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Drug of last resort
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Examples
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Other drugs Alosetron — used in the management of severe chronic diarrhea-predominant irritable bowel syndrome (IBS-D) in females not responsive to conventional therapy. Its use is restricted due to serious gastrointestinal adverse reactions, e.g. ischemic colitis and complications of constipation; Cisapride — used for severe gastroesophageal reflux disease (GERD); carries risk of heart arrhythmias; Clomethiazole — a sedative/hypnotic agent used in the treatment of alcohol withdrawal when benzodiazepines are not effective; Clozapine — used in treatment-resistant schizophrenia not responsive to at least two different antipsychotics; the main reason for such restriction is agranulocytosis and other severe side effects including seizures and myocarditis; Felbamate — an anticonvulsant used in refractory epilepsy; use is associated with an increased risk of aplastic anemia and liver failure; Isotretinoin — when all topical treatments or antibiotics against acne have failed, many dermatologists resort to isotretinoin, which is an oral treatment that permanently dries out the sebum production of the skin and is often a permanent solution against acne. It can cause severe nosebleed, causes birth defects when taken while pregnant, is said to cause depression, hair loss and can permanently dry out the skin all over the body and is therefore not the first treatment; Levosimendan — used in acutely decompensated severe chronic heart failure in situations where conventional therapy is not sufficient; Oral minoxidil for hypertension, however topical minoxidil is the first-line drug for hair loss; Monoamine oxidase inhibitors — due to potentially lethal dietary and drug interactions which may trigger hypertensive crisis and/or serotonin syndrome, they are generally used only when other classes of antidepressants (e.g., SSRIs or SNRIs) don't work; Thalidomide — withdrawn in 1961 owing to widespread incidence of severe birth defects (phocomelia or tetraamelia) after prenatal use by pregnant women, US Food and Drug Administration approved thalidomide for erythema nodosum leprosum (ENL) in 1998, and 2008 for new cases of multiple myeloma (administered with dexamethasone). A large "off-label" business in thalidomide began for rare cancers even while it was only FDA-approved for erythema nodosum leprosum; Tolcapone — used in patients with Parkinson's disease who are not appropriate candidates for other adjunctive therapies. Use is restricted due to hepatotoxicity; Vigabatrin — used only in extreme treatment-resistant epilepsy due to the risk of permanent vision loss.
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Agda (programming language)
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Agda (programming language)
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Agda is a dependently typed functional programming language originally developed by Ulf Norell at Chalmers University of Technology with implementation described in his PhD thesis. The original Agda system was developed at Chalmers by Catarina Coquand in 1999. The current version, originally known as Agda 2, is a full rewrite, which should be considered a new language that shares a name and tradition.
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Agda (programming language)
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Agda (programming language)
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Agda is also a proof assistant based on the propositions-as-types paradigm, but unlike Coq, has no separate tactics language, and proofs are written in a functional programming style. The language has ordinary programming constructs such as data types, pattern matching, records, let expressions and modules, and a Haskell-like syntax. The system has Emacs, Atom, and VS Code interfaces but can also be run in batch mode from the command line.
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Agda (programming language)
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Agda (programming language)
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Agda is based on Zhaohui Luo's unified theory of dependent types (UTT), a type theory similar to Martin-Löf type theory.
Agda is named after the Swedish song "Hönan Agda", written by Cornelis Vreeswijk, which is about a hen named Agda. This alludes to the name of the theorem prover Coq, which was named after Thierry Coquand, Catarina Coquand's husband.
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Agda (programming language)
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Features
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Inductive types The main way of defining data types in Agda is via inductive data types which are similar to algebraic data types in non-dependently typed programming languages.
Here is a definition of Peano numbers in Agda: Basically, it means that there are two ways to construct a value of type N , representing a natural number. To begin, zero is a natural number, and if n is a natural number, then suc n, standing for the successor of n, is a natural number too.
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Agda (programming language)
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Features
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Here is a definition of the "less than or equal" relation between two natural numbers: The first constructor, z≤n, corresponds to the axiom that zero is less than or equal to any natural number. The second constructor, s≤s, corresponds to an inference rule, allowing to turn a proof of n ≤ m into a proof of suc n ≤ suc m. So the value s≤s {zero} {suc zero} (z≤n {suc zero}) is a proof that one (the successor of zero), is less than or equal to two (the successor of one). The parameters provided in curly brackets may be omitted if they can be inferred.
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Agda (programming language)
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Features
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Dependently typed pattern matching In core type theory, induction and recursion principles are used to prove theorems about inductive types. In Agda, dependently typed pattern matching is used instead. For example, natural number addition can be defined like this: This way of writing recursive functions/inductive proofs is more natural than applying raw induction principles. In Agda, dependently typed pattern matching is a primitive of the language; the core language lacks the induction/recursion principles that pattern matching translates to.
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Agda (programming language)
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Features
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Metavariables One of the distinctive features of Agda, when compared with other similar systems such as Coq, is heavy reliance on metavariables for program construction. For example, one can write functions like this in Agda: ? here is a metavariable. When interacting with the system in emacs mode, it will show the user expected type and allow them to refine the metavariable, i.e., to replace it with more detailed code. This feature allows incremental program construction in a way similar to tactics-based proof assistants such as Coq.
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Agda (programming language)
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Features
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Proof automation Programming in pure type theory involves a lot of tedious and repetitive proofs. Although Agda has no separate tactics language, it is possible to program useful tactics within Agda itself. Typically, this works by writing an Agda function that optionally returns a proof of some property of interest. A tactic is then constructed by running this function at type-checking time, for example using the following auxiliary definitions: Given a function check-even : (n : N ) → Maybe (Even n) that inputs a number and optionally returns a proof of its evenness, a tactic can then be constructed as follows: The actual proof of each lemma will be automatically constructed at type-checking time. If the tactic fails, type-checking will fail.
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Agda (programming language)
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Features
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Additionally, to write more complex tactics, Agda has support for automation via reflection. The reflection mechanism allows one to quote program fragments into – or unquote them from – the abstract syntax tree. The way reflection is used is similar to the way Template Haskell works.Another mechanism for proof automation is proof search action in emacs mode. It enumerates possible proof terms (limited to 5 seconds), and if one of the terms fits the specification, it will be put in the meta variable where the action is invoked. This action accepts hints, e.g., which theorems and from which modules can be used, whether the action can use pattern matching, etc.
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Agda (programming language)
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Features
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Termination checking Agda is a total language, i.e., each program in it must terminate and all possible patterns must be matched. Without this feature, the logic behind the language becomes inconsistent, and it becomes possible to prove arbitrary statements. For termination checking, Agda uses the approach of the Foetus termination checker.
Standard library Agda has an extensive de facto standard library, which includes many useful definitions and theorems about basic data structures, such as natural numbers, lists, and vectors. The library is in beta, and is under active development.
Unicode One of the more notable features of Agda is a heavy reliance on Unicode in program source code. The standard emacs mode uses shortcuts for input, such as \Sigma for Σ.
Backends There are two compiler backends, MAlonzo for Haskell and one for JavaScript.
