spalde-v3-lexical
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0.0009760859538801014, "25292": 0.953857421875, "25458": 0.3554046154022217, "25690": 0.20818853378295898, "26179": 1.0298984050750732, "26244": 0.49864232540130615, "26279": 0.3012613356113434, "26402": 0.15860503911972046, "26524": 0.7737906575202942, "26601": 0.9531047344207764, "26721": 0.6664261221885681, "27133": 0.8917738795280457, "27544": 0.1358480453491211, "27651": 0.06886265426874161, "27709": 0.9710156321525574, "27753": 1.262204885482788, "27854": 0.10203468054533005, "27969": 0.23247487843036652, "28281": 0.3588210940361023, "28667": 0.554580807685852, "28691": 0.2637155055999756, "28699": 0.5898461937904358, "28835": 0.1734936386346817, "28991": 0.0913962796330452} | 7116734 | Nicotinamide (Nam) phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in mammalian NAD synthesis, catalyzing nicotinamide mononucleotide (NMN) formation from Nam and 5-phosphoribosyl 1-pyrophosphate (PRPP). NAMPT has also been described as an adipocytokine visfatin with a variety of actions, although physiological significance of this protein remains unclear. It has been proposed that possible actions of visfatin are mediated through the extracellular formation of NMN. However, we did not detect NMN in mouse blood plasma, even with a highly specific and sensitive liquid chromatography/tandem mass spectrometry. Furthermore, there is no or little ATP, the activator of NAMPT, in extracellular spaces. We thus questioned whether visfatin catalyzes the in situ formation of NMN under such extracellular milieus. To address this question, we here determined K(m) values for the substrates Nam and PRPP in the NAMPT reaction without or with ATP using a recombinant human enzyme and found that 1 mM ATP dramatically decreases K(m) values for the substrates, in particular PRPP to its intracellular concentration. Consistent with the kinetic data, only when ATP is present at millimolar levels, NAMPT efficiently catalyzed the NMN formation at the intracellular concentrations of the substrates. Much lower concentrations of Nam and almost the absence of PRPP and ATP in the blood plasma suggest that NAMPT should not efficiently catalyze its reaction under the extracellular milieu. Indeed, NAMPT did not form NMN in the blood plasma. From these kinetic analyses of the enzyme and quantitative determination of its substrates, activator, and product, we conclude that visfatin does not participate in NMN formation under the extracellular milieus. Together with the absence of NMN in the blood plasma, our conclusion does not support the concept of "NAMPT-mediated systemic NAD biosynthesis. " Our study would advance current understanding of visfatin physiology. | Nicotinamide Phosphoribosyltransferase/Visfatin Does Not Catalyze Nicotinamide Mononucleotide Formation in Blood Plasma |
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DNA (cccDNA), the replicative intermediate responsible for persistent HBV infection of hepatocytes, is the template for transcription of all viral mRNAs. Nuclear cccDNA accumulates as a stable episome organized into minichromosomes by histone and nonhistone proteins. In this study we investigated, by a newly developed sensitive and specific assay, the relationship between viral replication and HBV chromatin assembly, transcription, and interaction with viral and cellular regulatory proteins. METHODS To achieve this aim we coupled a quantitative chromatin immunoprecipitation (ChIP) technique to an established method that allows the amplification of virion-encapsidated HBV genomes after transfection of linear HBV DNA into human hepatoma HuH7 cells. The cccDNA-ChIP technique was also applied to study HBV minichromosome transcriptional regulation in liver tissue from HBV-infected patients. RESULTS The use of anti-acetyl-H4/-H3 specific antibodies to immunoprecipitate transcriptionally active chromatin revealed that HBV replication is regulated by the acetylation status of the cccDNA-bound H3/H4 histones. Class I histone deacetylases inhibitors induced an evident increase of both cccDNA-bound acetylated H4 and HBV replication. Finally, histones hypoacetylation and histone deacetylase 1 recruitment onto the cccDNA in liver tissue correlated with low HBV viremia in hepatitis B patients. CONCLUSIONS We developed a ChIP-based assay to analyze, in vitro and ex vivo, the transcriptional regulation of HBV cccDNA minichromosome. Our results provide new insights on the regulation of HBV replication and identify the enzymatic activities that modulate the acetylation of cccDNA-bound histones as new therapeutic targets for anti-HBV drugs. | Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. |
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distinction between live cells in the G(1) and S/G(2)/M phases by dual-color imaging. This technology relies upon ubiquitylation-mediated proteolysis, and transgenic mice expressing Fucci provide a powerful model system with which to study the coordination of the cell cycle and development. The mice were initially generated using the CAG promoter; lines expressing the G(1) and S/G(2)/M phase probes that emitted orange (mKO2) and green (mAG) fluorescence, respectively, were separately constructed. Owing to cell type-biased strength of the CAG promoter as well as the positional effects of random transgenesis, however, we noticed some variability in Fucci expression levels. To control more reliably the expression of cell cycle probes, we used different genetic approaches to create two types of reporter mouse lines with Fucci2 and Rosa26 transcriptional machinery. Fucci2 is a recently developed Fucci derivative, which emits red (mCherry) and green (mVenus) fluorescence and provides better color contrast than Fucci. A new transgenic line, R26p-Fucci2, utilizes the Rosa26 promoter and harbors the G(1) and S/G(2)/M phase probes in a single transgene to preserve their co-inheritance. In the other R26R-Fucci2 approach, the two probes are incorporated into Rosa26 locus conditionally. The Cre-mediated loxP recombination technique thus allows researchers to design cell-type-specific Fucci2 expression. By performing time-lapse imaging experiments using R26p-Fucci2 and R26-Fucci2 in which R26R-Fucci2 had undergone germline loxP recombination, we demonstrated the great promise of these mouse reporters for studying cell cycle behavior in vivo. | Visualization of cell cycle in mouse embryos with Fucci2 reporter directed by Rosa26 promoter. |
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Time-lapse fluorescence microscopy has documented striking dynamics of opposed T6SS organelles in adjacent sister cells of Pseudomonas aeruginosa. Such cell-cell interactions have been termed "T6SS dueling" and likely reflect a biological process that is driven by T6SS antibacterial attack. Here, we show that T6SS dueling behavior strongly influences the ability of P. aeruginosa to prey upon heterologous bacterial species. We show that, in the case of P. aeruginosa, T6SS-dependent killing of either Vibrio cholerae or Acinetobacter baylyi is greatly stimulated by T6SS activity occurring in those prey species. Our data suggest that, in P. aeruginosa, T6SS organelle assembly and lethal counterattack are regulated by a signal that corresponds to the point of attack of the T6SS apparatus elaborated by a second aggressive T6SS(+) bacterial cell. PAPERFLICK: | Tit-for-Tat: Type VI Secretion System Counterattack during Bacterial Cell-Cell Interactions |
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regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders. | The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. |
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They are also caused by ionizing radiation, chemical damage or as part of the series of programmed events that occur during meiosis. In yeast, DSB repair requires RAD52, a protein that plays a critical role in homologous recombination. Here we describe the actions of human RAD52 protein in a model system for single-strand annealing (SSA) using tailed (i.e. exonuclease resected) duplex DNA molecules. Purified human RAD52 protein binds resected DSBs and promotes associations between complementary DNA termini. Heteroduplex intermediates of these recombination reactions have been visualized by electron microscopy, revealing the specific binding of multiple rings of RAD52 to the resected termini and the formation of large protein complexes at heteroduplex joints formed by RAD52-mediated annealing. | Visualization of recombination intermediates produced by RAD52-mediated single-strand annealing. |
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"28788": 0.12814582884311676, "28873": 0.3005385100841522, "29076": 0.09938567131757736, "29166": 0.9279413223266602, "29290": 0.22548456490039825, "29300": 1.2047537565231323} | 7155555 | Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF)1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP−/− and to a lesser degree also IRF2−/− mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-γ in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-γ stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-γ–mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting. | Crucial Role of Interferon Consensus Sequence Binding Protein, but neither of Interferon Regulatory Factor 1 nor of Nitric Oxide Synthesis for Protection Against Murine Listeriosis |
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Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans. | Neuronal replacement from endogenous precursors in the adult brain after stroke |
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0.8366385698318481, "26083": 0.06246116757392883, "26402": 0.9994535446166992, "26520": 0.26820653676986694, "26534": 0.19541899859905243, "26651": 0.3283478021621704, "26661": 0.020300358533859253, "26745": 0.5495203733444214, "26773": 0.46302130818367004, "27144": 0.3777405619621277, "27184": 0.1332872211933136, "27218": 0.32764431834220886, "27373": 0.29400965571403503, "27881": 0.04394211992621422, "29490": 0.19220098853111267} | 7165938 | PURPOSE The circadian clock gene Bmal1 is involved in cancer cell proliferation and DNA damage sensitivity. The aim of this study was to explore the effect of Bmal1 on oxaliplatin sensitivity and to determine its clinical significance in colorectal cancer. EXPERIMENTAL DESIGN Three colorectal cancer cell lines, HCT116, THC8307 and HT29, were used. The Bmal1-mediated control of colorectal cancer cell proliferation was tested in vitro and in vivo. MTT and colony formation assays were performed to determine the sensitivity of colorectal cancer cells to oxaliplatin. Flow cytometry was used to examine changes in the cell-cycle distribution and apoptosis rate. Proteins expressed downstream of Bmal1 upon its overexpression were determined by Western blotting. Immunohistochemistry was used to analyze Bmal1 expression in 82 archived colorectal cancer tumors from patients treated with oxaliplatin-based regimens. RESULTS Bmal1 overexpression inhibited colorectal cancer cell proliferation and increased colorectal cancer sensitivity to oxaliplatin in three colorectal cancer cell lines and HCT116 cells model in vivo. Furthermore, the overall survival of patients with colorectal cancer with high Bmal1 levels in their primary tumors was significantly longer than that of patients with low Bmal1 levels (27 vs. 19 months; P = 0.043). The progression-free survival of patients with high Bmal1 expression was also significantly longer than that of patients with low Bmal1 expression (11 vs. 5 months; P = 0.015). Mechanistically, the effect of Bmal1 was associated with its ability to regulate G2-M arrest by activating the ATM pathway. CONCLUSION Bmal1 shows the potential as a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer. | Overexpression of the circadian clock gene Bmal1 increases sensitivity to oxaliplatin in colorectal cancer. |
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0.14518201351165771, "29327": 1.3735177516937256, "29458": 0.055094651877880096, "29562": 0.37707099318504333} | 7177329 | Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes. | Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape |
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0.9987343549728394, "26741": 0.014542185701429844, "26906": 1.1160377264022827, "26996": 0.8212929964065552, "27142": 0.7683706283569336, "27226": 0.29981520771980286, "27295": 0.15442965924739838, "27467": 0.32341301441192627, "27570": 0.4311734735965729, "27777": 0.0029254043474793434, "28054": 0.3656192123889923, "28079": 0.21765978634357452, "28268": 0.3601844012737274, "28283": 0.14686977863311768, "28467": 0.08871890604496002, "28767": 0.23864774405956268, "28964": 0.19782574474811554, "29090": 0.2089812457561493, "29180": 0.46117570996284485, "29290": 0.01934296265244484, "29516": 0.4286321699619293} | 7185591 | Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes. | Sir2-Independent Life Span Extension by Calorie Restriction in Yeast |
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0.045809537172317505, "23650": 0.0009760859538801014, "23736": 0.12814582884311676, "23900": 0.12038381397724152, "24327": 0.14939609169960022, "24335": 0.1602703034877777, "25034": 0.09938567131757736, "25055": 0.08692999184131622, "25458": 0.0317181795835495, "25468": 0.04860413447022438, "25604": 0.8666408061981201, "25610": 1.3695534467697144, "25714": 0.03925827145576477, "25778": 0.03831886500120163, "25937": 0.16607704758644104, "27090": 0.8715548515319824, "27321": 0.14349138736724854, "27784": 0.0606246218085289, "28073": 0.29400965571403503, "28428": 0.8941729068756104, "28479": 1.2210142612457275, "28696": 0.1751343309879303, "28788": 0.5104349255561829, "28873": 0.11081436276435852, "29720": 0.4938860833644867} | 7198295 | The aim of the study was to determine the effect of single whole-body cryotherapy (WBC) session applied prior to submaximal exercise on the activity of antioxidant enzymes, the concentration of lipid peroxidation products, total oxidative status, and the level of cytokines in blood of volleyball players. The study group consisted of 18 male professional volleyball players, who were subjected to extremely cold air (-130°C) prior to exercise performed on cycloergometer. Blood samples were taken five times: before WBC, after WBC procedure, after exercise preceded by cryotherapy (WBC exercise), and before and after exercise without WBC (control exercise). The activity of catalase statistically significantly increased after control exercise. Moreover, the activity of catalase and superoxide dismutase was lower after WBC exercise than after control exercise (P < 0.001). After WBC exercise, the level of IL-6 and IL-1β was also lower (P < 0.001) than after control exercise. The obtained results may suggest that cryotherapy prior to exercise may have some antioxidant and anti-inflammatory properties. The relations between the level of studied oxidative stress and inflammatory markers may testify to the contribution of reactive oxygen species in cytokines release into the blood system in response to exercise and WBC. | The Effect of Submaximal Exercise Preceded by Single Whole-Body Cryotherapy on the Markers of Oxidative Stress and Inflammation in Blood of Volleyball Players |
