the individuals from both LP and cross-sectional data assessed at time *T*. $\documentclass[12pt]{minimal}
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\begin{document}$$\beta_{0}^{\prime }$$\end{document}$ is the intercept of model, $\documentclass[12pt]{minimal}
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\begin{document}$$\beta_{1}^{\prime } ,\beta_{2}^{\prime }$$\end{document}$ and $\documentclass[12pt]{minimal}
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\begin{document}$$\beta_{3}^{\prime }$$\end{document}$ are the coefficients of respective terms T, T^2^ and *T* ^3^, and *W* is the new variable mentioned above. Then we performed a Wald test to determine whether this new variable made a statistically significant improvement to the global regression model and to determine whether the coefficients in the LP and cross-sectional surveys models were significantly different from each other.
Third, we calculated the monthly mean MUAC for cross-sectional surveys and for LP separately, with pooled data weighted by the population of each LHZ. Using the Bayesian-PROBIT estimator, the prevalence of GAM was estimated for each data source, and the differences (D) in prevalence estimates between these two data sources plotted. We calculated the mean difference ($\documentclass[12pt]{minimal}
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\begin{document}$${\bar{\text{D}}}$$\end{document}$), the SD of the differences, and the estimated limits of agreement as $\documentclass[12pt]{minimal}
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\begin{document}$${\bar{\text{D}}}$$\end{document}$ ± 1.96 SD. Agreement between the results from cross-sectional surveys and LP data was defined as being within these estimated limits of agreement \[[@CR30]\]. To investigate the trend for differences in GAM prevalence as a function of time (observational bias), the associated least squares line was calculated using a simple regression of the form:$$\documentclass[12pt]{minimal}
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\begin{document}$$Y = \beta_{0}^{\prime \prime } + \beta_{1}^{\prime \prime } T^{\prime \prime }$$\end{document}$$where *Y* is the absolute differences (D) in prevalence estimates between LP and cross-sectional surveys assessed at time $\documentclass[12pt]{minimal}
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\begin{document}$$T^{\prime \prime } ,\beta_{0}^{\prime \prime }$$\end{document}$ is the intercept of regression line and $\documentclass[12pt]{minimal}
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\begin{document}$$\beta_{1}^{\prime \prime }$$\end{document}$ is the coefficient associated with time. The time at which differences would become significant was estimated as the point where this line crossed the upper confidence limit for the mean.
Results {#Sec10}
=======
Cohort profile {#Sec11}
--------------
Sample sizes varied over the study period and between LHZ (Table [1](#Tab1){ref-type="table"}). Overall, median of the mean age was 15.9 months and did not change over time and between LHZ. Overall, the SD around the mean MUAC had a median of 9.6 mm, without difference over time and between LHZ (Fig. [2](#Fig2){ref-type="fig"}).Table 1Characteristics of Listening Posts and cross-sectional surveys data sources, Tapoa Province, Burkina Faso, 2011--2013Characteristics/livelihood zoneNordCentreSouthAll 3 LHZCross-sectional surveys (3 LHZ)Number of rounds, n363636365Sample size (number of children) median (IQR)119 (116--132)139 (135--144)162 (145--164)418 (410--423)287 (275--367)Mean age (months) median (IQR)15.6 (15.2--15.9)16.0 (15.4--16.2)16.0 (15.9--16.2)15.9 (15.4--16.2)14.7 (14.4--15.1)Mean MUAC (mm) median (IQR)133.4 (132.0--134.0)133.3 (131.8--134.4)134.6 (132.6--135.4)133.8 (132.3--134.7)133.2 (132.9--133.6)SD (mm), median (IQR)9.98 (9.42--10.60)9.11 (8.66--9.67)9.68 (9.01--10.23)9.60 (9.19--10.04)10.73 (10.43--10.77)DEFF, median (IQR)0.97 (0.76--1.31) 0.96 (0.80--1.25) 1.22 (1.07--1.46) 1.18 (1.09--1.31) 1.06 (1.04--1.14)*DEFF* design effect, *IQR* inter quartile range, *LHZ* livelihood zone, *SD* standard deviation Fig. 2Mean MUAC and its standard deviation among 6--24 months aged children, in 3 Livelihood zones of Tapoa Province, Burkina Faso, 2011--2013
Design effects were close to 1 over the study period and in all LHZs. The mean monthly replacement rate of the children in the cohort was 8.5 % (SD = 0.28 %) which is above the expected value due to aging of the cohort (1/18 = 5.6 %). The difference was explained by losses to follow up, defined as the absence of child at 3 consecutive visits before reaching their second birthday, which had a mean value of 2.8 % (SD = 0.17 %).