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Thermization
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Thermization
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Thermization, also spelled thermisation, is a method of sanitizing raw milk with low heat. "Thermization is a generic description of a range of subpasteurization heat treatments (57 to 68°C × 10 to 20 s) that markedly reduce the number of spoilage bacteria in milk with minimal heat damage." The process is not used on other food products, and is similar to pasteurization but uses lower temperatures, allowing the milk product to retain more of its original taste. In Europe, there is a distinction between cheeses made of thermized milk and raw-milk cheeses. However, the United States' Food and Drug Administration (FDA) places the same regulations on all unpasteurized cheeses. As a result, cheeses from thermized milk must be aged for 60 days or more before being sold in the United States, the same restriction placed on raw-milk cheeses by the FDA.Thermization involves heating milk at temperatures of around 145–149 °F (63–65 °C) for 15 seconds, while pasteurization involves heating milk at 160 °F (71 °C) for 15 seconds or at 145 °F (63 °C) for 30 minutes. Thermization is used to extend the keeping quality of raw milk (the length of time that milk is suitable for consumption) when it cannot be immediately used in other products, such as cheese. Thermization can also be used to extend the storage life of fermented milk products by inactivating microorganisms in the product.Thermization inactivates psychrotrophic bacteria in milk and allows the milk to be stored below 8 °C (46 °F) for three days, or stored at 0–1 °C (32–34 °F) for seven days. Later, the milk may be given stronger heat treatment to be preserved longer. Cooling thermized milk before reheating is necessary to delay/prevent the outgrowth of bacterial spores. When the milk is first heated, spores can begin to germinate, but their growth can be halted or delayed when the milk is refrigerated, depending on the microorganisms' growth requirements. Germinated spores are sensitive to subsequent heating, however since germination is not a homogeneous process, not all spores will germinate or be inactivated by subsequent heating.
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Sony FE 16-35mm F2.8 GM
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Sony FE 16-35mm F2.8 GM
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The Sony FE 16-35mm F2.8 GM is a premium constant maximum aperture wide-angle full-frame (FE) zoom lens for the Sony E-mount, announced by Sony on May 17, 2017. The lens is scheduled for release on August 31, 2017.This lens is part of Sony's professional GM zoom lens of the FE 12-24mm F2.8, FE 16-35mm F2.8, FE 24-70mm F2.8, and FE 70-200mm F2.8. Though designed for Sony's full frame E-mount cameras, the lens can be used on Sony's APS-C E-mount camera bodies, with an equivalent full-frame field-of-view of 24–52.5mm.
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Sony FE 16-35mm F2.8 GM
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Build quality
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The lens showcases a weather resistant matte-black plastic exterior with a pair of rubber focus and zoom rings. The barrel of the lens telescopes outward from the main lens body as it's zoomed in from 16mm to 35mm. The lens does not feature image stabilization.
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Supplementary weaving
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Supplementary weaving
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Supplementary weaving is a decorative technique in which additional threads are woven into a textile to create an ornamental pattern in addition to the ground pattern. The supplementary weave can be of the warp or of the weft. Supplementary weave is commonly used in many of thetextiles of Southeast Asia such as in Balinese textiles, the textiles of Sumba and the songket of Sumatra, Malaysia and Brunei.
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Supplementary weaving
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Supplementary of the warp weaving
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An additional set of threads are incorporated in the warp to create the design.
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Supplementary weaving
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Supplementary of the weft weaving
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An extra set of threads are woven into the weft between two regular weft threads to create an ornamental pattern in addition to the ground weave. Songket textiles are an example of supplementary weaving of the weft in which metallic threads are used to form the pattern.
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Supplementary weaving
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History
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Evidence from certain important textiles displaying ancient iconography and significant in ritual, suggests that supplementary weft patterning techniques existed before the period of Indian influence in Southeast Asia. Nevertheless, there is no doubt that the earliest weaving decorations in the region was predominantly warp oriented. However a fundamental shift from warp to weft decoration seems to have occurred throughout many parts of Southeast Asia during the period of Indian influence. The development of weft ornamentation is evident in woven patterns found throughout Indianized areas. In Cambodia during the Angkor period and in Thailand from the 11th to the 14th century, carved statues and sculptures record figures wearing textiles with stripes running down the torso.
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Ancestry-informative marker
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Ancestry-informative marker
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In population genetics, an ancestry-informative marker (AIM) is a single-nucleotide polymorphism that exhibits substantially different frequencies between different populations. A set of many AIMs can be used to estimate the proportion of ancestry of an individual derived from each population.
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Ancestry-informative marker
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Ancestry-informative marker
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A single-nucleotide polymorphism is a modification of a single nucleotide base within a DNA sequence. There are an estimated 15 million SNP (Single-nucleotide polymorphism) sites (out of roughly 3 billion base pairs, or about 0.4%) from among which AIMs may potentially be selected. The SNPs that relate to ancestry are often traced to the Y chromosome and mitochondrial DNA because both of these areas are inherited from one parent, eradicating complexities that come with parental gene recombination. SNP mutations are rare, so sequences with SNPs tend to be passed down through generations rather than altered each generation. However, because any given SNP is relatively common in a population, analysts must examine groups of SNPs (otherwise known as AIMS) to determine someone's ancestry. Using statistical methods such as apparent error rate and Improved Bayesian Estimate, the set of SNPs with the highest accuracy for predicting a specific ancestry can be found.Examining a suite of these markers more or less evenly spaced across the genome is also a cost-effective way to discover novel genes underlying complex diseases in a technique called admixture mapping or mapping by admixture linkage disequilibrium.
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Ancestry-informative marker
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Ancestry-informative marker
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As one example, the Duffy Null allele (FY*0) has a frequency of almost 100% of Sub-Saharan Africans, but occurs very infrequently in populations outside of this region. A person having this allele is thus more likely to have Sub-Saharan African ancestors. North and South Han Chinese ancestry can be distinguished unambiguously using a set of 140 AIMS.Collections of AIMs have been developed that can estimate the geographical origins of ancestors from within Europe.Following the development of ancient DNA databases, ancient ancestry-informative marker (aAIM) were similarly defined as a single-nucleotide polymorphism that exhibits substantially different frequencies between different ancient populations. A set of aAIMs can be used to identify the ancestry of ancient populations and eventually quantify the genetic similarity to modern-day individuals.
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Ancestry-informative marker
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Discovery and development
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The discovery of ancestry-informative markers was made possible by the development of next generation sequencing, or NGS. NGS enables the study of genetic markers by isolating specific gene sequences. One such method for sequence extraction is the use restriction enzymes, specifically endonuclease, which modifies the DNA sequence. This enzyme can be used with DNA ligase (connecting two different DNA), modifying DNA by inserting DNA from other organism. Another method, cDNA sequencing, or RNA-seq, can also help to acquire information of the transcriptomes in a broad range of organisms and find SNPs (single nucleotide polymorphisms), within a DNA sequence.
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Ancestry-informative marker
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Applications
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Ancestry informative markers have a number of applications in genetic research, forensics, and private industry. AIMs that indicate a predisposition for diseases such as type 2 diabetes mellitus and renal disease have been shown to reduce the effects of genetic admixture in ancestral mapping when using admixture mapping software. The differential ability of ancestry-informative markers allows scientists and researchers to narrow geographical populations of concern; for example, illegal organ trafficking can be traced to certain areas by comparing the samples taken from organ recipients and deciphering the foreign marker in their body. An array of private companies, such as 23andMe and AncestryDNA, provide cost-effective direct-to-consumers (DTC) genetic testing by analyzing ancestry informative markers to determine geographic origins. These private companies collect massive quantities of data such as biological samples and self-reported information from consumers, a practice known as biobanking, enabling their researchers to discover more insights on AIMs.Though AIM panels can be useful for disease screening, the Genetic Information Nondiscrimination Act (GINA) prevents the use of genetic information for insurance and workplace discrimination.