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0.007782140281051397, "24650": 0.29473719000816345, "25022": 0.4537591338157654, "25048": 0.38574060797691345, "25191": 0.3283478021621704, "25312": 0.02792670577764511, "25354": 0.987156867980957, "25406": 0.1064341589808464, "25604": 0.5290185213088989, "25937": 0.09584271162748337, "25947": 0.7105726003646851, "26319": 0.347847044467926, "26445": 0.08782484382390976, "27247": 0.1693800985813141, "27258": 0.06154331564903259, "27292": 0.1734936386346817, "27323": 0.7755908370018005, "27534": 0.04953393340110779, "27651": 0.04487626627087593, "28093": 0.5534584522247314, "28228": 0.8039615154266357, "28428": 0.1212492436170578, "28507": 0.08064348995685577, "28689": 0.3810817003250122, "28929": 1.223315715789795, "28977": 0.5696102976799011, "29101": 0.5232481360435486, "29160": 0.6916812658309937, "29264": 0.2394166737794876, "29333": 1.147526502609253, "29562": 0.3656192123889923} | 7209559 | CONTEXT The incidence of distal forearm fractures in children peaks around the time of the pubertal growth spurt, possibly because physical activity increases at the time of a transient deficit in cortical bone mass due to the increased calcium demand during maximal skeletal growth. Changes in physical activity or diet may therefore influence risk of forearm fracture. OBJECTIVE To determine whether there has been a change in the incidence of distal forearm fractures in children in recent years. DESIGN, SETTING, AND PATIENTS Population-based study among Rochester, Minn, residents younger than 35 years with distal forearm fractures in 1969-1971, 1979-1981, 1989-1991, and 1999-2001. MAIN OUTCOME MEASURE Estimated incidence of distal forearm fractures in 4 time periods. RESULTS Comparably age- and sex-adjusted annual incidence rates per 100 000 increased from 263.3 (95% confidence interval [CI], 231.1-295.4) in 1969-1971 to 322.3 (95% CI, 285.3-359.4) in 1979-1981 and to 399.8 (95% CI, 361.0-438.6) in 1989-1991 before leveling off at 372.9 (95% CI, 339.1-406.7) in 1999-2001. Age-adjusted incidence rates per 100 000 were 32% greater among male residents in 1999-2001 compared with 1969-1971 (409.4 [95% CI, 359.9-459.0] vs 309.4 [95% CI, 259.3-359.5]; P =.01) and 56% greater among female residents in the same time periods (334.3 [95% CI, 288.6-380.1] vs 214.6 [95% CI, 174.9-254.4]; P<.001). The peak incidence and greatest increase occurred between ages 11 and 14 years in boys and 8 and 11 years in girls. CONCLUSIONS There has been a statistically significant increase in the incidence of distal forearm fractures in children and adolescents, but whether this is due to changing patterns of physical activity, decreased bone acquisition due to poor calcium intake, or both is unclear at present. Given the large number of childhood fractures, however, studies are needed to define the cause(s) of this increase. | Incidence of childhood distal forearm fractures over 30 years: a population-based study. |
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"26305": 0.2478361576795578, "26702": 0.23015019297599792, "26745": 0.6389714479446411, "26874": 0.7898768186569214, "27002": 0.18978065252304077, "27152": 0.20102575421333313, "27258": 0.11168810725212097, "27287": 0.6202403903007507, "27354": 0.8298473954200745, "27642": 0.8633513450622559, "27697": 0.058784693479537964, "27710": 0.8633513450622559, "27790": 0.1889725625514984, "27794": 0.7086513638496399, "27881": 0.20818853378295898, "28024": 0.40806588530540466, "28086": 0.23556606471538544, "28667": 0.7333439588546753, "28828": 0.28963330388069153, "29060": 0.11256109178066254, "29129": 0.6400018334388733, "29206": 0.21687394380569458, "29251": 0.8425432443618774, "29458": 0.6517757177352905, "29494": 0.08603433519601822} | 7211056 | UNLABELLED The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04-21.37; validation data: HR, 1.59, 95% CI, 1.05-2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution. SIGNIFICANCE Our work sheds light on the importance of whole-genome–doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type. | Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. |
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"27781": 0.47402387857437134, "27854": 0.18167030811309814, "28156": 0.3269403576850891, "28290": 0.11081436276435852, "28487": 0.7454653382301331, "28731": 0.7482418417930603, "28767": 0.8764448165893555, "28873": 0.45994341373443604, "29295": 0.21293537318706512, "29720": 0.7229714393615723} | 7221410 | The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD. | Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta |
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0.5162794589996338, "27781": 0.06795065850019455, "27854": 0.23710809648036957, "27915": 0.45499902963638306, "28163": 0.15442965924739838, "28579": 0.41065993905067444, "28667": 0.1970241367816925, "28674": 0.0029254043474793434, "28691": 0.05970508232712746, "28741": 0.0174254160374403, "28829": 0.5057345628738403, "28835": 0.9470623731613159, "28927": 0.12038381397724152, "29088": 0.04113444685935974, "29290": 0.3262358605861664, "29393": 0.1510767638683319} | 7223604 | To study the effector function of the ADP- ribosylation factor (ARF) 6 GTP-binding protein, we transfected HeLa cells with wild-type, epitope-tagged ARF6. Previously shown to indirectly activate the ARF1 GTPase, aluminum fluoride (AIF) treatment of ARF6-transfected cells resulted in a redistribution of both ARF6 and actin to discrete sites on the plasma membrane, which became increasingly protrusive over time. The effects of AIF were reversible, specific to cells transfected with wild-type ARF6, and resembled the cellular protrusions observed in cells expressing the GTPase defective mutant of ARF6. Importantly, the protrusions observed in cells transfected with ARF6 were distinct from the enhanced stress fibers and membrane ruffles observed in cells transfected with RhoA and Rac1, respectively. In cells forming protrusions, there was an apparent stimulation of macropinocytosis and membrane recycling within the protrusive structures. In contrast, no block in transferrin uptake or alteration of the distribution of clathrin AP-2 complexes was detected in these cells. The AIF-induced, ARF6- dependent formation of protrusive structures was blocked by cytochalasin D and inhibitors of the lipoxygenase pathway. These observations support a novel role for the ARF6 GTPase in modeling the plasma membrane and underlying cytoskeleton. | Aluminum fluoride stimulates surface protrusions in cells overexpressing the ARF6 GTPase |
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0.31845372915267944, "28436": 0.12642613053321838, "28472": 0.007782140281051397, "28527": 0.7426811456680298, "28667": 0.010684899985790253, "28715": 0.1751343309879303, "28739": 0.9680526852607727, "28929": 0.006812678650021553, "29060": 0.5364705324172974, "29212": 0.040196798741817474, "29295": 0.2822965085506439, "29450": 0.9710156321525574} | 7224632 | The extent of structural injury in sports-related concussion (SRC) is central to the course of recovery, long-term effects, and the decision to return to play. In the present longitudinal study, we used diffusion tensor imaging (DTI) to assess white matter (WM) fiber tract integrity within 2 days, 2 weeks, and 2 months of concussive injury. Participants were right-handed male varsity contact-sport athletes (20.2±1.0 years of age) with a medically diagnosed SRC (no loss of consciousness). They were compared to right-handed male varsity non-contact-sport athletes serving as controls (19.9±1.7 years). We found significantly increased radial diffusivity (RD) in concussed athletes (n=12; paired t-test, tract-based spatial statistics; p<0.025) at 2 days, when compared to the 2-week postinjury time point. The increase was found in a cluster of right hemisphere voxels, spanning the posterior limb of the internal capsule (IC), the retrolenticular part of the IC, the inferior longitudinal fasciculus, the inferior fronto-occipital fasciculus (sagittal stratum), and the anterior thalamic radiation. Post-hoc, univariate, between-group (controls vs. concussed), mixed-effects analysis of the cluster showed significantly higher RD at 2 days (p=0.002), as compared to the controls, with a trend in the same direction at 2 months (p=0.11). Results for fractional anisotropy (FA) in the same cluster showed a similar, but inverted, pattern; FA was decreased at 2 days and at 2 months postinjury, when compared to healthy controls. At 2 weeks postinjury, no statistical differences between concussed and control athletes were found with regard to either RD or FA. These results support the hypothesis of increased RD and reduced FA within 72 h postinjury, followed by recovery that may extend beyond 2 weeks. RD appears to be a sensitive measure of concussive injury. | A longitudinal diffusion tensor imaging study assessing white matter fiber tracts after sports-related concussion. |
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Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection. | HIV–1 Infects Multipotent Progenitor Cells Causing Cell Death and Establishing Latent Cellular Reservoirs |
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"26402": 0.9485763907432556, "26512": 0.32270604372024536, "26520": 0.1221139207482338, "26524": 0.006812678650021553, "26534": 0.6207655072212219, "26651": 0.1510767638683319, "26773": 0.7018978595733643, "26775": 0.8039615154266357, "26914": 0.13755162060260773, "27009": 0.3949938118457794, "27058": 0.8813109993934631, "27099": 0.13925230503082275, "28516": 0.034552380442619324, "28691": 0.1212492436170578, "28696": 0.0009760859538801014, "28848": 0.10467668622732162, "29206": 0.12814582884311676, "29290": 0.45499902963638306} | 7225911 | It is well known that upon stress, the level of the tumor suppressor p53 is remarkably elevated. However, despite extensive studies, the underlying mechanism involving important inter-players for stress-induced p53 regulation is still not fully understood. We present evidence that the human lincRNA-RoR (RoR) is a strong negative regulator of p53. Unlike MDM2 that causes p53 degradation through the ubiquitin-proteasome pathway, RoR suppresses p53 translation through direct interaction with the heterogeneous nuclear ribonucleoprotein I (hnRNP I). Importantly, a 28-base RoR sequence carrying hnRNP I binding motifs is essential and sufficient for p53 repression. We further show that RoR inhibits p53-mediated cell cycle arrest and apoptosis. Finally, we demonstrate a RoR-p53 autoregulatory feedback loop where p53 transcriptionally induces RoR expression. Together, these results suggest that the RoR-hnRNP I-p53 axis may constitute an additional surveillance network for the cell to better respond to various stresses. | The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage |
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"28156": 0.45932671427726746, "28215": 1.0101795196533203, "28309": 0.21687394380569458, "28329": 0.11081436276435852, "28436": 0.029824240133166313, "28648": 0.53589928150177, "28712": 1.018678069114685, "28846": 0.036437395960092545, "28915": 0.39762192964553833, "29167": 0.053244512528181076, "29299": 0.2607102394104004, "29458": 0.6684301495552063, "29516": 0.18978065252304077, "29610": 0.006812678650021553} | 7227763 | The increase in lactate (L) and pyruvate (P) content of arterial blood during experimental and clinical shock states and the extent to which such increases serve as measures of oxygen deficit and irreversible injury were investigated on an empirical basis. A standardized method for production of hemorrhagic shock in the Wistar rat was employed. During a 4-hour bleeding period, oxygen consumption of the rat was reduced to approximately 40% of control value, pH was reduced from 7.39 to 7.08, and a concurrent increase in L from 0.80 to 6.06 mm and in P from 0.07 to 0.18 mm were observed. Cumulative oxygen debt correlated with log L (r = 0.50; P < 0.0005) and both were significantly related to survival. Correlation of cumulative oxygen debt and survival, both with P and with computed values of the lactate pyruvate ratio (L/P) and excess lactate (XL), were of no higher magnitude. Partial correlation analysis demonstrated that neither the measurement of P nor the computation of L/P or XL improved predictability... | Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). |
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0.5827828645706177, "28483": 0.02412080205976963, "28873": 0.05786345899105072, "29533": 0.12986256182193756} | 7228140 | Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical. | Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma |
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"29090": 0.2034190446138382, "29308": 0.1384023278951645, "29490": 0.15359249711036682, "29607": 0.3163207769393921} | 7230315 | The high-output pathway of nitric oxide production helps protect mice from infection by several pathogens, including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it is controversial whether human mononuclear phagocytes can express the corresponding inducible nitric oxide synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed directly after bronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecific for human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each of five clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in the same proportion that they stained for NOS2, under assay conditions wherein the diaphorase reaction was strictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection often express catalytically competent NOS2. | Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis |
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In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development. | The use of mouse models to understand and improve cognitive deficits in Down syndrome |
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Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available. | position-specific gap penalties |