Global acute malnutrition {#Sec12}
-------------------------
95 % credible interval around GAM prevalence in a single LHZ ranged between +6.5 and −6.0 % on a prevalence of 36.1 % and between +3.5 and −2.9 % on a prevalence of 10.8 %. These levels of precision are consistent with the surveillance round having an effective sample size of *n* = 227 and *n* = 362 respectively. Using *n* = 132 proved therefore to be suitable for the LP sample design and analysis plan. The GAM prevalence estimates, based on mean MUAC, did not differ between the three LHZ's (Fig. [3](#Fig3){ref-type="fig"}).Fig. 3Prevalence (by MUAC) and its 95 % Credible Intervals of Global Acute Malnutrition among 6--24 months aged children, in 3 Livelihood zones of Tapoa Province, Burkina Faso, 2011--2013
In the three LHZ of Tapoa province, GAM prevalence followed a seasonal variation with an increase during the dry season (January to May) and a decrease during the rainy season (June to September). Over the 3 years, GAM decreased during 2011, increased till the middle of 2013, and then decreased again during the last months of 2013 (Fig. [3](#Fig3){ref-type="fig"}).
External validity {#Sec13}
-----------------
Characteristics of collected data in pooled LP and pooled cross-sectional surveys are displayed in Table [1](#Tab1){ref-type="table"}. While mean age was slightly higher in LP than in cross-sectional surveys, mean MUAC was slightly lower in cross-sectional surveys. The SD was lower for LP than cross-sectional surveys, with a median of 9.60 and 10.73 mm, respectively. Design effect had a median of 1.18 and 1.06, for LP and cross-sectional surveys, respectively.
Continuous MUAC as the dependent variable was explained by time, squared time and cubed time as independent variables together (Table [2](#Tab2){ref-type="table"}), which is consistent with the shape of time-series results plotted in Fig. [3](#Fig3){ref-type="fig"}. The Wald test results showed that the values of MUAC were not significantly different (p = 0.6337) between LP and cross-sectional surveys models. Thus the time trends of continuous MUAC were similar between the two models/data sources.Table 2Regression coefficients, confidence intervals and p value taking continuous MUAC as dependent variable, Tapoa province, Burkina Faso, 2011--2013VariablesCoefficient(95 % CI)p valueLP model^a^ Time1.1597(0.9897, 1.3296)\<0.001 Squared time−0.0653(−0.0757, −0.0549)\<0.001 Cubed time0.0011(0.0009, 0.0012)\<0.001 Intercept128.02(127.27, 128.76)\<0.001Cross-sectional surveys model^b^ Time1.2149(0.3633, 2.0661)0.005 Squared time−0.0773(−0.1328, −0.0219)0.006 Cubed time0.0013(0.0003, 0.0023)0.008 Intercept129.87(127.14, 132.60)\<0.001^a^Number of observations in LP model = 14,534^b^Number of observations in cross-sectional surveys model = 1623
The monthly GAM was estimated with its 95 % credible intervals at five time points from cross-sectional surveys and LP surveys (Table [3](#Tab3){ref-type="table"}). All differences (D) in prevalence estimates between cross-sectional surveys and LP lay within estimated confidence limits (−8.47 to 5.38 %) (Fig. [4](#Fig4){ref-type="fig"}), indicating fair agreement between the two datasets. However, the plot showed an increase as a function of time, namely as a function of the number of months; the corresponding equation was:$$\documentclass[12pt]{minimal}
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\begin{document}$${\text{y}} = 0.264045{\text{t}} - 6.744944$$\end{document}$$indicating a monthly increase of about 0.26 % in GAM prevalence for cross-sectional compared to LP.Table 3Prevalence (by mean MUAC) and its 95 % Credible Interval of Global Acute Malnutrition among 6--24 months aged children, by Listening Posts and cross-sectional surveys, Tapoa province, Burkina Faso, 2011--2013Time pointsListening post surveysCross-sectional surveysMean MUAC (SD) in mmPrevalence (%)(95 % CI)Mean MUAC (SD) in mmPrevalence (%)(95 % CI)March 2011130.6 (10.7)30.12(26.87, 33.52)133.0 (11.7)23.61(20.21, 27.32)May 2012133.7 (10.2)21.44(18.69, 24.41)134.8 (10.1)19.08(16.04, 22.46)December 2012132.9 (9.1)23.01(20.28, 26.12)133.1 (10.7)22.66(19.11, 26.55)May 2013131.8 (9.6)27.13(24.03, 30.42)132.2 (12.0)25.40(22.52, 28.47)October 2013135.8 (9.8)18.41(15.95, 21.08)133.6 (10.4)21.68(18.80, 24.80) Fig. 4Difference in prevalence estimates between cross-sectional surveys and LP surveys, with mean and estimated 95 % limits of agreement, in 3 Livelihood zones of Tapoa province, Burkina Faso, 2011--2013
Extrapolation of the line crossed the upper border of the confidence interval of the mean at time t = 45.96 months, indicating that the difference in GAM prevalence would probably become significant 3 years and 10 months after the beginning of the surveillance.