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Ancestry-informative marker
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Medical research
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Different ancestral traits and their affiliation to diseases can help scientists determine appropriate approaches of treatment for a specific population. Medical researchers have revealed the link between ancestry traits and some common diseases; for example, individuals of African descent have been found to be at higher risk of asthma than those of European ancestry.AIM panels can be used for detecting disease risk factors. One such panel was created for African American ancestry based on subsets of commercially available SNP arrays. These types of arrays can help reduce the cost of identifying risk factors, since they allow researchers to screen for ancestry markers instead of the entire genome. This is due to the fact that these SNP arrays narrow the scope of the necessary screening from hundreds of thousands of SNP markers to a panel of a few thousands of AIMs.While some believe that structured populations should be used in studies to better ascertain genetic associations to diseases, the social implications of the potential racial stigma that may result from such studies is a major concern. However, the study done by Yang et al. (2005) suggests that the technology to conduct deeper research into and identify ancestry-associated variations in human disease does already exist.
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Meteorological instrumentation
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Meteorological instrumentation
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Meteorological instruments (or weather instruments), including meteorological sensors (weather sensors), are the equipment used to find the state of the atmosphere at a given time. Each science has its own unique sets of laboratory equipment. Meteorology, however, is a science which does not use much laboratory equipment but relies more on on-site observation and remote sensing equipment. In science, an observation, or observable, is an abstract idea that can be measured and for which data can be taken. Rain was one of the first quantities to be measured historically. Two other accurately measured weather-related variables are wind and humidity. Many attempts had been made prior to the 15th century to construct adequate equipment to measure atmospheric variables.
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Meteorological instrumentation
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History
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Devices used to measure weather phenomena in the mid-20th century were the rain gauge, the anemometer, and the hygrometer. The 17th century saw the development of the barometer and the Galileo thermometer while the 18th century saw the development of the thermometer with the Fahrenheit and Celsius scales. The 20th century developed new remote sensing tools, such as weather radars, weather satellites and wind profilers, which provide better sampling both regionally and globally. Remote sensing instruments collect data from weather events some distance from the instrument and typically stores the data where the instrument is located and often transmits the data at defined intervals to central data centers.
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Meteorological instrumentation
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History
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In 1441, king Sejong's son, Prince Munjong, invented the first standardized rain gauge. These were sent throughout the Joseon Dynasty of South Korea as an official tool to assess land taxes based upon a farmer's potential harvest. In 1450, Leone Battista Alberti developed a swinging-plate anemometer, and is known as the first anemometer. In 1607, Galileo Galilei constructs a thermoscope. In 1643, Evangelista Torricelli invents the mercury barometer. In 1662, Sir Christopher Wren invented the mechanical, self-emptying, tipping bucket rain gauge. In 1714, Gabriel Fahrenheit creates a reliable scale for measuring temperature with a mercury-type thermometer. In 1742, Anders Celsius, a Swedish astronomer, proposed the 'centigrade' temperature scale, the predecessor of the current Celsius scale. In 1783, the first hair hygrometer is demonstrated by Horace-Bénédict de Saussure. In 1806, Francis Beaufort introduced his system for classifying wind speeds. The April 1960 launch of the first successful weather satellite, TIROS-1, marked the beginning of the age where weather information became available globally.
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Meteorological instrumentation
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History
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This was also used to measure the temperature of the surrounding air.
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Meteorological instrumentation
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Types
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A thermometer measures air temperature, or the kinetic energy of the molecules within air. A barometer measures atmospheric pressure, or the pressure exerted by the weight of the Earth's atmosphere above a particular location. An anemometer measures the wind speed and the direction the wind is blowing from at the site where it is mounted. A hygrometer measures the relative humidity at a location, which can then be used to compute the dew point. Radiosondes directly measure most of these quantities, except for wind, which is determined by tracking the radiosonde signal with an antenna or theodolite. Supplementing the radiosondes a network of aircraft collection is organized by the World Meteorological Organization (WMO), which also use these instruments to report weather conditions at their respective locations. A sounding rocket or rocketsonde, sometimes called a research rocket, is an instrument-carrying rocket designed to take measurements and perform scientific experiments during its suborbital flight.
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Meteorological instrumentation
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Types
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A pyranometer is a type of actinometer used to measure broadband solar irradiance on a planar surface and is a sensor that is designed to measure the solar radiation flux density (in watts per metre square) from a field of view of 180 degrees. A ceilometer is a device that uses a laser or other light source to determine the height of a cloud base. Ceilometers can also be used to measure the aerosol concentration within the atmosphere. A ceiling balloon is used by meteorologists to determine the height of the base of clouds above ground level during daylight hours. The principle behind the ceiling balloon is a balloon with a known ascent rate (how fast it climbs) and determining how long the balloon rises until it disappears into the cloud. Ascent rate times ascent time yields the ceiling height. A disdrometer is an instrument used to measure the drop size distribution and velocity of falling hydrometeors. Rain gauges are used to measure the precipitation which falls at any point on the Earth's landmass.
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Meteorological instrumentation
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Types
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Remote sensing, as used in meteorology, is the concept of collecting data from remote weather events and subsequently producing weather information. Each remote sensing instrument collects data about the atmosphere from a remote location and, usually, stores the data where the instrument is located. The most common types of remote sensing are radar, lidar, and satellites (also photogrammetry). The main uses of radar are to collect information concerning the coverage and characteristics of precipitation and wind. Satellites are chiefly used to determine cloud cover, as well as wind. SODAR (SOnic Detection And Ranging) is a meteorological instrument as one form of wind profiler, which measures the scattering of sound waves by atmospheric turbulence. Sodar systems are used to measure wind speed at various heights above the ground, and the thermodynamic structure of the lower layer of the atmosphere. Radar and lidar are not passive because both use electromagnetic radiation to illuminate a specific portion of the atmosphere. Weather satellites along with more general-purpose Earth-observing satellites circling the earth at various altitudes have become an indispensable tool for studying a wide range of phenomena from forest fires to El Niño.
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Meteorological instrumentation
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Weather stations
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A weather station is a facility with instruments and equipment to make observations of atmospheric conditions in order to provide information to make weather forecasts and to study the weather and climate. The measurements taken include temperature, barometric pressure, humidity, wind speed, wind direction, and precipitation amounts. Wind measurements are taken as free of other obstructions as possible, while temperature and humidity measurements are kept free from direct solar radiation, or insolation. Manual observations are taken at least once daily, while automated observations are taken at least once an hour.
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Meteorological instrumentation
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Surface weather observations
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Surface weather observations are the fundamental data used for safety as well as climatological reasons to forecast weather and issue warnings worldwide. They can be taken manually, by a weather observer, by computer through the use of automated weather stations, or in a hybrid scheme using weather observers to augment the otherwise automated weather station. The ICAO defines the International Standard Atmosphere, which is the model of the standard variation of pressure, temperature, density, and viscosity with altitude in the Earth's atmosphere, and is used to reduce a station pressure to sea level pressure. Airport observations can be transmitted worldwide through the use of the METAR observing code. Personal weather stations taking automated observations can transmit their data to the United States mesonet through the use of the Citizen Weather Observer Program (CWOP), or internationally through the Weather Underground Internet site. A thirty-year average of a location's weather observations is traditionally used to determine the station's climate.