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"29458": 0.47827014327049255} | 7261402 | We describe algorithms for detecting pedestrians in videos acquired by infrared (and color) sensors. Two approaches are proposed based on gait. The first employs computationally efficient periodicity measurements. Unlike other methods, it estimates a periodic motion frequency using two cascading hypothesis testing steps to filter out non-cyclic pixels so that it works well for both radial and lateral walking directions. The extraction of the period is efficient and robust with respect to sensor noise and cluttered background. In order to integrate shape and motion, we convert the cyclic pattern into a binary sequence by Maximal Principal Gait Angle (MPGA) fitting in the second method. It does not require alignment and continuously estimates the period using a Phase-locked Loop. Both methods are evaluated by experimental results that measure performance as a function of size, movement direction, frame rate and sequence length. | Pedestrian Detection via Periodic Motion Analysis |
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retroviruses feline immunodeficiency virus (FIV), feline leukemia virus (FeLV) and feline syncytial virus (FSV) in Taiwan, we collected a total of 75 blood samples from cats from veterinary hospitals, a breeding cattery and a homeless shelter in 1993 and 1994. We examined the presences of anti-FIV and FSV antibodies and FeLV-p27 antigen in these samples by the indirect immunofluorescence and/or enzyme-linked immunosorbent assays. All of the serum samples positive for FIV were obtained from homeless cats and the overall FIV positive rate was 4%. The overall positive rates of FSV and FeLV were 28% and 1.3%, respectively. From these results, together with previous seroepidemiological surveys by others, it was revealed that the prevalence of FIV and FeLV infections appeared to be lower in Taiwan than in the United States or Japan. In contrast, the prevalence of FSV infection in Taiwan was as high as that in Japan. | Seroepidemiological survey of feline retrovirus infections in cats in Taiwan in 1993 and 1994. |
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0.08064348995685577, "29206": 0.2184450328350067, "29290": 0.016465263441205025} | 7268522 | The proteolytic cleavages elicited by activation of the Notch receptor release an intracellular fragment, Notch intracellular domain, which enters the nucleus to activate the transcription of targets. Changes in transcription are therefore a major output of this pathway. However, the Notch outputs clearly differ from cell type to cell type. In this review we discuss current understanding of Notch targets, the mechanisms involved in their transcriptional regulation, and what might underlie the activation of different sets of targets in different cell types. | Notch targets and their regulation. |
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0.2478361576795578, "29458": 0.33605360984802246} | 7277084 | The analysis of periodic or repetitive motions is useful in many applications, such as the recognition and classification of human and animal activities. Existing methods for the analysis of periodic motions first extract motion trajectories using spatial information and then determine if they are periodic. These approaches are mostly based on feature matching or spatial correlation, which are often infeasible, unreliable, or computationally demanding. In this paper, we present a new approach, based on the time- frequency analysis of the video sequence as a whole. Multiple periodic trajectories are extracted and their periods are estimated simultaneously. The objects that are moving in a periodic manner are extracted using the spatial domain information. Experiments with synthetic and real sequences display the capabilities of this approach. | Extraction and Analysis of Multiple Periodic Motions in Video Sequences |
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0.07250232994556427, "25644": 0.36697331070899963, "26179": 1.2797396183013916, "26180": 0.9635916948318481, "26187": 0.16110190749168396, "26261": 0.05694137513637543, "26358": 0.03831886500120163, "26402": 0.9394577741622925, "26512": 0.04113444685935974, "26534": 0.28743788599967957, "26565": 0.822151780128479, "26736": 0.3683255612850189, "26773": 0.6451379656791687, "26835": 0.13670019805431366, "27321": 0.016465263441205025, "27354": 0.1693800985813141, "27395": 1.3833603858947754, "27854": 0.06246116757392883, "28093": 0.9256220459938049, "28156": 0.4203280806541443, "28848": 1.0881409645080566, "28873": 0.02792670577764511, "29206": 0.10993985831737518, "29290": 0.6006163358688354, "29336": 0.8633513450622559, "29458": 0.5849615335464478} | 7281161 | Allergic airway inflammation is characterized by marked in situ changes in gene and protein expression, yet the role of microRNAs (miRNAs), a new family of key mRNA regulatory molecules, in this process has not yet been reported. Using a highly sensitive microarray-based approach, we identified 21 miRNAs with differential expression between doxycycline-induced lung-specific IL-13 transgenic mice (with allergic airway inflammation) and control mice. In particular, we observed overexpression of miR-21 and underexpression of miR-1 in the induced IL-13 transgenic mice compared with control mice. These findings were validated in two independent models of allergen-induced allergic airway inflammation and in IL-4 lung transgenic mice. Although IL-13-induced miR-21 expression was IL-13Ralpha1 dependent, allergen-induced miR-21 expression was mediated mainly independent of IL-13Ralpha1 and STAT6. Notably, predictive algorithms identified potential direct miR-21 targets among IL-13-regulated lung transcripts, such as IL-12p35 mRNA, which was decreased in IL-13 transgenic mice. Introduction of pre-miR-21 dose dependently inhibited cellular expression of a reporter vector harboring the 3'-untranslated region of IL-12p35. Moreover, mutating miR-21 binding sites in IL-12p35 3'-untranslated region abrogated miR-21-mediated repression. In summary, we have identified a miRNA signature in allergic airway inflammation, which includes miR-21 that modulates IL-12, a molecule germane to Th cell polarization. | MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. |
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Some of the risk factors for COPD are well-known and include smoking, occupational exposures, air pollution, airway hyperresponsiveness, asthma, and certain genetic variations, although many questions, such as why < 20% of smokers develop significant airway obstruction, remain. Precise definitions of COPD vary and are frequently dependent on an accurate diagnosis of the problem by a physician. These differences in the definition of COPD can have large effects on the estimates of COPD in the population. Furthermore, evidence that COPD represents several different disease processes with potentially different interventions continues to emerge. In most of the world, COPD prevalence and mortality are still increasing and likely will continue to rise in response to increases in smoking, particularly by women and adolescents. Resources aimed at smoking cessation and prevention, COPD education and early detection, and better treatment will be of the most benefit in our continuing efforts against this important cause of morbidity and mortality. | COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. |
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0.11168810725212097, "25206": 0.20739519596099854, "25219": 1.286776065826416, "25262": 0.32553088665008545, "25357": 0.2145126610994339, "25604": 0.06977381557226181, "26305": 0.09672962874174118, "26348": 0.2105647772550583, "26378": 0.04113444685935974, "26640": 0.02412080205976963, "26735": 0.46914875507354736, "26835": 1.2808253765106201, "27301": 0.4673144817352295, "27602": 0.9363996982574463, "28436": 0.31845372915267944, "28498": 0.11081436276435852, "28561": 0.3910386264324188, "28736": 0.33675122261047363, "28892": 0.052318159490823746, "29458": 0.5882205963134766, "29494": 0.006812678650021553} | 7299977 | The geographic ranges of ticks and tick-borne pathogens are changing due to global and local environmental (including climatic) changes. In this review we explore current knowledge of the drivers for changes in the ranges of ticks and tick-borne pathogen species and strains via effects on their basic reproduction number (R 0), and the mechanisms of dispersal that allow ticks and tick-borne pathogens to invade suitable environments. Using the expanding geographic distribution of the vectors and agent of Lyme disease as an example we then investigate what could be expected of the diversity of tick-borne pathogens during the process of range expansion, and compare this with what is currently being observed. Lastly we explore how historic population and range expansions and contractions could be reflected in the phylogeography of ticks and tick-borne pathogens seen in recent years, and conclude that combined study of currently changing tick and tick-borne pathogen ranges and diversity, with phylogeographic analysis, may help us better predict future patterns of invasion and diversity. | Changing geographic ranges of ticks and tick-borne pathogens: drivers, mechanisms and consequences for pathogen diversity |
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0.7018978595733643, "27697": 0.08154398202896118, "27790": 0.0752234235405922, "27854": 0.06886265426874161, "28071": 0.056018441915512085, "28156": 0.4400174915790558, "28615": 0.34508460760116577, "28691": 0.09050461649894714, "28848": 0.39367714524269104, "28976": 0.4067663550376892} | 7317051 | Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target. | Mutant KRAS is a druggable target for pancreatic cancer. |
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"22822": 0.19782574474811554, "22911": 0.151916041970253, "22979": 0.32764431834220886, "23419": 0.06154331564903259, "23951": 0.5551415085792542, "24088": 0.16110190749168396, "24558": 1.2894693613052368, "24977": 0.2674594223499298, "25331": 0.16110190749168396, "25524": 0.3134697377681732, "25582": 0.10379679501056671, "25718": 1.0914250612258911, "25855": 0.09495500475168228, "26215": 0.6931471824645996, "26282": 0.11430477350950241, "26351": 0.04860413447022438, "26563": 0.1212492436170578, "26601": 0.12470348179340363, "26677": 0.9710156321525574, "27024": 0.2969166338443756, "27487": 0.3615458607673645, "27711": 0.3346569836139679, "28213": 0.0038986403960734606, "29003": 0.12642613053321838, "29093": 1.141931176185608, "29181": 0.2470736801624298, "29296": 0.2317005842924118, "29299": 0.036437395960092545} | 7324039 | MOTIVATION Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. RESULTS The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. AVAILABILITY AND IMPLEMENTATION Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic CONTACT [email protected] SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online. | Trimmomatic: a flexible trimmer for Illumina sequence data |
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"25775": 0.21293537318706512, "26399": 0.8989537954330444, "26402": 0.8674615025520325, "26520": 0.9739698171615601, "26534": 0.29328158497810364, "26572": 0.2493593990802765, "26651": 0.23710809648036957, "26773": 0.4500300884246826, "26835": 0.3019835948944092, "27144": 0.6223390698432922, "27295": 0.5517725944519043, "27781": 0.8715548515319824, "27854": 1.0172666311264038, "27881": 0.38041436672210693, "28117": 0.0174254160374403, "28207": 0.04394211992621422, "28577": 0.681853175163269, "28696": 0.1229778528213501, "28788": 0.6016870141029358, "28873": 0.41840189695358276, "28896": 0.04767346754670143, "29290": 0.004870930220931768} | 7343711 | Successful cancer treatment requires understanding host immune response against tumor cells. PD-1 belongs to the CD28 superfamily of receptors that work as “checkpoints” of immune activation. PD-1 maintains immune self-tolerance to prevent autoimmunity and controls T-cell reaction during infection to prevent excessive tissue damage. Tumor cells that arise from normal tissue acquire mutations that can be targeted by lymphocytes. Accumulating lines of evidence suggest that tumor cells evade host immune attack by expressing physiological PD-1 ligands and stimulating PD-1 on the lymphocytes. Based on this idea, researchers have successfully demonstrated that systemic administration of monoclonal antibodies that inhibit the binding of PD-1 to the ligands reactivated T cells and augmented the anti-cancer immune response. In this review, I summarize the basics of T-cell biology and its regulation by PD-1 and discuss the current understanding and questions about this multifaceted molecule. | Basics of PD-1 in self-tolerance, infection, and cancer immunity |
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"29516": 0.053244512528181076, "29566": 0.33325836062431335, "29596": 0.02316705882549286, "29720": 0.1751343309879303} | 7357135 | Drug seeking is maintained by encounters with drug-associated cues, and disrupting retrieval of these drug-cue associations would reduce the risk of relapse. Retrieval of cocaine-associated memories is dependent on β-adrenergic receptor (β-AR) activation, and blockade of these receptors induces a persistent retrieval deficit. Whether retrieval of cocaine-associated memory is mediated by a specific β-AR subtype, however, remains unclear. Using a cocaine conditioned place preference (CPP) procedure, we examined whether retrieval of a cocaine CPP memory is mediated collectively by β1- and β2-ARs, or by one of these β-AR subtypes alone. We show that co-blockade of β1- and β2-ARs abolished CPP expression on that and subsequent drug-free CPP tests, resulting in a long-lasting retrieval deficit that prevented subsequent cocaine-induced reinstatement. To dissociate the necessity of either β1- or β2-ARs alone, we administered subtype-specific antagonists prior to retrieval. Administration of a β1-AR antagonist before the initial CPP trial dose-dependently reduced expression of a CPP on that and subsequent drug-free trials as compared to vehicle administration. In contrast, administration of a β2-AR antagonist had no effect on initial CPP expression, although the highest dose reduced subsequent CPP expression. Importantly, either β1- or β2-AR blockade prior to an initial retrieval trial prevented subsequent cocaine-induced reinstatement. Our findings indicate that the β1-AR subtype mediates retrieval of a cocaine CPP, and that acutely blocking either β1- or β2-ARs can prevent subsequent cocaine-induced reinstatement. Thus, β-AR antagonists, particularly β1-ARs antagonists, could serve as adjuncts for addiction therapies to prevent retrieval of drug-associated memories and provide protection against relapse. | Dissociation of β1- and β2-adrenergic receptor subtypes in the retrieval of cocaine-associated memory. |
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"29290": 0.36900100111961365, "29610": 0.1212492436170578} | 7370282 | To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces. | Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2 |