Discussion {#Sec14}
==========
This paper presents the methodology for nutrition surveillance that was tested by ACF in a rural area of Burkina Faso, using a small open cohort in community-based sentinel sites. It provides detailed information on how to implement it and assess the reliability of its data in term of selection and observational biases. This methodology has been shown to be valid in following trends for a period of 3 years without selection bias.
Criticisms on sentinel system address the representativeness of the sample, including selection and observational biases. In our study, we used CSAS sampling rather than a purposive sampling technique. CSAS sampling has been shown to approximate random sampling \[[@CR21]\] and is thereby representative of the survey area. Although mean age of the cohort remained constant over time, we cannot exclude that a selection bias might have been introduced when lost to follow up children were replaced at each round. Dataset comparisons between LP and repeated cross-sectional surveys did not detect any statistical difference in estimating mean MUAC over a 3-year period in our setting. Post-hoc power analysis showed that for these comparisons, the working power was between 79 and 97 %, thus the corresponding tests were not underpowered. Moreover, the use of the *Bayesian*-*PROBIT* approach to estimate GAM has increased the precision of prevalence estimate compared to the use of a frequentist analysis and classical estimator. Using a reduced age-group (i.e. \<2 years old) proved to be also interesting in term of reducing the design effect close to 1, probably by spreading the sample in each community and hence, increasing the heterogeneity in each cluster.
A higher decrease in GAM prevalence (0.26 % per visit) was observed in LP compared to cross-sectional surveys. It is probable that in the field, information provided to families by our staff and referral of malnourished children have improved the nutritional status of the children within these sentinel villages. Likewise, the observational bias reported in a recent study piloted in Northern Nigeria by Médecins sans Frontières (MSF) was a progressive deviation of the nutritional status of the sentinel site from that of the wider community it is presumed to represent \[[@CR10]\]. In the MSF study, the prevalence of GAM decreased by 1.6 % (95 % CI 0.4--2.7 %; p = 0.012) relative to the prevalence observed during the previous visit. The smaller observational bias in our study might be partially explained by the normal--normal conjugate analysis that uses the same prior for both data sources (see limitations). Other explanations might include program coverage as well as impact of messages and referral in these two contexts. The quality of the surveillance system improved over time which might explain why LP and cross-sectional survey estimates are more different at the beginning (i.e. March 2011) than in 2013. Globally we conclude that in the course of the LP surveys, there was a slight observational bias (defined as the difference in GAM prevalence between the two data sources) that would probably become statistically significant after a 3 year and 10 months period. It would seem reasonable to take a new sample of sentinel sites every 3 years.
The thresholds for GAM by MUAC are internationally agreed and apply to any child in the 6--59 months of age group. However, as surveillance systems do not focus on single estimates but rather look at trends, there were difficulties in interpreting the curves during the first year, where no comparison was available. For the following years, the historical limit approach was applied. However, there is no clear guidance on how to use this approach in the nutrition sector, as it is more commonly used for infectious diseases \[[@CR31]\].
While the system is still ongoing and has even been extended to Gnagna province, questions remain regarding its sustainability. The same system was set up in Montserrado, Liberia, and was stopped after 21 months. Reasons for stopping were: (1) low prevalence of GAM; (2) weak connection with ACF programs; (3) no possible integration of this methodology into the national system; (4) the challenging issue of urban sampling and the fact that few data were available to assess the validity of our results in greater Monrovia. In Burkina Faso, the Ministry of Agriculture (MoA) was first interested to use this methodology to develop an early warning system (EWS) for food and nutrition. However, its capacities remain limited and there is actually no fund for a EWR. Furthermore, they are still doubts that MoA is responsible to collect nutritional data. Alternatively, the system could be extended to other areas through other partners. Suggestions to improve the uptake include more regular workshops, set up of a dedicated website and a better design of the newsletter.
The LP system provides monthly information that allows prompt interventions if needed. Alternative methodologies, such as cross-sectional surveys, are usually not frequent enough for early warning systems. Furthermore, cost of the LP system is limited with around 50,000 dollars per year for the 3 LHZ. In comparison, costs of cross-sectional surveys are around 20,000 dollars per survey. Finally, its set up is easier than repeated cross-sectional surveys. We think the LP methodology is adapted to areas with high burden of acute undernutrition and poor access to feeding centres that require continuous monitoring and an early warning system.