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Bhimpalasi
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Bhimpalasi
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Bhimpalasi or Bheempalasi (also known as Bhimpalas or Bheempalas) is a joint raga or “jor raga” it's a mixture of raga "bhim(Bheem) also known as raga gavti" and raga "palasi or palas" , where raga bhim is a creation of babaAllauddin Khan (founder of rampur maihar seniya gharana) and raga palasi is a traditional raga Raga Bhimpalasi belongs to the Kafi Thaat.
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Bhimpalasi
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Theory
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Aarohana: Ṉ̣ S G̱ M P Ṉ Ṡ Avaroha: Ṡ Ṉ D P M G̱ R SThe raga has komal Ni and Ga. Rishabh (second) and dhaivat (sixth) are skipped in āroha (ascending) passages, but are given due importance when descending (avroha). Since the scale has 5 notes ascending and all 7 descending, the resulting jāti is Audav–Sampūrṇa. It is performed in the early afternoon, from 12:00 P.M. to 3:00 P.M. (the third prahar of the day).Use of dhaivat and rishabh is symmetrical in that both are approached via the succeeding notes (D from Ṉ, and R from G̱).G̱ is sung with a kaṇ-svara (grace note) of M. Similarly, Ṉ is sung with a kaṇ-svara from S.
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Bhimpalasi
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Theory
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Vadi Swar: M Samavadi Swar: S Thaat: Kafi Pakad or Chalan: Ṉ̣ S M ❟ M G̱ P M ❟ G̱ M G̱ R S
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Bhimpalasi
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Bandish Examples
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A bandish is a composition in Hindustani classical music. Both of the following bandishes are examples of Bhimpalasi.
Bandish by Naimat Khan "Sadarang" This bandish is set in Teental. Pandit Jasraj is known for having sung this particular bandish; it is also in the repertoire of Sanjeev Abhyankar.
Prominent Bandish(Composition) by Acharya Dr. Pandit Gokulotsavji Maharaj "MadhurPiya" The Bandish Initials(Bandish Name): "Gāo Bajāo Sab Mil Ātā Umaṅg So" The Bandish is set in tāla Ektal Organisation and relationships Related/similar ragas: Bageshree, Dhanashree, Dhani, Patdeep, Hamsakinkini, Patdeepaki In Carnatic music, Karnataka Devagandhari is the most similar raga, falling with Melakarta 22 (Karaharapriya).
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Bhimpalasi
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Behaviour
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The madhyam (fourth) is the most important note. It is also a nyāsa-svara (resting note) with emphasized elaboration around this note - S G̱ M ❟ M G̱ M ❟ G̱ M P ❟ M P G̱ M P ( M ) G̱ ( M ) G̱ M.
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Bhimpalasi
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Film songs
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Language: Hindi Language: Tamil Note that the following songs are composed in Abheri, the equivalent of raga Bhimpalasi in Carnatic music.
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Bhimpalasi
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Sources
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Bor, Joep; Rao, Suvarnalata (1999). The Raga Guide: A Survey of 74 Hindustani Ragas. Nimbus Records with Rotterdam Conservatory of Music. p. 40. ISBN 9780954397609.
Bhimpalāsi Rāga (Hin), The Oxford Encyclopaedia of the Music of India. Oxford University Press. ISBN 9780195650983. Retrieved 12 October 2018.
Gosvami, O. (1957). The Story Of Indian Music. Bombay: Asia Publishing House.
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Iff card
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Iff card
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Iff card is a contactless smart card introduced in Cardiff in 2010. It allows customers to travel on Cardiff Bus services after having pre-paid.The name "Iff card" is a play on the word "Cardiff".
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Iff card
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Launch
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Having been an aspiration of Cardiff Bus for many years beforehand, the card was launched in October 2010 during a publicity event outside Cardiff Central Library. The first 30,000 cards were issued free of charge and pre-loaded with £3 of credit, after which the cards were charged at £5. The cards are now issued free.The company spent £300,000 on developing the card whose ITSO technology can be shared with other transport providers and public bodies in the future.More than 25,000 applications for the card were received within the first few weeks of its launch.
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Iff card
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Use
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An amount of money is electronically loaded onto the card, either upon boarding a bus or at the Cardiff Bus customer service centre. A passenger then chooses a ticket type. The card can also be used as a season ticket. The card should be topped up when the balance is low, but the card allows the customer to acquire a negative balance up to £3, the first operator in the UK to do so.
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Iff card
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Use
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Those who have registered for an Iff card will be able to be sent service updates via text or e-mail during spells of bad weather.
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Iff card
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Restrictions
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The card can be topped-up in units of £5, £10 and £20 up to maximum amount of £50. The card may be used by persons aged between 6 and 60. The Iff card cannot be used to pay a partial amount. The card would be cancelled if not used for a continuous period of one year
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Iff card
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Future
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The Managing Director of Cardiff Bus hopes the online topping up service would be available by 2011. Executive Member for Cardiff Council hopes the card would become integrated with rail companies so it could be used across all transport systems. Deputy First Minister for Wales, Ieuan Wyn Jones hopes to see the smartcard technology rolled out throughout Wales by 2014.
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Paul Babitzke
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Paul Babitzke
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Paul Babitzke is a professor of biochemistry and molecular biology and director of the Center for RNA Molecular Biology at Pennsylvania State University.
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Paul Babitzke
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Education
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Paul Babitzke obtained his B.A. in biomedical science from St. Cloud State University in Minnesota in 1994. He earned his Ph.D. in genetics from the University of Georgia in 1991.
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Paul Babitzke
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Career
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Before he started at Penn State University in 1994, Babitzke worked as a postdoctoral scientist at Stanford University's department of biological sciences for 3 years. Currently, he is professor of biochemistry and molecular biology at Penn State.He became an assistant professor of biochemistry and molecular biology in 1994 and associate professor in 2000. In 2006, Babitzke was promoted to full professor.Since 2009, he has been serving as director of the Center for RNA Molecular Biology in the Penn State Huck Institutes of the Life Sciences. His research focuses on the regulation of gene expression mediated by RNA polymerase pausing, transcription termination, RNA structure, and RNA-binding proteins.
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Paul Babitzke
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Career
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In 2016, he was elected as Fellow of the American Association for the Advancement of Science.In 2017, he was elected as Fellow of the American Academy of Microbiology.
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Paul Babitzke
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Honors and awards
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Chair, Division H, American Society for Microbiology (ASM) (2006) Chair, NIGMS Microbial Physiology and Genetics-subcommittee 2 (MBC-2) (2004) Daniel R. Tershak Teaching Award (2009) Divisional Group IV Representative, American Society for Microbiology (ASM) (2011-2015) Charles E. Kaufman New Initiative Research Award (2016) Fellow, American Association for the Advancement of Science (AAAS) (2016) Fellow, American Academy of Microbiology (AAM) (2017) St. Cloud State University Biological Sciences Distinguished Alumni Award (2018)
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Paul Babitzke
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Selected publications
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Baker, C.S., Morozov, I., Suzuki, K., Romeo, T., and Babitzke, P. (2002) CsrA regulates glycogen biosynthesis by preventing translation of glgC in Escherichia coli. Mol. Microbiol. 44:1599-1610.