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0.3019835948944092, "24577": 0.4709797203540802, "24658": 0.34922540187835693, "24670": 0.5936289429664612, "24767": 0.2478361576795578, "24978": 0.0038986403960734606, "25006": 0.5438674688339233, "25077": 0.8135309815406799, "25090": 0.15693697333335876, "25136": 0.12556517124176025, "25174": 0.004870930220931768, "25644": 0.16276304423809052, "25860": 0.23092569410800934, "25870": 0.17431432008743286, "26029": 0.7047978043556213, "26097": 0.07159364968538284, "26189": 0.39762192964553833, "26236": 0.07884006202220917, "26771": 0.05970508232712746, "26773": 0.6070231795310974, "28268": 0.03360854089260101, "28400": 0.16524957120418549, "28450": 0.14349138736724854, "29180": 0.3485364317893982, "29455": 0.3810817003250122, "29536": 0.09584271162748337} | 7373120 | UNLABELLED Coalitions of multinational food and drink businesses have pledged to reformulate their products and to market them responsibly. Largely business-led and self-regulated, the integrity of these voluntary initiatives has been questioned. The Public Health Responsibility Deal in England is an example of a voluntary initiative that is government-led. Does this approach provide evidence that with public leadership there is potential for voluntary actions to deliver meaningful results for public health? METHODS The subject of the research is the calorie reduction initiative of the Responsibility Deal. Source material was obtained primarily through a series of UK Freedom of Information requests and comprises previously unpublished Department of Health documentation relating to relevant meetings held during 2011 and 2012. RESULTS The Responsibility Deal approach to calorie reduction deliberately involves the food industry in the specification of the measures it is to implement (reformulation and portion control). Finding the common ground between private and public interests has resulted in the deflection of public health objectives and the preclusion of adequate monitoring and evaluation. CONCLUSIONS The Responsibility Deal approach is fundamentally flawed in its expectation that industry will take voluntary actions that prioritise public health interests above its own. Being government-led counts for little in the absence of sanctions to drive compliance. Instead the initiative affords private interests the opportunity to influence in their favour the public health policies and strategies that affect their products. | The Public Health Responsibility Deal: brokering a deal for public health, but on whose terms? |
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"26745": 0.11778303235769272, "27179": 0.42990362644195557, "27598": 0.4831010699272156, "27673": 0.1602703034877777, "27697": 0.6425731778144836, "27790": 0.6502478122711182, "27833": 0.04487626627087593, "28041": 0.1485546976327896, "28297": 0.1889725625514984, "28353": 0.31560876965522766, "28487": 1.246605634689331, "28517": 0.021256839856505394, "28687": 0.46853771805763245, "28696": 0.014542185701429844, "28715": 0.8433839678764343, "28817": 0.022212404757738113, "28915": 0.5903874635696411, "29166": 1.1506214141845703, "29290": 0.6634125709533691, "29486": 0.3757305145263672} | 7373453 | Although the entire coronary tree is exposed to the atherogenic effect of the systemic risk factors, atherosclerotic lesions form at specific arterial regions, where low and oscillatory endothelial shear stress (ESS) occur. Low ESS modulates endothelial gene expression through complex mechanoreception and mechanotransduction processes, inducing an atherogenic endothelial phenotype and formation of an early atherosclerotic plaque. Each early plaque exhibits an individual natural history of progression, regression, or stabilization, which is dependent not only on the formation and progression of atherosclerosis but also on the vascular remodeling response. Although the pathophysiologic mechanisms involved in the remodeling of the atherosclerotic wall are incompletely understood, the dynamic interplay between local hemodynamic milieu, low ESS in particular, and the biology of the wall is likely to be important. In this review, we explore the molecular, cellular, and vascular processes supporting the role of low ESS in the natural history of coronary atherosclerosis and vascular remodeling and indicate likely mechanisms concerning the different natural history trajectories of individual coronary lesions. Atherosclerotic plaques associated with excessive expansive remodeling evolve to high-risk plaques, because low ESS conditions persist, thereby promoting continued local lipid accumulation, inflammation, oxidative stress, matrix breakdown, and eventually further plaque progression and excessive expansive remodeling. An enhanced understanding of the pathobiologic processes responsible for atherosclerosis and vascular remodeling might allow for early identification of a high-risk coronary plaque and thereby provide a rationale for innovative diagnostic and/or therapeutic strategies for the management of coronary patients and prevention of acute coronary syndromes. | Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. |
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1.133164644241333, "26709": 0.16690383851528168, "26773": 0.46363574266433716, "26835": 1.0375399589538574, "27099": 0.3070250153541565, "27152": 0.5784112811088562, "27295": 0.5104349255561829, "27395": 0.8169882297515869, "27777": 0.22001366317272186, "27781": 0.05694137513637543, "27822": 0.018384648486971855, "27854": 1.0001721382141113, "27895": 0.15860503911972046, "28086": 0.06154331564903259, "28156": 0.4419025182723999, "28516": 0.004870930220931768, "28577": 0.07884006202220917, "28696": 0.23556606471538544, "28788": 0.31560876965522766, "28873": 0.34370049834251404, "29090": 0.03266380727291107, "29107": 0.04207121208310127, "29170": 0.04674193635582924, "29290": 0.8135309815406799, "29461": 0.8583967685699463, "29610": 0.11081436276435852} | 7386360 | Infectious pathogens can selectively stimulate activation or suppression of T cells to facilitate their survival within humans. In this study we demonstrate that the trematode parasite Schistosoma mansoni has evolved with two distinct mechanisms to suppress T cell activation. During the initial 4- to 12-wk acute stages of a worm infection both CD4(+) and CD8(+) T cells are anergized. In contrast, infection with male and female worms induced T cell anergy at 4 wk, which was replaced after egg laying by T cell suppression via a known NO-dependent mechanism, that was detected for up to 40 wk after infection. Worm-induced anergy was mediated by splenic F4/80(+) macrophages (Mphi) via an IL-4-, IL-13-, IL-10-, TGF-beta-, and NO-independent, but cell contact-dependent, mechanism. F4/80(+) Mphi isolated from worm-infected mice were shown to induce anergy of naive T cells in vitro. Furthermore, naive Mphi exposed to live worms in vitro also induced anergy in naive T cells. Flow cytometry on in vivo and in vitro worm-modulated Mphi revealed that of the family of B7 costimulatory molecules, only programmed death ligand 1 (PD-L1) was selectively up-regulated. The addition of inhibitory mAb against PD-L1, but not PD-L2, to worm-modulated Mphi completely blocked the ability of these cells to anergize T cells. These data highlight a novel mechanism through which S. mansoni worms have usurped the natural function of PD-L1 to reduce T cell activation during early acute stages of infection before the subsequent emergence of egg-induced T cell suppression in the chronic stages of infection. | Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages. |
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0.10906458646059036, "22835": 0.472198486328125, "23032": 0.09938567131757736, "23362": 0.2749055027961731, "23435": 0.16359257698059082, "23452": 0.4512746334075928, "23521": 0.20580662786960602, "24134": 0.011650617234408855, "24155": 0.6139179468154907, "24296": 0.40806588530540466, "24710": 0.1685553640127182, "24817": 0.31845372915267944, "24977": 0.48850810527801514, "25095": 0.39893341064453125, "25188": 0.23324857652187347, "25416": 0.03360854089260101, "25666": 0.04953393340110779, "26163": 0.02412080205976963, "26633": 0.06795065850019455, "26743": 0.47402387857437134, "27448": 1.1337933540344238, "28024": 0.04487626627087593, "28041": 0.09938567131757736, "28433": 0.043007105588912964, "29104": 0.0354953333735466, "29296": 0.5662899017333984} | 7396492 | BACKGROUND A novel method of microarray preprocessing--Frozen Robust Multi-array Analysis (fRMA)--has recently been developed. This algorithm allows the user to preprocess arrays individually while retaining the advantages of multi-array preprocessing methods. The frozen parameter estimates required by this algorithm are generated using a large database of publicly available arrays. Curation of such a database and creation of the frozen parameter estimates is time-consuming; therefore, fRMA has only been implemented on the most widely used Affymetrix platforms. RESULTS We present an R package, frmaTools, that allows the user to quickly create his or her own frozen parameter vectors. We describe how this package fits into a preprocessing workflow and explore the size of the training dataset needed to generate reliable frozen parameter estimates. This is followed by a discussion of specific situations in which one might wish to create one's own fRMA implementation. For a few specific scenarios, we demonstrate that fRMA performs well even when a large database of arrays in unavailable. CONCLUSIONS By allowing the user to easily create his or her own fRMA implementation, the frmaTools package greatly increases the applicability of the fRMA algorithm. The frmaTools package is freely available as part of the Bioconductor project. | Thawing Frozen Robust Multi-array Analysis (fRMA) |
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0.1873544454574585, "29610": 0.16524957120418549} | 7399084 | T cell homeostasis is crucial for a functional immune system, as the accumulation of T cells resulting from lack of regulatory T cells or an inability to shut down immune responses can lead to inflammation and autoimmune pathology. Here we show that Blimp-1, a transcriptional repressor that is a 'master regulator' of terminal B cell differentiation, was expressed in a subset of antigen-experienced CD4+ and CD8+ T cells. Mice reconstituted with fetal liver stem cells expressing a mutant Blimp-1 lacking the DNA-binding domain developed a lethal multiorgan inflammatory disease caused by an accumulation of effector and memory T cells. These data identify Blimp-1 as an essential regulator of T cell homeostasis and suggest that Blimp-1 regulates both B cell and T cell differentiation. | Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance |
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"26994": 0.6461620330810547, "27216": 0.0752234235405922, "27241": 0.012615402229130268, "27321": 0.1718502640724182, "27642": 0.8349450826644897, "27697": 0.08603433519601822, "27790": 0.151916041970253, "28086": 0.47827014327049255, "28120": 0.4145384132862091, "28488": 0.39433568716049194, "28667": 0.18167030811309814, "28696": 0.010684899985790253, "28848": 0.41065993905067444, "29129": 0.8764448165893555, "29206": 1.0285027027130127, "29458": 0.037378571927547455} | 7416873 | Interphase nuclear repositioning of chromosomes has been implicated in the epigenetic regulation of RNA polymerase (pol) II transcription. However, little is known about the nuclear position–dependent regulation of RNA pol I–transcribed loci. Trypanosoma brucei is an excellent model system to address this question because its two main surface protein genes, procyclin and variant surface glycoprotein (VSG), are transcribed by pol I and undergo distinct transcriptional activation or downregulation events during developmental differentiation. Although the monoallelically expressed VSG locus is exclusively localized to an extranucleolar body in the bloodstream form, in this study, we report that nonmutually exclusive procyclin genes are located at the nucleolar periphery. Interestingly, ribosomal DNA loci and pol I transcription activity are restricted to similar perinucleolar positions. Upon developmental transcriptional downregulation, however, the active VSG promoter selectively undergoes a rapid and dramatic repositioning to the nuclear envelope. Subsequently, the VSG promoter region was subjected to chromatin condensation. We propose a model whereby the VSG expression site pol I promoter is selectively targeted by temporal nuclear repositioning during developmental silencing. | Nuclear repositioning of the VSG promoter during developmental silencing in Trypanosoma brucei |
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0.3381449282169342, "29277": 0.052318159490823746, "29427": 0.15693697333335876, "29458": 0.5370414853096008} | 7419612 | BACKGROUND Readmission soon after hospital discharge is an expensive and often preventable event for patients with heart failure. We present a model approved by the National Quality Forum for the purpose of public reporting of hospital-level readmission rates by the Centers for Medicare & Medicaid Services. METHODS AND RESULTS We developed a hierarchical logistic regression model to calculate hospital risk-standardized 30-day all-cause readmission rates for patients hospitalized with heart failure. The model was derived with the use of Medicare claims data for a 2004 cohort and validated with the use of claims and medical record data. The unadjusted readmission rate was 23.6%. The final model included 37 variables, had discrimination ranging from 15% observed 30-day readmission rate in the lowest predictive decile to 37% in the upper decile, and had a c statistic of 0.60. The 25th and 75th percentiles of the risk-standardized readmission rates across 4669 hospitals were 23.1% and 24.0%, with 5th and 95th percentiles of 22.2% and 25.1%, respectively. The odds of all-cause readmission for a hospital 1 standard deviation above average was 1.30 times that of a hospital 1 standard deviation below average. State-level adjusted readmission rates developed with the use of the claims model are similar to rates produced for the same cohort with the use of a medical record model (correlation, 0.97; median difference, 0.06 percentage points). CONCLUSIONS This claims-based model of hospital risk-standardized readmission rates for heart failure patients produces estimates that may serve as surrogates for those derived from a medical record model. | An administrative claims measure suitable for profiling hospital performance on the basis of 30-day all-cause readmission rates among patients with heart failure. |