There were some limitations in our study. It would have been better if the number and timing of the cross-sectional surveys were the same as surveillance rounds. It would have allowed us to better compare trends from LP and repeated-cross sectional data over shorter time periods. Furthermore, in order to compare with cross-sectional surveys' area, we had to pool 3 LHZs, increasing the sample size. This has limited our ability to validate MUAC trends for each LHZ. However, it has improved the precision of the LP estimates, increasing our power. The use of the Bayesian normal--normal conjugate analysis may have biased the posterior estimate towards the prior mode, which was the same for the surveillance data and the cross-sectional survey data. We use the same prior for all applications. The prior was, however, tested with computer based simulations using data derived from cross-sectional surveys; we found that it did not introduce a bias even when used with relatively small likelihood survey sample sizes such as n = 96 and n = 132. Recent literature \[[@CR17], [@CR18]\] has identified small systematic biases in PROBIT estimates in given populations. This is problematic when estimating prevalence in one-shot cross-sectional surveys. Systematic bias is less important for surveillance systems. Surveillance systems accept bias and attempt to keep it systematic (i.e. consistent) over time in order to observe patterns of change. To detect change, precision (reliability, repeatability) is a more important issue than accuracy (bias) in surveillance applications. For a given sample size, the PROBIT method has greater precision than the more "conventional" methods \[[@CR17], [@CR18]\]. The Bayesian approach contributes some additional information (i.e. the prior) which also improves precision. The cohort approach also reduces between-round sampling variation. The use of the Bayesian PROBIT estimator and an open cohort in the LP method reflects the importance of precision in surveillance applications. Other methods, such as conventional prevalence method, can be used to analyze the data as a 6 × 22 cluster sample. They won't, however, provide the same precision as the Bayesian PROBIT estimator.
Finally, our study was not designed and did not aim to assess the Bayesian-PROBIT methodology in estimating GAM prevalence in comparison to SMART survey methodology. Further studies may be needed to validate this methodology in estimating GAM prevalence in different contexts.
Conclusions {#Sec15}
===========
This paper presented a methodology for nutrition surveillance using a small open cohort from community-based sentinel sites in a rural setting of Burkina Faso. This methodology has proved to be valid in following trends of GAM prevalence over a 3 years period without selection bias; conversely, a slight but significant observational bias was detected, requiring periodical reselection of sentinel sites. We recommend this approach for areas with high burden of acute under-nutrition and poor access to feeding centres where early warning systems are strongly needed. Advocacy is necessary to develop sustainable nutrition surveillance system and to support the use of surveillance data in guiding nutritional programs.
MA coordinated the research and drafted the manuscript. CF and BJ undertook the statistical analyses. ML coordinated the field data collection. MM and CA critically revised the manuscript. All authors read and approved the final manuscript.
Acknowledgements {#FPar1}
================
The history of this project and its methodology came first from a discussion between Rebecca Brown (ACF Nutrition senior advisor at that time), Claudine Prudhon (Epidemiologist at the World Health Organization) and Frances Mason (Save the Children France, SCF). The methodology was then developed by SCF (Anna Taylor, Alex Rees, Brian Kriz, Abigail Perry, Mickael Manske) and ACF (Rebecca Brown, Hélène Deret) with the support of Brixton Health (Mark Myatt). We are very thankful to all these people. We also thank the field teams of ACF in Burkina Faso, in particular the Listening Post team for gathering data and the ACF coordination team, Thomas Loreaux (Head of Mission) and Claire Gaillardou (Head of Department Disaster Risk Management) for supporting this project. We are also thankful to Chloe Milloz for her operational expertise and for reviewing. We wish to thank the village authorities and all the families from investigated villages for their participation in this project.
Competing interests {#FPar2}
===================
The authors declare that they have no competing interests.
Availability of data and materials {#FPar3}
==================================
The data supporting our findings are available by asking directly to the corresponding author.
Ethics approval and consent to participate {#FPar4}
==========================================
Ethical approval was obtained from the Institutional Review Board of the Ministry of Health in Burkina Faso (no 2010-028). A Memorandum of Understanding was also signed with the Ministry of Agriculture and its regional office concerning the Listening Post project and ACF support in strengthening the early warning system in Tapoa province. Data from nutritional cross-sectional surveys were collected with the agreement of the Ministry of Health of Burkina Faso. We followed the Declaration of Helsinki, aiming to provide assurance that the rights, integrity, and confidentiality of participants were protected. We obtained oral consent from participants or their parents or guardians. Participation was voluntary. We ensured privacy and confidentiality in the data collected from the participants both during and after the conduct of the study. We entered and analyzed all information anonymously and anonymised findings were shared with all stakeholders in Burkina Faso.
Funding {#FPar5}
=======
This study was funded by Action Contre la Faim (ACF). ACF collected the data, designed the study protocol, contributed to the interpretation of the data and preparation of the manuscript.
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Nor does Mrs. Trump display any of the histrionics about men exhibited by her American counterparts. … |
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puts (1..1000).map(&:to_s).sort |
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