Yakhnin, A.V., and Babitzke, P. (2002) NusA-stimulated RNA polymerase pausing and termination participates in the Bacillus subtilis trp operon attenuation mechanism in vitro. Proc. Natl. Acad. Sci. USA. 99:11067-11072.
Yakhnin, A.V., Yakhnin, H., and Babitzke, P. (2006) RNA polymerase pausing participates in the Bacillus subtilis trpE translation control mechanism by providing additional time for TRAP to bind to the nascent trp leader transcript. Mol. Cell 24:547-557.
Yakhnin, A.V., Yakhnin, H., and Babitzke, P. (2008) Function of the Bacillus subtilis transcription elongation factor NusG in hairpin-dependent RNA polymerase pausing in the trp leader. Proc. Natl. Acad. Sci. USA 105:16131-16136.
Yakhnin, H., Yakhnin, A.V., Baker, C.S., Sineva, E., Berezin, I., Romeo, T., and Babitzke, P. (2011) Complex regulation of the global regulatory gene csrA: CsrA-mediated translational repression, transcription from five promoters by Es70 and EsS, and indirect transcriptional activation by CsrA. Mol. Microbiol. 81:689-704.
Yakhnin, A.V., Baker, C.S., Vakulskas, C.A., Yakhnin, H., Berezin, I., Romeo, T., and Babitzke, P. (2013) CsrA activates flhDC expression by protecting flhDC mRNA from RNase E-mediated cleavage. Mol. Microbiol. 87:851-866.
Mondal, S., Yakhnin, A.V., Sebastian, A., Albert, I., and Babitzke, P. (2016) NusA-dependent transcription termination prevents misregulation of global gene expression. Nat. Microbiol. 1:15007.
Potts, A.H., Vakulskas, C.A., Pannuri, A., Yakhnin, H., Babitzke, P., and Romeo, T. (2017) Global role of the bacterial post-transcriptional regulator CsrA revealed by integrated transcriptomics. Nat. Commun. 8:1596.
Yakhnin, A.V., FitzGerald, P.C., McIntosh, C., Yakhnin, H., Kireeva, M., Turek-Herman, J., Mandell, Z.F., Kashlev, M., and Babitzke, P. (2020) NusG controls transcription pausing and RNA polymerase translocation throughout the Bacillus subtilis genome. Proc. Natl. Acad. Sci. USA 117:21628-21636.
Mandell, Z.F., Oshiro, R.T., Yakhnin, A.V., Kashlev, M., Kearns, D.B., and Babitzke, P. (2021) NusG is an intrinsic transcription termination factor that stimulates motility and coordinates gene expression with NusA. eLife 10:e61880.
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Beckmann thermometer
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Beckmann thermometer
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A Beckmann thermometer is a device used to measure small differences of temperature, but not absolute temperature values. It was invented by Ernst Otto Beckmann (1853 – 1923), a German chemist, for his measurements of colligative properties in 1905. Today its use has largely been superseded by platinum PT100 resistance thermometers and thermocouples.
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Beckmann thermometer
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Beckmann thermometer
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A Beckmann thermometer's length is usually 40 – 50 cm. The temperature scale typically covers about 5 °C and it is divided into hundredths of a degree. With a magnifier it is possible to estimate temperature changes to 0.001 °C. The peculiarity of Beckmann's thermometer design is a reservoir (R on diagram) at the upper end of the tube, by means of which the quantity of mercury in the bulb can be increased or diminished so that the instrument can be set to measure temperature differences at either high or low temperature values. In contrast, the range of a typical mercury-in-glass thermometer is fixed, being set by the calibration marks etched on the glass or the marks on the printed scale.
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Beckmann thermometer
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Calibration
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In setting the thermometer, a sufficient amount of mercury must be left in the bulb and stem to give readings between the required temperatures. First, the thermometer is inverted and gently tapped so that the mercury in the reservoir lodges in the bend (B) at the end of the stem. Next, the bulb is heated until the mercury in the stem joins the mercury in the reservoir. The thermometer is then placed in a bath one or two degrees above the upper limit of temperatures to be measured.
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Beckmann thermometer
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Calibration
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The upper end of the tube is gently tapped with the finger, and the mercury suspended in the upper part of the reservoir will be jarred down, thus separating it from the thread at the bend (B). The thermometer will then be set for readings between the required temperatures.
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Dog Barbos and Unusual Cross
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Dog Barbos and Unusual Cross
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Dog Barbos and Unusual Cross or (Russian: Пёс Барбос и необычный кросс, romanized: Pyos Barbos i neobychnij kross) is a 1961 Soviet short comedy film directed by Leonid Gaidai.
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Dog Barbos and Unusual Cross
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Plot
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A trio of petty criminals – The Coward, The Fool and The Pro go "fishing". They do not only want to eat and drink well, but they also wish to catch a fish. But the conmen do not want to sit on the beach with a fishing rod and wait patiently for a fish to bite, instead they decide to go poaching; their plan is to stun fish using dynamite! Dropping a stick with a dynamite block tied to it into the river, the crooks rub their hands in anticipation of a magnificent "catch", but ... the unruly dog Barbos interferes. The dog manages to fish out the stick of dynamite which is about to explode from the river and rushes towards the poachers! In a panic, the scoundrels run away, but Barbos chases after them, and the three men climb a tall tree. But the cunning dog throws dynamite with a burning safety fuse under a tree, runs away ... and after that there is a loud blast! Poachers who were going to blow away the fish have instead knocked themselves senseless and their clothes get tattered to shreds.
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Dog Barbos and Unusual Cross
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Cast
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Yuri Nikulin – The Fool Georgy Vitsin – The Coward Yevgeny Morgunov – The Pro Georgy Millyar – Water-bailiff (uncredited) Leonid Gaidai – Bear in a tent (deleted scene) Dog Bryokh – Dog Barbos
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Dog Barbos and Unusual Cross
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Filming
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Filming took place in the vicinity of the village of Snegiri in the Istrinsky District of Moscow region, on the banks of the Istra River, and the scene with the explosion of dynamite were shot near the summer residence of Ivan Kozlovsky.
Filmed material in total was enough for a half-hour, but the director Leonid Gaidai reduced it to a ten minutes running time and removed a lot of stunt scenes that were later used in Bootleggers.
During the filming, Yuri Nikulin had huge false eyelashes applied, and the actor diligently blinked. Thus, according to the director, The Fool's face was supposed to look even more silly.
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Dog Barbos and Unusual Cross
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Awards
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Nominated for Short Film Palme d'Or at the 1961 Cannes Film Festival.
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Autosomal dominant hypophosphatemic rickets
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Autosomal dominant hypophosphatemic rickets
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Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary disease in which excessive loss of phosphate in the urine leads to poorly formed bones (rickets), bone pain, and tooth abscesses. ADHR is caused by a mutation in the fibroblast growth factor 23 (FGF23). ADHR affects men and women equally; symptoms may become apparent at any point from childhood through early adulthood. Blood tests reveal low levels of phosphate (hypophosphatemia) and inappropriately normal levels of vitamin D. Occasionally, hypophosphatemia may improve over time as urine losses of phosphate partially correct.ADHR may be lumped in with X-linked hypophosphatemia under general terms such as hypophosphatemic rickets. Hypophosphatemic rickets are associated with at least nine other genetic mutations. Clinical management of hypophosphatemic rickets may differ depending on the specific mutations associated with an individual case, but treatments are aimed at raising phosphate levels to promote normal bone formation. In a 2019 randomised, clinical trial the rickets in children with X-linked hypophosphataemia treated with a human monoclonal antibody against FGF23 called burosumab improved significantly compared to conventional therapy.