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interactions between vast and diverse cellular species. While these diagrams are useful for analyzing biological systems on a large scale, a detailed understanding of the molecular mechanisms that underlie the observed network connections is critical for the further development of systems and synthetic biology. Here, we use queueing theory to investigate how 'waiting lines' can lead to correlations between protein 'customers' that are coupled solely through a downstream set of enzymatic 'servers'. Using the E. coli ClpXP degradation machine as a model processing system, we observe significant cross-talk between two networks that are indirectly coupled through a common set of processors. We further illustrate the implications of enzymatic queueing using a synthetic biology application, in which two independent synthetic networks demonstrate synchronized behavior when common ClpXP machinery is overburdened. Our results demonstrate that such post-translational processes can lead to dynamic connections in cellular networks and may provide a mechanistic understanding of existing but currently inexplicable links. | Queueing up for enzymatic processing: correlated signaling through coupled degradation |
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0.5404602885246277, "25654": 0.03266380727291107, "25714": 0.1946154683828354, "25761": 0.17431432008743286, "25932": 0.4093637466430664, "26314": 0.49030399322509766, "26402": 0.33115679025650024, "26417": 0.08782484382390976, "26773": 0.2478361576795578, "26780": 0.3388410806655884, "26953": 0.20102575421333313, "27788": 0.1401015669107437, "27790": 0.0752234235405922, "28086": 1.2324692010879517, "28156": 0.3127557039260864, "28268": 0.14433705806732178, "28403": 0.1718502640724182, "28405": 0.1510767638683319, "28522": 0.8400169610977173, "28667": 0.2160874605178833, "28964": 0.9340999722480774, "29175": 0.1332872211933136, "29206": 1.005902886390686, "29290": 0.5290185213088989, "29494": 0.6410312056541443} | 7426741 | Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) resets the epigenome to an embryonic-like state. Vitamin C enhances the reprogramming process, but the underlying mechanisms are unclear. Here we show that the histone demethylases Jhdm1a/1b are key effectors of somatic cell reprogramming downstream of vitamin C. We first observed that vitamin C induces H3K36me2/3 demethylation in mouse embryonic fibroblasts in culture and during reprogramming. We then identified Jhdm1a/1b, two known vitamin-C-dependent H3K36 demethylases, as potent regulators of reprogramming through gain- and loss-of-function approaches. Furthermore, we found that Jhdm1b accelerates cell cycle progression and suppresses cell senescence during reprogramming by repressing the Ink4/Arf locus. Jhdm1b also cooperates with Oct4 to activate the microRNA cluster 302/367, an integral component of the pluripotency machinery. Our results therefore reveal a role for H3K36me2/3 in cell fate determination and establish a link between histone demethylases and vitamin-C-induced reprogramming. | The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. |
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0.7086513638496399, "28281": 0.29619070887565613, "28297": 0.9583619832992554, "28309": 0.00875066313892603, "28696": 0.17922431230545044, "28873": 0.020300358533859253, "28896": 0.018384648486971855, "29090": 0.11343330889940262, "29172": 0.12986256182193756, "29290": 0.3615458607673645, "29295": 0.19622190296649933, "29486": 0.45251765847206116} | 7433668 | Tuberculosis and helminthic infections coexist in many parts of the world, yet the impact of helminth-elicited Th2 responses on the ability of the host to control Mycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected with the intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance to airborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterial burden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth-induced Th2 environment resulted in the accumulation of alternatively activated macrophages (AAMs) in the lung. Co-infected mice lacking interleukin (IL) 4Rα exhibited improved ability to control Mtb infection, which was accompanied by significantly reduced accumulation of AAMs. Moreover, IL-4Rα(-/-) mice adoptively transferred with wild-type macrophages had a significantly higher Mtb load in their lungs compared with those that received IL-4Rα(-/-) macrophages, suggesting a direct contribution for the IL-4R pathway to the heightened susceptibility of co-infected animals. The Th2 response can thus enhance the intracellular persistence of Mtb, in part by mediating the alternative activation of macrophages via the IL-4Rα signaling pathway. | Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway |
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0.11256109178066254, "26210": 0.9123768210411072, "26282": 0.6471850275993347, "26427": 0.07341018319129944, "26591": 0.3499138653278351, "26754": 0.6921701431274414, "26835": 0.17840765416622162, "28148": 1.1549384593963623, "28173": 0.7276995778083801, "28256": 0.6583697199821472, "28479": 0.05970508232712746, "28498": 0.11778303235769272, "28500": 0.043007105588912964, "29347": 0.12642613053321838, "29389": 0.2317005842924118, "29393": 0.20421554148197174, "29607": 0.30486753582954407} | 7438803 | Archaea constitute a considerable fraction of the microbial biomass on Earth. Like Bacteria they have evolved a variety of energy metabolisms using organic and/or inorganic electron donors and acceptors, and many of them are able to fix carbon from inorganic sources. Archaea thus play crucial roles in the Earth's global geochemical cycles and influence greenhouse gas emissions. Methanogenesis and anaerobic methane oxidation are important steps in the carbon cycle; both are performed exclusively by anaerobic archaea. Oxidation of ammonia to nitrite is performed by Thaumarchaeota. They represent the only archaeal group that resides in large numbers in the global aerobic terrestrial and marine environments on Earth. Sulfur-dependent archaea are confined mostly to hot environments, but metal leaching by acidophiles and reduction of sulfate by anaerobic, nonthermophilic methane oxidizers have a potential impact on the environment. The metabolisms of a large number of archaea, in particular those dominating the subsurface, remain to be explored. | Archaea in biogeochemical cycles. |
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0.004870930220931768, "28397": 0.04394211992621422, "28577": 0.3019835948944092, "28613": 0.9052929878234863, "29090": 0.27786844968795776, "29167": 0.026976587250828743, "29226": 0.6568518877029419, "29251": 0.10291612148284912, "29397": 0.04767346754670143, "29495": 0.07884006202220917, "29514": 0.7426811456680298} | 7447120 | After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases. | Novel proteinaceous infectious particles cause scrapie. |
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recognized for thousands of years. Egyptians believed that cancer occurred at the will of the gods. Hippocrates believed human disease resulted from an imbalance of the four humors: blood, phlegm, yellow bile, and black bile with cancer being caused by excess black bile. The lymph theory of cancer replaced the humoral theory and the blastema theory replaced the lymph theory. Rudolph Virchow was the first to recognize that cancer cells like all cells came from other cells and believed chronic irritation caused cancer. At the same time there was a belief that trauma caused cancer, though it never evolved after many experiments inducing trauma. The birth of virology occurred in 1892 when Dimitri Ivanofsky demonstrated that diseased tobacco plants remained infective after filtering their sap through a filter that trapped bacteria. Martinus Beijerinck would call the tiny infective agent a virus and both Dimitri Ivanofsky and Marinus Beijerinck would become the fathers of virology. Not to long thereafter, Payton Rous founded the field of tumor virology in 1911 with his discovery of a transmittable sarcoma of chickens by what would come to be called Rous sarcoma virus or RSV for short. The first identified human tumor virus was the Epstein-Barr virus (EBV), named after Tony Epstein and Yvonne Barr who visualized the virus particles in Burkitt's lymphoma cells by electron microscopy in 1965. Since that time, many viruses have been associated with carcinogenesis including the most studied, human papilloma virus associated with cervical carcinoma, many other anogenital carcinomas, and oropharyngeal carcinoma. The World Health Organization currently estimates that approximately 22% of worldwide cancers are attributable to infectious etiologies, of which viral etiologies is estimated at 15-20%. The field of tumor virology/viral carcinogenesis has not only identified viruses as etiologic agents of human cancers, but has also given molecular insights to all human cancers including the oncogene activation and tumor suppressor gene inactivation. | Viral Carcinogenesis. |
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proteins perform their roles within macromolecular assemblies. Hence, an understanding of how these multiprotein complexes form is a fundamental question in cell biology. We developed a translation-controlled pulse-chase system that allows time-resolved isolation of newly forming multiprotein complexes in chemical quantities suitable for biochemical and cell biological analysis. The "pulse" is triggered by an unnatural amino acid, which induces immediate translation of an amber stop codon repressed mRNA encoding the protein of interest with a built-in tag for detection and purification. The "chase" is elicited by stopping translation of this bait via a riboswitch in the respective mRNA. Over the course of validating our method, we discovered a distinct time-resolved assembly step during NPC biogenesis and could directly monitor the spatiotemporal maturation of preribosomes via immunofluorescence detection and purification of a pulse-labeled ribosomal protein. Thus, we provide an innovative strategy to study dynamic protein assembly within cellular networks. | Monitoring spatiotemporal biogenesis of macromolecular assemblies by pulse-chase epitope labeling. |
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the evidence-based lowering of cardiovascular disease (CVD) risk. The use of these drugs for secondary prevention of CVD is well founded, but their expanding use in primary prevention—in individuals without documented CVD—has raised some concerns. Firstly, evidence suggests that, in primary prevention, statins substantially decrease CVD morbidity, but only moderately reduce CVD mortality. Secondly, long-term statin use might cause adverse effects, such as incident diabetes mellitus. Thirdly, the cost-effectiveness of such a strategy is unclear, and has to be balanced against the risk of 'overmedicating' the general population. Data clearly support the use of statins for primary prevention in high-risk individuals, in whom the strategy is cost-effective and the benefits exceed the risks. Whether primary prevention is beneficial in individuals at low or moderate risk is not certain. Therefore, the prescription of statins for primary prevention should be individualized on the basis of clinical judgment, particularly for low-risk individuals. In appropriately selected individuals, statins should also be used for primary prevention of ischaemic stroke and transient ischaemic attack. | Statins in the primary prevention of cardiovascular disease |
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involves p53 activation, bax transcription, and cytochrome c release from mitochondria. Apurinic/apyrimidinic endonuclease-1 (APE-1) regulates transcriptional activity of p53, and H pylori induce APE-1 expression in human GECs. H pylori infection increases intracellular calcium ion concentration [Ca2+]i of GECs, which induces APE-1 acetylation. We investigated the effects of H pylori infection and APE-1 acetylation on GEC apoptosis. METHODS AGS cells (wild-type or with suppressed APE-1), KATO III cells, and cells isolated from gastric biopsy specimens were infected with H pylori. Effects were examined by immunoblotting, real-time reverse-transcription polymerase chain reaction, immunoprecipitation, immunofluorescence microscopy, chromatin immunoprecipitation, mobility shift, DNA binding, and luciferase assays. RESULTS H pylori infection increased [Ca2+]i and acetylation of APE-1 in GECs, but the acetylation status of APE-1 did not affect the transcriptional activity of p53. In GECs, expression of a form of APE-1 that could not be acetylated increased total and mitochondrial levels of Bax and induced release of cytochrome c and fragmentation of DNA; expression of wild-type APE-1 reduced these apoptotic events. We identified a negative calcium response element in the human bax promoter and found that poly (adenosine diphosphate-ribose) polymerase 1 recruited the acetylated APE-1/histone deacetylase-1 repressor complex to bax nCaRE. CONCLUSIONS H pylori-mediated acetylation of APE-1 suppresses Bax expression; this prevents p53-mediated apoptosis when H pylori infect GECs. | Acetylation of apurinic/apyrimidinic endonuclease-1 regulates Helicobacter pylori-mediated gastric epithelial cell apoptosis. |
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Of course much has been learned over the years, and we now appreciate that telomeres are comprised of the multimeric protein/DNA shelterin complex and that the formation of t-loops provides protection from DNA damage machinery. Deriving their name from D-loops, t-loops are generated by the insertion of the 3' overhang into telomeric repeats facilitated by the binding of TRF2. Recent studies have uncovered novel forms of chromosome end-structure that may implicate telomere organization in cellular processes beyond its essential role in telomere protection and homeostasis. In particular, we have recently described that t-loops form in a TRF2-dependent manner at interstitial telomere repeat sequences, which we termed interstitial telomere loops (ITLs). These structures are also dependent on association of lamin A/C, a canonical component of the nucleoskeleton that is mutated in myriad human diseases, including human segmental progeroid syndromes. Since ITLs are associated with telomere stability and require functional lamin A/C, our study suggests a mechanistic link between cellular aging (replicative senescence induced by telomere shortening) and organismal aging (modeled by Hutchinson Gilford Progeria Syndrome). Here we speculate on other potential ramifications of ITL formation, from gene expression to genome stability to chromosome structure. | A beginning of the end: new insights into the functional organization of telomeres |
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"25320": 0.022212404757738113, "25509": 0.22704219818115234, "25531": 0.8212929964065552, "25608": 0.0019512200960889459, "25714": 0.8901712894439697, "25761": 0.03266380727291107, "26244": 0.15693697333335876, "26282": 0.3883931338787079, "26402": 0.11256109178066254, "26591": 0.3262358605861664, "26835": 0.42608439922332764, "28406": 1.034073829650879, "28498": 0.1751343309879303, "28667": 0.5290185213088989, "28745": 1.3331490755081177, "29090": 0.7276995778083801, "29390": 0.14433705806732178, "29610": 0.30989447236061096} | 7481159 | Gram-negative bacteria use the Type VI secretion system (T6SS) to inject toxic proteins into rival bacteria or eukaryotic cells. However, the mechanism of the T6SS is incompletely understood. In the present study, we investigated a conserved component of the T6SS, TssK, using the antibacterial T6SS of Serratia marcescens as a model system. TssK was confirmed to be essential for effector secretion by the T6SS. The native protein, although not an integral membrane protein, appeared to localize to the inner membrane, consistent with its presence within a membrane-anchored assembly. Recombinant TssK purified from S. marcescens was found to exist in several stable oligomeric forms, namely trimer, hexamer and higher-order species. Native-level purification of TssK identified TssF and TssG as interacting proteins. TssF and TssG, conserved T6SS components of unknown function, were required for T6SS activity, but not for correct localization of TssK. A complex containing TssK, TssF and TssG was subsequently purified in vitro, confirming that these three proteins form a new subcomplex within the T6SS. Our findings provide new insight into the T6SS assembly, allowing us to propose a model whereby TssK recruits TssFG into the membrane-associated T6SS complex and different oligomeric states of TssK may contribute to the dynamic mechanism of the system. | Biochemical analysis of TssK, a core component of the bacterial Type VI secretion system, reveals distinct oligomeric states of TssK and identifies a TssK–TssFG subcomplex |
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"28779": 0.021256839856505394, "28788": 0.22782009840011597, "28828": 0.31132611632347107, "28873": 0.0019512200960889459, "29290": 0.17840765416622162, "29388": 0.10818854719400406} | 7482674 | Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation. | Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes |
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"26163": 0.31845372915267944, "26168": 0.28597161173820496, "26319": 0.6754127144813538, "26358": 0.08961215615272522, "26745": 0.052318159490823746, "26770": 0.021256839856505394, "26835": 0.7105726003646851, "26957": 0.07884006202220917, "27000": 0.11865071207284927, "27080": 0.06337817758321762, "27109": 0.6170841455459595, "27142": 0.02316705882549286, "27152": 0.2089812457561493, "27258": 0.18573370575904846, "27363": 0.3381449282169342, "27859": 0.06337817758321762, "28055": 0.4203280806541443, "28062": 0.020300358533859253, "28093": 0.6714286804199219, "28170": 0.1212492436170578, "28252": 0.12814582884311676, "28255": 0.8592242002487183, "28321": 0.11256109178066254, "28329": 0.006812678650021553, "28436": 0.11517547070980072, "28498": 0.056018441915512085, "28731": 0.2659635543823242, "28732": 0.03925827145576477, "28937": 0.2637155055999756, "29110": 0.15860503911972046, "29361": 0.15860503911972046, "29458": 0.36697331070899963} | 7485455 | BACKGROUND Prior to emergence in human populations, zoonoses such as SARS cause occasional infections in human populations exposed to reservoir species. The risk of widespread epidemics in humans can be assessed by monitoring the reproduction number R (average number of persons infected by a human case). However, until now, estimating R required detailed outbreak investigations of human clusters, for which resources and expertise are not always available. Additionally, existing methods do not correct for important selection and under-ascertainment biases. Here, we present simple estimation methods that overcome many of these limitations. METHODS AND FINDINGS Our approach is based on a parsimonious mathematical model of disease transmission and only requires data collected through routine surveillance and standard case investigations. We apply it to assess the transmissibility of swine-origin influenza A H3N2v-M virus in the US, Nipah virus in Malaysia and Bangladesh, and also present a non-zoonotic example (cholera in the Dominican Republic). Estimation is based on two simple summary statistics, the proportion infected by the natural reservoir among detected cases (G) and among the subset of the first detected cases in each cluster (F). If detection of a case does not affect detection of other cases from the same cluster, we find that R can be estimated by 1-G; otherwise R can be estimated by 1-F when the case detection rate is low. In more general cases, bounds on R can still be derived. CONCLUSIONS We have developed a simple approach with limited data requirements that enables robust assessment of the risks posed by emerging zoonoses. We illustrate this by deriving transmissibility estimates for the H3N2v-M virus, an important step in evaluating the possible pandemic threat posed by this virus. Please see later in the article for the Editors' Summary. | Using Routine Surveillance Data to Estimate the Epidemic Potential of Emerging Zoonoses: Application to the Emergence of US Swine Origin Influenza A H3N2v Virus |
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0.07159364968538284, "26305": 0.30917787551879883, "26483": 0.9084475636482239, "26534": 0.18573370575904846, "27000": 0.09495500475168228, "27152": 0.6980181336402893, "27453": 0.5941681861877441, "27691": 0.34300774335861206, "28086": 0.18492233753204346, "28314": 0.28670501708984375, "28436": 0.3949938118457794, "28442": 0.15693697333335876, "28488": 0.8772575259208679, "28521": 0.09938567131757736, "28667": 0.6754127144813538, "28699": 0.9310253858566284} | 7486516 | Asexuals are an important test case for theories of why species exist. If asexual clades displayed the same pattern of discrete variation as sexual clades, this would challenge the traditional view that sex is necessary for diversification into species. However, critical evidence has been lacking: all putative examples have involved organisms with recent or ongoing histories of recombination and have relied on visual interpretation of patterns of genetic and phenotypic variation rather than on formal tests of alternative evolutionary scenarios. Here we show that a classic asexual clade, the bdelloid rotifers, has diversified into distinct evolutionary species. Intensive sampling of the genus Rotaria reveals the presence of well-separated genetic clusters indicative of independent evolution. Moreover, combined genetic and morphological analyses reveal divergent selection in feeding morphology, indicative of niche divergence. Some of the morphologically coherent groups experiencing divergent selection contain several genetic clusters, in common with findings of cryptic species in sexual organisms. Our results show that the main causes of speciation in sexual organisms, population isolation and divergent selection, have the same qualitative effects in an asexual clade. The study also demonstrates how combined molecular and morphological analyses can shed new light on the evolutionary nature of species. | Independently Evolving Species in Asexual Bdelloid Rotifers |
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"27532": 0.7352184057235718, "27642": 0.7229714393615723, "27718": 0.20102575421333313, "27989": 0.21135559678077698, "28086": 0.1905880719423294, "28227": 0.26146242022514343, "28450": 0.15023678541183472, "28466": 0.06795065850019455, "28498": 0.9256220459938049, "28591": 0.1358480453491211, "28685": 0.17759032547473907, "28691": 0.24171993136405945, "28828": 0.4248080551624298, "28829": 0.5762182474136353, "28848": 0.01934296265244484, "28927": 0.22704219818115234, "29206": 0.24554696679115295, "29238": 0.083342544734478, "29516": 0.09050461649894714} | 7487927 | The production of ribosomes is ubiquitous and fundamental to life. As such, it is surprising that defects in ribosome biogenesis underlie a growing number of symptomatically distinct inherited disorders, collectively called ribosomopathies. We previously determined that the nucleolar protein, NOL11, is essential for optimal pre-rRNA transcription and processing in human tissue culture cells. However, the role of NOL11 in the development of a multicellular organism remains unknown. Here, we reveal a critical function for NOL11 in vertebrate ribosome biogenesis and craniofacial development. Nol11 is strongly expressed in the developing cranial neural crest (CNC) of both amphibians and mammals, and knockdown of Xenopus nol11 results in impaired pre-rRNA transcription and processing, increased apoptosis, and abnormal development of the craniofacial cartilages. Inhibition of p53 rescues this skeletal phenotype, but not the underlying ribosome biogenesis defect, demonstrating an evolutionarily conserved control mechanism through which ribosome-impaired craniofacial cells are removed. Excessive activation of this mechanism impairs craniofacial development. Together, our findings reveal a novel requirement for Nol11 in craniofacial development, present the first frog model of a ribosomopathy, and provide further insight into the clinically important relationship between specific ribosome biogenesis proteins and craniofacial cell survival. | The Ribosome Biogenesis Factor Nol11 Is Required for Optimal rDNA Transcription and Craniofacial Development in Xenopus |
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redundancy and indirect effects. Genome-wide reconstitution of promoter nucleosome organization with purified proteins resolves this problem and is therefore a critical goal. Here, we reconstitute four stages of nucleosome architecture using purified components: yeast genomic DNA, histones, sequence-specific Abf1/Reb1, and remodelers RSC, ISW2, INO80, and ISW1a. We identify direct, specific, and sufficient contributions that in vivo observations validate. First, RSC clears promoters by translating poly(dA:dT) into directional nucleosome removal. Second, partial redundancy is recapitulated where INO80 alone, or ISW2 at Abf1/Reb1sites, positions +1 nucleosomes. Third, INO80 and ISW2 each align downstream nucleosomal arrays. Fourth, ISW1a tightens the spacing to canonical repeat lengths. Such a minimal set of rules and proteins establishes core mechanisms by which promoter chromatin architecture arises through a blend of redundancy and specialization. | Genomic Nucleosome Organization Reconstituted with Pure Proteins |
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Here we show that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the cords of the subcapsular red pulp and are distinct from macrophages and DCs. In response to ischemic myocardial injury, splenic monocytes increase their motility, exit the spleen en masse, accumulate in injured tissue, and participate in wound healing. These observations uncover a role for the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes as a resource that the body exploits to regulate inflammation. | Identification of splenic reservoir monocytes and their deployment to inflammatory sites. |
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0.18816383183002472, "25604": 0.05139094591140747, "26305": 0.05786345899105072, "26524": 0.7314660549163818, "26534": 0.2637155055999756, "26741": 0.07341018319129944, "26773": 0.14179791510105133, "26807": 0.04487626627087593, "26838": 0.15693697333335876, "27287": 0.817850649356842, "27532": 0.06429435312747955, "27651": 0.053244512528181076, "27892": 0.1401015669107437, "28086": 1.0887986421585083, "28177": 0.2026219218969345, "28179": 0.11343330889940262, "28228": 0.34508460760116577, "28290": 0.0797421783208847, "28712": 0.2711893916130066, "28767": 0.09050461649894714, "29101": 0.1602703034877777, "29206": 0.13670019805431366, "29222": 0.26146242022514343, "29290": 0.29619070887565613, "29484": 0.29981520771980286, "29610": 0.4728073179721832} | 7492250 | The dentate gyrus has an important role in learning and memory, and adult neurogenesis in the subgranular zone of the dentate gyrus may play a role in the acquisition of new memories. The homeobox gene Prox1 is expressed in the dentate gyrus during embryonic development and adult neurogenesis. Here we show that Prox1 is necessary for the maturation of granule cells in the dentate gyrus during development and for the maintenance of intermediate progenitors during adult neurogenesis. We also demonstrate that Prox1-expressing intermediate progenitors are required for adult neural stem cell self-maintenance in the subgranular zone; thus, we have identified a previously unknown non-cell autonomous regulatory feedback mechanism that controls adult neurogenesis in this region of the mammalian brain. Finally, we show that the ectopic expression of Prox1 induces premature differentiation of neural stem cells. | Prox1 Is Required for Granule Cell Maturation and Intermediate Progenitor Maintenance During Brain Neurogenesis |
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"28198": 0.6714286804199219, "28252": 0.17840765416622162, "28297": 0.07159364968538284, "28405": 0.26446542143821716, "28723": 0.06337817758321762, "28731": 0.8357921838760376, "28788": 0.058784693479537964, "29060": 0.014542185701429844, "29290": 0.20501139760017395} | 7492420 | Human embryonic stem cells (hESCs) and induced pluripotent stem cells proliferate rapidly and divide symmetrically producing equivalent progeny cells. In contrast, lineage committed cells acquire an extended symmetrical cell cycle. Self-renewal of tissue-specific stem cells is sustained by asymmetric cell division where one progeny cell remains a progenitor while the partner progeny cell exits the cell cycle and differentiates. There are three principal contexts for considering the operation and regulation of the pluripotent cell cycle: temporal, regulatory, and structural. The primary temporal context that the pluripotent self-renewal cell cycle of hESCs is a short G1 period without reducing periods of time allocated to S phase, G2, and mitosis. The rules that govern proliferation in hESCs remain to be comprehensively established. However, several lines of evidence suggest a key role for the naïve transcriptome of hESCs, which is competent to stringently regulate the embryonic stem cell (ESC) cell cycle. This supports the requirements of pluripotent cells to self-propagate while suppressing expression of genes that confer lineage commitment and/or tissue specificity. However, for the first time, we consider unique dimensions to the architectural organization and assembly of regulatory machinery for gene expression in nuclear microenviornments that define parameters of pluripotency. From both fundamental biological and clinical perspectives, understanding control of the abbreviated ESC cycle can provide options to coordinate control of proliferation versus differentiation. Wound healing, tissue engineering, and cell-based therapy to mitigate developmental aberrations illustrate applications that benefit from knowledge of the biology of the pluripotent cell cycle. | The abbreviated pluripotent cell cycle. |