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Shadow marks
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Shadow marks
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Shadow marks (shadow relief) are a form of archaeological feature visible from the air. Unlike cropmarks, frost marks and soil marks they require upstanding features to work and are therefore more commonly seen in the context of extant sites rather than previously undiscovered buried ones.
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Shadow marks
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Shadow marks
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They are caused by the differences in height on the ground produced by archaeological remains. In the case of ancient, eroded earthworks these differences are often small and they are most apparent when viewed from the air, when the sun is low in the sky. This causes long shadows to be cast by the higher features, which are illuminated from one side by the sun, with dark shadows marking hollows and depressions.
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Shadow marks
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Shadow marks
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Artificial shadow marks can be created easily by constructing a virtual model of a site by merging aerial images (Photogrammetry) and then vectoring in a virtual light source from any direction and at any angle.
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Potential flow around a circular cylinder
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Potential flow around a circular cylinder
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In mathematics, potential flow around a circular cylinder is a classical solution for the flow of an inviscid, incompressible fluid around a cylinder that is transverse to the flow. Far from the cylinder, the flow is unidirectional and uniform. The flow has no vorticity and thus the velocity field is irrotational and can be modeled as a potential flow. Unlike a real fluid, this solution indicates a net zero drag on the body, a result known as d'Alembert's paradox.
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Potential flow around a circular cylinder
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Mathematical solution
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A cylinder (or disk) of radius R is placed in a two-dimensional, incompressible, inviscid flow. The goal is to find the steady velocity vector V and pressure p in a plane, subject to the condition that far from the cylinder the velocity vector (relative to unit vectors i and j) is: V=Ui+0j, where U is a constant, and at the boundary of the cylinder V⋅n^=0, where n̂ is the vector normal to the cylinder surface. The upstream flow is uniform and has no vorticity. The flow is inviscid, incompressible and has constant mass density ρ. The flow therefore remains without vorticity, or is said to be irrotational, with ∇ × V = 0 everywhere. Being irrotational, there must exist a velocity potential φ: V=∇ϕ.
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Potential flow around a circular cylinder
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Mathematical solution
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Being incompressible, ∇ · V = 0, so φ must satisfy Laplace's equation: ∇2ϕ=0.
The solution for φ is obtained most easily in polar coordinates r and θ, related to conventional Cartesian coordinates by x = r cos θ and y = r sin θ. In polar coordinates, Laplace's equation is (see Del in cylindrical and spherical coordinates): 1r∂∂r(r∂ϕ∂r)+1r2∂2ϕ∂θ2=0.
The solution that satisfies the boundary conditions is cos θ.
The velocity components in polar coordinates are obtained from the components of ∇φ in polar coordinates: cos θ and sin θ.
Being inviscid and irrotational, Bernoulli's equation allows the solution for pressure field to be obtained directly from the velocity field: p=12ρ(U2−V2)+p∞, where the constants U and p∞ appear so that p → p∞ far from the cylinder, where V = U. Using V2 = V2r + V2θ, cos (2θ)−R4r4)+p∞.
In the figures, the colorized field referred to as "pressure" is a plot of cos (2θ)−R4r4.
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Potential flow around a circular cylinder
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Mathematical solution
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On the surface of the cylinder, or r = R, pressure varies from a maximum of 1 (shown in the diagram in red) at the stagnation points at θ = 0 and θ = π to a minimum of −3 (shown in blue) on the sides of the cylinder, at θ = π/2 and θ = 3π/2. Likewise, V varies from V = 0 at the stagnation points to V = 2U on the sides, in the low pressure.
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Potential flow around a circular cylinder
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Mathematical solution
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Stream function The flow being incompressible, a stream function can be found such that V=∇ψ×k.
It follows from this definition, using vector identities, V⋅∇ψ=0.
Therefore, a contour of a constant value of ψ will also be a streamline, a line tangent to V. For the flow past a cylinder, we find: sin θ.
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Potential flow around a circular cylinder
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Physical interpretation
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Laplace's equation is linear, and is one of the most elementary partial differential equations. This simple equation yields the entire solution for both V and p because of the constraint of irrotationality and incompressibility. Having obtained the solution for V and p, the consistency of the pressure gradient with the accelerations can be noted.
The dynamic pressure at the upstream stagnation point has value of 1/2ρU2. a value needed to decelerate the free stream flow of speed U. This same value appears at the downstream stagnation point, this high pressure is again needed to decelerate the flow to zero speed. This symmetry arises only because the flow is completely frictionless.
The low pressure on sides on the cylinder is needed to provide the centripetal acceleration of the flow: ∂p∂r=ρV2L, where L is the radius of curvature of the flow. But L ≈ R, and V ≈ U. The integral of the equation for centripetal acceleration over a distance Δr ≈ R will thus yield p−p∞≈−ρU2.
The exact solution has, for the lowest pressure, p−p∞=−32ρU2.
The low pressure, which must be present to provide the centripetal acceleration, will also increase the flow speed as the fluid travels from higher to lower values of pressure. Thus we find the maximum speed in the flow, V = 2U, in the low pressure on the sides of the cylinder.
A value of V > U is consistent with conservation of the volume of fluid. With the cylinder blocking some of the flow, V must be greater than U somewhere in the plane through the center of the cylinder and transverse to the flow.
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Potential flow around a circular cylinder
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Comparison with flow of a real fluid past a cylinder
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The symmetry of this ideal solution has a stagnation point on the rear side of the cylinder, as well as on the front side. The pressure distribution over the front and rear sides are identical, leading to the peculiar property of having zero drag on the cylinder, a property known as d'Alembert's paradox. Unlike an ideal inviscid fluid, a viscous flow past a cylinder, no matter how small the viscosity, will acquire a thin boundary layer adjacent to the surface of the cylinder. Boundary layer separation will occur, and a trailing wake will exist in the flow behind the cylinder. The pressure at each point on the wake side of the cylinder will be lower than on the upstream side, resulting in a drag force in the downstream direction.
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Potential flow around a circular cylinder
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Janzen–Rayleigh expansion
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The problem of potential compressible flow over circular cylinder was first studied by O. Janzen in 1913 and by Lord Rayleigh in 1916 with small compressible effects. Here, the small parameter is square of the Mach number M2=U2/c2≪1 , where c is the speed of sound. Then the solution to first-order approximation in terms of the velocity potential is cos 12 13 cos cos 3θ]+O(M4) where a is the radius of the cylinder.
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Potential flow around a circular cylinder
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Potential flow over a circular cylinder with slight variations
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Regular perturbation analysis for a flow around a cylinder with slight perturbation in the configurations can be found in Milton Van Dyke (1975). In the following, ε will represent a small positive parameter and a is the radius of the cylinder. For more detailed analyses and discussions, readers are referred to Milton Van Dyke's 1975 book Perturbation Methods in Fluid Mechanics.
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Potential flow around a circular cylinder
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Potential flow over a circular cylinder with slight variations
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Slightly distorted cylinder Here the radius of the cylinder is not r = a, but a slightly distorted form r = a(1 − ε sin2 θ). Then the solution to first-order approximation is sin sin sin 3θ)+O(ε2) Slightly pulsating circle Here the radius of the cylinder varies with time slightly so r = a(1 + ε f(t)). Then the solution to first-order approximation is sin sin θ)+O(ε2) Flow with slight vorticity In general, the free-stream velocity U is uniform, in other words ψ = Uy, but here a small vorticity is imposed in the outer flow.