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0.4855078160762787, "29311": 0.3662964701652527} | 7506409 | Human mesenchymal stem cells (hMSCs) have been widely studied as a source of primary adult stem cells for cell therapy because of their multidifferentiation potential; however, the growth arrest (also known as "premature senescence") often found in hMSCs cultured in vitro has been a major obstacle to the in-depth characterization of these cells. In addition, the inability to maintain constant cell growth hampers the development of additional genetic modifications aimed at achieving desired levels of differentiation to specific tissues; however, the molecular mechanisms that govern this phenomenon remain unclear, with the exception of a few studies demonstrating that induction of p16INK4a is responsible for this senescence-like event. Here, we observed that the premature growth arrest in hMSCs occurs in parallel with the induction of p16INK4a, following abrogation of inhibitory phosphorylation of retinoblastoma protein. These stress responses were concurrent with increased formation of reactive oxygen species (ROSs) from mitochondria and increased p38 mitogen-activated protein kinase (MAPK) activity. The introduction of Wip1 (wild-type p53 inducible phosphatase-1), a well-studied stress modulator, significantly lowered p16INK4a expression and led to p38 MAPK inactivation, although it failed to affect the levels of ROSs. Moreover, the suppression of stress responses by Wip1 apparently extended the life span of hMSCs, compared with control conditions, while maintaining their multilineage differentiation potential. Based on these results, we suggest that senescent growth arrest in hMSCs may result from activation of stress signaling pathways and consequent onset of stress responses, due in part to ROS production during prolonged in vitro culture. | Senescent growth arrest in mesenchymal stem cells is bypassed by Wip1-mediated downregulation of intrinsic stress signaling pathways. |
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0.684319257736206, "29172": 0.3141832649707794, "29206": 0.03266380727291107, "29516": 0.16524957120418549} | 7514614 | Evolutionary considerations suggest aging is caused not by active gene programming but by evolved limitations in somatic maintenance, resulting in a build-up of damage. Ecological factors such as hazard rates and food availability influence the trade-offs between investing in growth, reproduction, and somatic survival, explaining why species evolved different life spans and why aging rate can sometimes be altered, for example, by dietary restriction. To understand the cell and molecular basis of aging is to unravel the multiplicity of mechanisms causing damage to accumulate and the complex array of systems working to keep damage at bay. | Understanding the Odd Science of Aging |
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"26512": 0.7398891448974609, "26524": 0.1718502640724182, "26632": 1.2012346982955933, "26708": 0.026025565341114998, "26773": 0.09317722171545029, "26835": 0.06977381557226181, "26906": 0.2160874605178833, "27162": 0.24325250089168549, "27321": 1.2192846536636353, "27790": 0.0354953333735466, "27998": 0.7201237678527832, "28309": 0.14518201351165771, "28424": 0.0317181795835495, "28667": 0.41195443272590637, "28788": 0.6170841455459595, "28873": 0.1229778528213501, "29206": 0.020300358533859253} | 7521113 | Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, contribute to tissue integrity as well as to innate and adaptive immune defense. Emerging evidence for labor division indicates that manipulation of these cells could bear therapeutic potential. However, specific ontogenies of individual populations and the overall functional organization of this cellular network are not well defined. Here we report a fate-mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX(3)CR1 promoter-driven Cre recombinase expression. We have demonstrated that major tissue-resident macrophage populations, including liver Kupffer cells and lung alveolar, splenic, and peritoneal macrophages, are established prior to birth and maintain themselves subsequently during adulthood independent of replenishment by blood monocytes. Furthermore, we have established that short-lived Ly6C(+) monocytes constitute obligatory steady-state precursors of blood-resident Ly6C(-) cells and that the abundance of Ly6C(+) blood monocytes dynamically controls the circulation lifespan of their progeny. | Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. |
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"20792": 0.16690383851528168, "21150": 0.3297532796859741, "21230": 0.5607312321662903, "21374": 0.012615402229130268, "21407": 0.23556606471538544, "21499": 0.35745587944984436, "21770": 1.2398450374603271, "21893": 0.18411032855510712, "22329": 1.2267581224441528, "22835": 0.6654226183891296, "23521": 0.34370049834251404, "23737": 0.016465263441205025, "23900": 0.7276995778083801, "23924": 0.31132611632347107, "24004": 0.38905516266822815, "24026": 0.7239188551902771, "24155": 0.3084607720375061, "24710": 0.151916041970253, "24854": 0.4151833653450012, "25077": 0.3810817003250122, "25095": 0.29255300760269165, "25613": 0.04860413447022438, "26237": 0.2447827309370041, "26319": 0.18411032855510712, "27354": 0.06429435312747955, "28093": 0.35813871026039124, "28102": 0.02316705882549286, "28436": 0.12986256182193756, "29165": 0.10203468054533005} | 7547329 | BACKGROUND Dealing with heterogeneity in meta-analyses is often tricky, and there is only limited advice for authors on what to do. We investigated how authors addressed different degrees of heterogeneity, in particular whether they used a fixed effect model, which assumes that all the included studies are estimating the same true effect, or a random effects model where this is not assumed. METHODS We sampled randomly 60 Cochrane reviews from 2008, which presented a result in its first meta-analysis with substantial heterogeneity (I2 greater than 50%, i.e. more than 50% of the variation is due to heterogeneity rather than chance). We extracted information on choice of statistical model, how the authors had handled the heterogeneity, and assessed the methodological quality of the reviews in relation to this. RESULTS The distribution of heterogeneity was rather uniform in the whole I2 interval, 50-100%. A fixed effect model was used in 33 reviews (55%), but there was no correlation between I2 and choice of model (P = 0.79). We considered that 20 reviews (33%), 16 of which had used a fixed effect model, had major problems. The most common problems were: use of a fixed effect model and lack of rationale for choice of that model, lack of comment on even severe heterogeneity and of reservations and explanations of its likely causes. The problematic reviews had significantly fewer included trials than other reviews (4.3 vs. 8.0, P = 0.024). The problems became less pronounced with time, as those reviews that were most recently updated more often used a random effects model. CONCLUSION One-third of Cochrane reviews with substantial heterogeneity had major problems in relation to their handling of heterogeneity. More attention is needed to this issue, as the problems we identified can be essential for the conclusions of the reviews. | Dealing with substantial heterogeneity in Cochrane reviews. Cross-sectional study |
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"26014": 0.10291612148284912, "26042": 0.09228714555501938, "26131": 0.1734936386346817, "26305": 0.11256109178066254, "26402": 0.3547199070453644, "26512": 0.02792670577764511, "26520": 0.11430477350950241, "26702": 0.06703783571720123, "26773": 0.4190443754196167, "26780": 0.3141832649707794, "27118": 0.5903874635696411, "27467": 0.347847044467926, "27531": 1.335720419883728, "27598": 0.9052929878234863, "27717": 0.8366385698318481, "27846": 0.23864774405956268, "27989": 0.037378571927547455, "28041": 0.2667117714881897, "28079": 0.2160874605178833, "28268": 0.06612417846918106, "28685": 0.08513788133859634, "28691": 0.26446542143821716, "28828": 0.14602625370025635, "28829": 0.8973627090454102, "28927": 0.3683255612850189, "29109": 0.04207121208310127, "29228": 0.1994270235300064, "29290": 0.4679262638092041, "29297": 1.1726272106170654, "29516": 0.9576126337051392} | 7548577 | In the yeast Saccharomyces cerevisiae, glycogen is accumulated as a carbohydrate reserve when cells are deprived of nutrients. Yeast mutated in SNF1, a gene encoding a protein kinase required for glucose derepression, has diminished glycogen accumulation and concomitant inactivation of glycogen synthase. Restoration of synthesis in an snf1 strain results only in transient glycogen accumulation, implying the existence of other SNF1-dependent controls of glycogen storage. A genetic screen revealed that two genes involved in autophagy, APG1 and APG13, may be regulated by SNF1. Increased autophagic activity was observed in wild-type cells entering the stationary phase, but this induction was impaired in an snf1 strain. Mutants defective for autophagy were able to synthesize glycogen upon approaching the stationary phase, but were unable to maintain their glycogen stores, because subsequent synthesis was impaired and degradation by phosphorylase, Gph1p, was enhanced. Thus, deletion of GPH1 partially reversed the loss of glycogen accumulation in autophagy mutants. Loss of the vacuolar glucosidase, SGA1, also protected glycogen stores, but only very late in the stationary phase. Gph1p and Sga1p may therefore degrade physically distinct pools of glycogen. Pho85p is a cyclin-dependent protein kinase that antagonizes SNF1 control of glycogen synthesis. Induction of autophagy in pho85 mutants entering the stationary phase was exaggerated compared to the level in wild-type cells, but was blocked in apg1 pho85 mutants. We propose that Snf1p and Pho85p are, respectively, positive and negative regulators of autophagy, probably via Apg1 and/or Apg13. Defective glycogen storage in snf1 cells can be attributed to both defective synthesis upon entry into stationary phase and impaired maintenance of glycogen levels caused by the lack of autophagy. | Antagonistic Controls of Autophagy and Glycogen Accumulation by Snf1p, the Yeast Homolog of AMP-Activated Protein Kinase, and the Cyclin-Dependent |
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"26396": 0.05417001247406006, "27094": 0.27934664487838745, "27169": 0.06703783571720123, "27226": 0.5139457583427429, "27356": 0.06886265426874161, "27598": 0.9225212931632996, "27781": 1.068206787109375, "27854": 0.3923587501049042, "28041": 0.33325836062431335, "28251": 1.307593584060669, "28281": 0.5500838756561279, "28553": 0.11691460013389587, "28727": 0.0009760859538801014, "28873": 0.18816383183002472, "29105": 0.6704301834106445, "29489": 0.53589928150177, "29490": 0.02792670577764511} | 7549811 | Polarized transport in neurons is fundamental for the formation of neuronal circuitry. A motor domain-containing truncated KIF5 (a kinesin-1) recognizes axonal microtubules, which are enriched in EB1 binding sites, and selectively accumulates at the tips of axons. However, it remains unknown what cue KIF5 recognizes to result in this selective accumulation. We found that axonal microtubules were preferentially stained by the anti-GTP-tubulin antibody hMB11. Super-resolution microscopy combined with EM immunocytochemistry revealed that hMB11 was localized at KIF5 attachment sites. In addition, EB1, which binds preferentially to guanylyl-methylene-diphosphate (GMPCPP) microtubules in vitro, recognized hMB11 binding sites on axonal microtubules. Further, expression of hMB11 antibody in neurons disrupted the selective accumulation of truncated KIF5 in the axon tips. In vitro studies revealed approximately threefold stronger binding of KIF5 motor head to GMPCPP microtubules than to GDP microtubules. Collectively, these data suggest that the abundance of GTP-tubulin in axonal microtubules may underlie selective KIF5 localization and polarized axonal vesicular transport. | Preferential binding of a kinesin-1 motor to GTP-tubulin–rich microtubules underlies polarized vesicle transport |
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"24004": 0.029824240133166313, "24012": 0.055094651877880096, "24080": 0.18654440343379974, "24176": 0.7583568692207336, "24209": 0.6456501483917236, "24278": 0.2822965085506439, "24374": 0.176772341132164, "24382": 0.5646255612373352, "24454": 0.6568518877029419, "24755": 0.026976587250828743, "24759": 0.47463157773017883, "24933": 0.0029254043474793434, "25194": 0.08961215615272522, "25320": 0.47463157773017883, "25476": 0.567951500415802, "25662": 0.07250232994556427, "25700": 0.952351450920105, "25714": 0.5860490798950195, "26033": 0.8699195384979248, "26376": 0.7845434546470642, "26524": 0.4228905141353607, "26734": 0.8152611255645752, "26775": 0.07884006202220917, "27118": 0.7629209756851196, "27343": 0.28890204429626465, "27381": 1.0030416250228882, "27480": 0.08154398202896118, "28086": 0.969535231590271, "28667": 0.05046287178993225, "28788": 0.1602703034877777} | 7552147 | The pancreas is an organ containing two distinct populations of cells, the exocrine cells that secrete enzymes into the digestive tract, and the endocrine cells that secrete hormones into the bloodstream. It arises from the endoderm as a dorsal and a ventral bud which fuse together to form the single organ. Mammals, birds, reptiles and amphibians have a pancreas with similar histology and mode of development, while in some fish, the islet cells are segregated as Brockmann bodies. Invertebrates do not have a pancreas, but comparable endocrine cells may be found in the gut or the brain. The early pancreatic bud shows uniform expression of the homeobox gene IPF-1 (also known as IDX-1, STF-1 or PDX), which when mutated to inactivity leads to total absence of the organ. The occurrence of heterotopic pancreas in the embryo, and also the metaplasias that can be displayed by a regenerating pancreas in the adult, both suggest that only a few gene products distinguish the pancreatic cell state from that of the surrounding tissues of duodenum, gall bladder and liver. In the developing pancreatic buds, the endocrine cells start to differentiate before the exocrine cells, and co-expression of different hormones by the same cell is often observed at early stages. Although pancreatic endocrine cells produce many gene products also characteristic of neurons, evidence from in vitro cultures and from quailchick grafts shows that they are of endogenous and not of neural crest origin. Observational studies suggest strongly that both endocrine and exocrine cells arise from the same endodermal rudiment. Development of the pancreas in embryonic life requires a trophic stimulus from the associated mesenchyme. In postnatal life, all cell types in the pancreas continue to grow. Destruction of acinar tissue by duct ligation or ethionine treatment is followed by rapid regeneration. Surgical removal of parts of the pancreas is followed by moderate but incomplete regeneration of both acini and islets. Poisoning with alloxan or streptozotocin can lead to permanent depletion of beta cells. Although the cell kinetics of the pancreas are not understood, it seems likely that there is a continuous slow turnover of cells, fed from a stem cells population in the ducts, and that the controls on the production rate of each cell type are local rather than systemic. | Developmental biology of the pancreas. |