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Potential flow around a circular cylinder
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Potential flow over a circular cylinder with slight variations
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Linear shear Here a linear shear in the velocity is introduced.
as x→−∞, where ε is the small parameter. The governing equation is ∇2ψ=−ω(ψ).
Then the solution to first-order approximation is sin cos cos 2θ−ar)+O(ε2).
Parabolic shear Here a parabolic shear in the outer velocity is introduced.
as x→−∞.
Then the solution to the first-order approximation is sin sin ln sin θ+χ)+O(ε2), where χ is the homogeneous solution to the Laplace equation which restores the boundary conditions.
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Potential flow around a circular cylinder
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Potential flow over a circular cylinder with slight variations
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Slightly porous cylinder Let Cps represent the surface pressure coefficient for an impermeable cylinder: sin cos 2θ−1, where ps is the surface pressure of the impermeable cylinder. Now let Cpi be the internal pressure coefficient inside the cylinder, then a slight normal velocity due to the slight porousness is given by cos at r=a, but the zero net flux condition ∫02π1r∂ψ∂θdθ=0 requires that Cpi = −1. Therefore, cos at r=a.
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Potential flow around a circular cylinder
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Potential flow over a circular cylinder with slight variations
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Then the solution to the first-order approximation is sin sin 2θ+O(ε2).
Corrugated quasi-cylinder If the cylinder has variable radius in the axial direction, the z-axis, r = a (1 + ε sin z/b), then the solution to the first-order approximation in terms of the three-dimensional velocity potential is cos cos sin zb+O(ε2), where K1(r/b) is the modified Bessel function of the first kind of order one.
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EOTD
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EOTD
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eOTD is the acronym for the ECCMA Open Technical Dictionary. The dictionary is a language-independent database of concepts with associated terms, definitions and images used to unambiguously describe individuals, organizations, locations, goods, services, processes, rules, and regulations. The eOTD is maintained by the Electronic Commerce Code Management Association (ECCMA).
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EOTD
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History
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The eOTD was developed with the support of the Defense Logistics Information Service (DLIS) an agency of the US Defense Logistics Agency (DLA). The eOTD is the first dictionary to be compliant with ISO 22745 (open technical dictionaries).
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EOTD
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Structure
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The eOTD contains terms, definitions and images linked to concept identifiers. eOTD concept identifiers are used to create unambiguous language independent descriptions of individuals, organizations, locations, goods, services, processes, rules and regulations. The process of using concept identifiers from an external open technical dictionary is a form of semantic encoding compliant with the requirements of ISO 8000-110:2008, the international standard for the exchange of quality master data.
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EOTD
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Structure
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The eOTD concept identifiers are in the public domain. Using public domain identifiers as metadata creates portable data that can be legally separated from the software application that was used to create it. The dictionary contains concepts from international, national and industry standards including over 400,000 concepts of class (approved item name), property (attribute), units of measure, currency and common enumerated value (e.g., days of the week). The eOTD does not include a class hierarchy or class-property relationships.
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EOTD
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Use
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Companies use the eOTD to create data requirement specifications as Identification Guides (IGs) or cataloging templates. These Identification Guides contain the class-property relationships and are used for cataloging, to measure data quality as well as to create requests for data or requests for data validation.
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EOTD
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Industrial products and services categorization standards
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eCl@ss ETIM (standard) UNSPSC eOTD RosettaNet
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Smoke point
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Smoke point
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The smoke point, also referred to as the burning point, is the temperature at which an oil or fat begins to produce a continuous bluish smoke that becomes clearly visible, dependent upon specific and defined conditions. Smoke point values can vary greatly, depending on factors such as the volume of oil utilized, the size of the container, the presence of air currents, the type and source of light as well as the quality of the oil and its acidity content, otherwise known as free fatty acid (FFA) content. The more FFA an oil contains, the quicker it will break down and start smoking. The lower the value of FFA, the higher the smoke point. However, the FFA content typically represents less than 1% of the total oil and consequently renders smoke point a poor indicator of the capacity of a fat or oil to withstand heat.
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Smoke point
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Temperature
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The smoke point of an oil correlates with its level of refinement. Many cooking oils have smoke points above standard home cooking temperatures: Pan frying (sauté) on stove top heat: 120 °C (248 °F) Deep frying: 160–180 °C (320–356 °F) Oven baking: Average of 180 °C (356 °F)Smoke point decreases at different pace in different oils.Considerably above the temperature of the smoke point is the flash point, the point at which the vapours from the oil can ignite in air, given an ignition source.
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Smoke point
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Temperature
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The following table presents smoke points of various fats and oils.
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Smoke point
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Oxidative stability
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Hydrolysis and oxidation are the two primary degradation processes that occur in an oil during cooking. Oxidative stability is how resistant an oil is to reacting with oxygen, breaking down and potentially producing harmful compounds while exposed to continuous heat. Oxidative stability is the best predictor of how an oil behaves during cooking.The Rancimat method is one of the most common methods for testing oxidative stability in oils. This determination entails speeding up the oxidation process in the oil (under heat and forced air), which enables its stability to be evaluated by monitoring volatile substances associated with rancidity. It is measured as "induction time" and recorded as total hours before the oil breaks down. Canola oil requires 7.5 hours, for example, whereas extra virgin olive oil (EVOO) and virgin coconut oil will last over a day at 110 °C of continuous heat. The differing stabilities correlate with lower levels of polyunsaturated fatty acids, which are more prone to oxidation. EVOO is high in monounsaturated fatty acids and antioxidants, conferring stability. Some plant cultivars have been bred to produce "high-oleic" oils with more monounsaturated oleic acid and less polyunsaturated linoleic acid for enhanced stability.The oxidative stability does not directly correspond to the smoke point and thus the latter cannot be used as a reference for safe and healthy cooking.
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Articular cartilage repair
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Articular cartilage repair
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Articular cartilage repair treatment involves the repair of the surface of an articular joint's hyaline cartilage. Over the last few decades, surgeons and researchers have made progress in elaborating surgical cartilage repair interventions. Though these solutions do not perfectly restore the articular cartilage, some of the latest technologies have started to bring very promising results in repairing cartilages from traumatic injuries or chondropathies. These treatments have been shown to be especially beneficial for patients who have articular cartilage damage. They can provide some measure of pain relief, while at the same time slowing down the accumulation of damage, or considerably delaying the need for joint replacement (knee replacement) surgery.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Though the different articular cartilage repair procedures differ in the technologies and surgical techniques used, they all share the same aim to repair articular cartilage whilst keeping options open for alternative treatments in the future. Broadly taken, there are five major types of articular cartilage repair: Arthroscopic lavage / debridement Arthroscopic lavage is a "cleaning up" procedure of the knee joint. This short-term solution is not considered as an articular cartilage repair procedure but rather a palliative treatment to reduce pain, mechanical restriction and inflammation. Lavage focuses on removing degenerative articular cartilage flaps and fibrous tissue. The main target groups are patients with very small defects of the articular cartilage.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Marrow stimulation techniques (micro-fracture surgery and others) Marrow stimulating techniques attempt to solve articular cartilage damage through an arthroscopic procedure. Firstly, the damaged cartilage is drilled or punched until the underlying bone is exposed. By doing this, the subchondral bone is perforated to generate a blood clot within the defect. Studies, however, have shown that marrow stimulation techniques often have insufficiently filled the chondral defect and the repair material is often fibrocartilage (which is not as good mechanically as hyaline cartilage). The blood clot takes about 8 weeks to become fibrous tissue and it takes 4 months to become fibrocartilage. This has implications for the rehabilitation.Further on, chances are high that after only 1 or 2 years of the surgery symptoms start to return as the fibrocartilage wears away, forcing the patient to reengage in articular cartilage repair. This is not always the case and microfracture surgery is therefore considered to be an intermediate step.An evolvement of the microfracture technique is the implantation of a collagen membrane onto the site of the microfracture to protect and stabilize the blood clot and to enhance the chondrogenic differentiation of the MSCs. This technique is known as AMIC (Autologous Matrix-Induced Chondrogenesis) and was first published in 2003.Microfracture techniques show new potential, as animal studies indicate that microfracture-activated skeletal stem-cells form articular cartilage, instead of fibrous tissue, when co-delivered with a combination of BMP2 and VEGF receptor antagonist.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Marrow stimulation augmented with hydrogel implant A hydrogel implant to help the body regrow cartilage in the knee is currently being studied in U.S. and European clinical trials. Called GelrinC, the implant is made of a synthetic material called polyethylene glycol (PEG) and denatured human fibrinogen protein.During the standard microfracture procedure, the implant is applied to the cartilage defect as a liquid. It is then exposed to UVA light for 90 seconds, turning it into a solid, soft implant that completely occupies the space of the cartilage defect.
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Articular cartilage repair
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Different articular cartilage repair procedures
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The implant is designed to support the formation of hyaline cartilage through a unique guided tissue mechanism. It protects the repair site from infiltration of undesired fibrous tissue while providing the appropriate environment for hyaline cartilage matrix formation. Over six to 12 months, the implant resorbs from its surface inward, enabling it to be gradually replaced with new cartilage.Preliminary clinical studies in Europe have shown the implant improves pain and function.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Marrow stimulation augmented with peripheral blood stem cells A 2011 study reports histologically confirmed hyaline cartilage regrowth in a 5 patient case-series, 2 with grade IV bipolar or kissing lesions in the knee. The successful protocol involves arthroscopic microdrilling/ microfracture surgery followed by postoperative injections of autologous peripheral blood progenitor cells (PBPC's) and hyaluronic acid (HA). PBPC's are a blood product containing mesenchymal stem cells and is obtained by mobilizing the stem cells into the peripheral blood. Khay Yong Saw and his team propose that the microdrilling surgery creates a blood clot scaffold on which injected PBPC's can be recruited and enhance chondrogenesis at the site of the contained lesion. They explain that the significance of this cartilage regeneration protocol is that it is successful in patients with historically difficult-to-treat grade IV bipolar or bone-on-bone osteochondral lesions.Saw and his team are currently conducting a larger randomized trial and working towards beginning a multicenter study. The work of the Malaysian research team is gaining international attention.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Osteochondral autografts and allografts This technique/repair requires transplant sections of bone and cartilage. First, the damaged section of bone and cartilage is removed from the joint. Then a new healthy dowel of bone with its cartilage covering is punched out of the same joint and replanted into the hole left from removing the old damaged bone and cartilage. The healthy bone and cartilage are taken from areas of low stress in the joint so as to prevent weakening the joint. Depending on the severity and overall size of the damage multiple plugs or dowels may be required to adequately repair the joint, which becomes difficult for osteochondral autografts. The clinical results may deteriorate over time.For osteochondral allografts, the plugs are taken from deceased donors. This has the advantage that more osteochondral tissue is available and larger damages can be repaired using either the plug (snowman) technique or by hand carving larger grafts. There are, however, worries on the histocompatibility, though no rejection drugs are required and infection has been shown to be lesser than that of a total knee or hip. Osteochondral allografting using donor cartilage has been used most historically in knees, but is also emerging in hips, ankles, shoulders and elbows. Patients are typically younger than 55, with BMI below 35, and have a desire to maintain a higher activity level that traditional joint replacements would not allow. Advances in tissue preservation and surgical technique are quickly growing this surgery in popularity.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Joint distraction arthroplasty This technique involves physically separating a joint for a period of time (typically 8–12 weeks) to allow for cartilage regeneration.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Cell-based repairs Aiming to obtain the best possible results, scientists have striven to replace damaged articular cartilage with healthy articular cartilage. Previous repair procedures, however, always generated fibrocartilage or, at best, a combination of hyaline and fibrocartilage repair tissue. Autologous chondrocyte implantation (ACI) procedures are cell-based repairs that aim to achieve a repair consisting of healthy articular cartilage.ACI articular cartilage repair procedures take place in three stages. First, cartilage cells are extracted arthroscopically from the patient's healthy articular cartilage that is located in a non load-bearing area of either the intercondylar notch or the superior ridge of the femoral condyles. Then these extracted cells are transferred to an in vitro environment in specialised laboratories where they grow and replicate, for approximately four to six weeks, until their population has increased to a sufficient amount. Finally, the patient undergoes a second surgery where the in vitro chondrocytes are applied to the damaged area. In this procedure, chondrocytes are injected and applied to the damaged area in combination with either a membrane or a matrix structure. These transplanted cells thrive in their new environment, forming new articular cartilage.
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Articular cartilage repair
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Different articular cartilage repair procedures
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Autologous mesenchymal stem cell transplant For years, the concept of harvesting stem cells and re-implanting them into one's own body to regenerate organs and tissues has been embraced and researched in animal models. In particular, mesenchymal stem cells have been shown in animal models to regenerate cartilage. Recently, there has been a published case report of decrease in knee pain in a single individual using autologous mesenchymal stem cells. An advantage to this approach is that a person's own stem cells are used, avoiding transmission of genetic diseases. It is also minimally invasive, minimally painful and has a very short recovery period. This alternative to the current available treatments was shown not to cause cancer in patients who were followed for 3 years after the procedure.See also Stem cell transplantation for articular cartilage repair Drug therapies While there are currently no drugs approved for human use, there are multiple drugs currently in development which are aimed at slowing the progression of cartilage degeneration and even potentially repairing it. These are usually referred to DMOADs.
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Articular cartilage repair
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The importance of rehabilitation in articular cartilage repair
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Rehabilitation following any articular cartilage repair procedure is paramount for the success of any articular cartilage resurfacing technique. The rehabilitation is often long and demanding. The main reason is that it takes a long time for the cartilage cells to adapt and mature into repair tissue. Cartilage is a slow adapting substance. Where a muscle takes approximately 35 weeks to fully adapt itself, cartilage only undergoes 75% adaptation in 2 years. If the rehabilitation period is too short, the cartilage repair might be put under too much stress, causing the repair to fail.
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Articular cartilage repair
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Concerns
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New research by Robert Litchfield, September 2008, of the University of Western Ontario concluded that routinely practised knee surgery is ineffective at reducing joint pain or improving joint function in people with osteoarthritis. The researchers did however find that arthroscopic surgery did help a minority of patients with milder symptoms, large tears or other damage to the meniscus — cartilage pads that improve the congruence between femur and tibia bones. Similarly, a 2013 Finnish study found surgery to be ineffective for knee surgery (arthroscopic partial meniscectomy), by comparing to sham treatment.
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