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DESIGN Updated meta-analysis of randomised trials. DATA SOURCES Medline, Embase, the Cochrane controlled trials register, the Current Science meta-register of controlled trials, and reference lists of identified articles. All data sources were searched from December 2002 (end date of last search) to December 2006. STUDIES REVIEWED Double blind randomised placebo controlled trials of approved anti-obesity drugs used in adults (age over 18) for one year or longer. RESULTS 30 trials of one to four years' duration met the inclusion criteria: 16 orlistat (n=10 631 participants), 10 sibutramine (n=2623), and four rimonabant (n=6365). Of these, 14 trials were new and 16 had previously been identified. Attrition rates averaged 30-40%. Compared with placebo, orlistat reduced weight by 2.9 kg (95% confidence interval 2.5 kg to 3.2 kg), sibutramine by 4.2 kg (3.6 kg to 4.7 kg), and rimonabant by 4.7 kg (4.1 kg to 5.3 kg). Patients receiving active drug treatment were significantly more likely to achieve 5% and 10% weight loss thresholds. Orlistat reduced the incidence of diabetes and improved concentrations of total cholesterol and low density lipoprotein cholesterol, blood pressure, and glycaemic control in patients with diabetes but increased rates of gastrointestinal side effects and slightly lowered concentrations of high density lipoprotein. Sibutramine improved [corrected] concentrations of high density lipoprotein cholesterol and triglycerides [corrected] Rimonabant improved concentrations of high density lipoprotein cholesterol and triglycerides, blood pressure, and glycaemic control in patients with diabetes but increased the risk of mood disorders. CONCLUSIONS Orlistat, sibutramine, and rimonabant modestly reduce weight, have differing effects on cardiovascular risk profiles, and have specific adverse effects. | Long term pharmacotherapy for obesity and overweight: updated meta-analysis. |
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They influence the morphology of the microtubule cytoskeleton, function as the base for the primary cilium and serve as a nexus for important signalling pathways. At the core of a typical centrosome are two cylindrical microtubule-based structures termed centrioles, which recruit a matrix of associated pericentriolar material. Cells begin the cell cycle with exactly one centrosome, and the duplication of centrioles is constrained such that it occurs only once per cell cycle and at a specific site in the cell. As a result of this duplication mechanism, the two centrioles differ in age and maturity, and thus have different functions; for example, the older of the two centrioles can initiate the formation of a ciliary axoneme. We discuss spatial aspects of the centrosome duplication cycle, the mechanism of centriole assembly and the possible consequences of the inherent asymmetry of centrioles and centrosomes. | The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetries |
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"29301": 0.14095009863376617, "29441": 0.0058422754518687725} | 7568596 | Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched 'on' by engagement with bone-lining cells or osteoblasts, and switched 'off' by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse. | Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche |
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from blastocyst-stage embryos but have very different biological properties, and molecular analyses suggest that the pluripotent state of human ESCs isolated so far corresponds to that of mouse-derived epiblast stem cells (EpiSCs). Here we rewire the identity of conventional human ESCs into a more immature state that extensively shares defining features with pluripotent mouse ESCs. This was achieved by ectopic induction of Oct4, Klf4, and Klf2 factors combined with LIF and inhibitors of glycogen synthase kinase 3beta (GSK3beta) and mitogen-activated protein kinase (ERK1/2) pathway. Forskolin, a protein kinase A pathway agonist which can induce Klf4 and Klf2 expression, transiently substitutes for the requirement for ectopic transgene expression. In contrast to conventional human ESCs, these epigenetically converted cells have growth properties, an X-chromosome activation state (XaXa), a gene expression profile, and a signaling pathway dependence that are highly similar to those of mouse ESCs. Finally, the same growth conditions allow the derivation of human induced pluripotent stem (iPS) cells with similar properties as mouse iPS cells. The generation of validated "naïve" human ESCs will allow the molecular dissection of a previously undefined pluripotent state in humans and may open up new opportunities for patient-specific, disease-relevant research. | Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. |
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0.11256109178066254, "28086": 0.0606246218085289, "28472": 0.2837681770324707, "28516": 0.3777405619621277, "28674": 0.9256220459938049, "28723": 0.9485763907432556, "28991": 0.1734936386346817, "29130": 0.13157635927200317, "29543": 0.05970508232712746, "29659": 0.35128939151763916} | 7583104 | PURPOSE Mesh surgeries are counted among the most frequently applied surgical procedures. Despite global spread of mesh applying surgeries, there is no current systematic analysis of incidence and possible prevention of adverse events after mesh implantation. MATERIALS AND METHODS Based on the recommendations of IDEAL an in vitro test system for biocompatibility of surgical meshes has been generated (Innovation). Coating strategies for biocompatibility optimization have been developed (Development). The native and modified alloplastic materials have been tested in an animal model over 2 years (Exploration and Assessment and Long-term study). RESULTS In 3 meshes, implanted in sheep and explanted at 4 different time points (a, 3 months; b, 6 months; c, 12 months; and d, 24 months) over 24 months, thickness of inflammatory tissue (TVT a, 35 µm; b, 32 µm; c, 33 µm; d, 28 µm; UltraPro, a, 25 µm; b, 24 µm; c, 21 µm; d, 22 µm; PVDF a, 20 µm; b, 21 µm; c, 14 µm; d, 15µm), connective tissue (TVT a, 37 µm; b, 36 µm; c, 43 µm; d, 41 µm; UltraPro a, 33 µm; b, 32 µm; c, 40 µm; d, 38 µm; PVDF a, 25 µm; b, 22 µm; c, 22 µm; d, 24 µm), and macrophage infiltration (TVT a, 36%; b, 33%; c, 23%; d, 20%; UltraPro a, 34%; b, 28%; c, 25%; d, 22%; PVDF a, 24%; b, 18%; c, 18%; d, 16%) revealed comparable ranking characteristics at every time point after explantation. The in vivo performance of these meshes in a sheep model was predictable with a previously developed in vitro test system. Coating of meshes with autologous plasma prior to implantation seems to have a positive effect on the meshes biocompatibility. CONCLUSION We have applied IDEAL criteria on a new innovation for surgical meshes. The results permit the generation of a ranking of currently available meshes with potential to optimize future meshes. | IDEAL in meshes for prolapse, urinary incontinence, and hernia repair. |
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In syngeneic and semisyngeneic grafts of bone marrow under the renal capsule bone and bone marrow are formed. In allogeneic grafts only bone is formed; this bone is subsequently resorbed. In 14-month semisyngeneic transplants the bone marrow consists of recipient cells. This is true for both the proliferating pool and the stem cells of hematopoietic tissue. At the same time, osteogenic precursor cells and bone tissue in these transplants are of donor origin. A discussion is presented of the interrelationship between determinated osteogenic precursor cells (preosteoblasts) and hematopoietic stem cells (or their descendants) in which osteogenesis is inducible. | Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. |
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TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, thereby modifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation. | TRPM7 is required for breast tumor cell metastasis. |
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However, it is becoming recognized that frailty may be a distinct clinical syndrome with a biological basis. The frailty process appears to be a transitional state in the dynamic progression from robustness to functional decline. During this process, total physiological reserves decrease and become less likely to be sufficient for the maintenance and repair of the ageing body. Central to the clinical concept of frailty is that no single altered system alone defines it, but that multiple systems are involved. Clinical consensus regarding the phenotype which constitutes frailty, drawing upon the opinions of numerous authors, shows the characteristics to include wasting (loss of both muscle mass and strength and weight loss), loss of endurance, decreased balance and mobility, slowed performance, relative inactivity and, potentially, decreased cognitive function. Frailty is a distinct entity easily recognized by clinicians, with multiple manifestations and with no single symptom being sufficient or essential in its presentation. Manifestations include appearance (consistent or not with age), nutritional status (thin, weight loss), subjective health rating (health perception), performance (cognition, fatigue), sensory/physical impairments (vision, hearing, strength) and current care (medication, hospital). Although the early stages of the frailty process may be clinically silent, when depleted reserves reach an aggregate threshold leading to serious vulnerability, the syndrome may become detectable by looking at clinical, functional, behavioral and biological markers. Thus, a better understanding of these clinical changes and their underlying mechanisms, beginning in the pre-frail state, may confirm the impression held by many geriatricians that increasing frailty is distinguishable from ageing and in consequence is potentially reversible. We therefore provide an update of the physiopathology and clinical and biological characteristics of the frailty process and speculate on possible preventative approaches. | Frailty Syndrome: A Transitional State in a Dynamic Process |
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0.15693697333335876, "27651": 0.15860503911972046, "27673": 0.3325583338737488, "27718": 0.08603433519601822, "27794": 0.8901712894439697, "27833": 0.08782484382390976, "27989": 0.5762182474136353, "28228": 0.0009760859538801014, "28281": 0.09495500475168228, "28283": 0.4512746334075928, "28353": 0.8004589080810547, "28466": 1.2210142612457275, "28697": 0.28082266449928284, "28793": 0.10379679501056671, "28828": 0.10906458646059036, "28915": 0.3982778787612915, "28927": 0.08782484382390976, "29048": 0.966567873954773} | 7602348 | BACKGROUND Preclinical diastolic dysfunction (PDD) has been defined as subjects with normal systolic function, diastolic dysfunction but no symptoms of heart failure (HF). The clinical phenotype and natural history of the syndrome remains poorly defined. This study's objective was to determine the clinical phenotype and progression to HF in a group of patients with normal systolic function and moderate or severe diastolic dysfunction as determinate by Doppler criteria without any clinical diagnosis of HF according to the Framingham criteria or any symptoms of HF, specifically dyspnoea, oedema or fatigue at the time of echocardiography. METHODS The authors used resources of the Mayo Clinic echocardiography database to consecutively select among patients who had an echocardiogram in 2005, a cohort with moderate or severe diastolic dysfunction by Doppler criteria and EF >or=50%. Patients could not have a diagnosis of HF, or any HF symptoms-specifically dyspnoea, oedema or fatigue-at the time of echocardiography; nor grade 3 or greater valvular dysfunction (except tricuspid valve). A total of 82 patients had their medical chart reviewed. Primary endpoint was the time to the development of (1) HF according to the Framingham criteria or (2) any symptoms of dyspnoea, oedema or fatigue. RESULTS The mean age of the cohort of PDD subjects was 69+/-10 years with a female (67%) preponderance. Presence of hypertension was 76%, coronary artery disease was 29%, paroxysmal atrial fibrillation was 26%, estimated creatinine clearance <60 ml/min was 51%. The 2-year cumulative probability of development of HF according to the Framingham criteria was 1.9%; however, the 2-year cumulative probability of development of any symptoms was 31.1%. The 2-year cumulative probability for cardiac hospitalisation was 21.2%. Peripheral vascular disease and hypertension were independently associated with increased likelihood for the development of symptoms. CONCLUSION The study demonstrates that hypertension, hyperlipidaemia, CAD and renal dysfunction are prevalent in patients with PDD. More importantly, although the progression to the development of clinical HF over 2 years was low, there was a moderate degree of progression to development of symptoms and cardiac hospitalisations over 2 years. Based on the finding that only PVD and hypertension were independently associated with the progression to the development of symptoms in subject with PDD, the authors speculate that ventricular-arterial interaction may be important to the progression of diastolic dysfunction to the development of symptoms. | Progression of preclinical diastolic dysfunction to the development of symptoms. |
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"23971": 0.010684899985790253, "24759": 0.10906458646059036, "25006": 0.450652539730072, "25409": 0.9115922451019287, "25778": 0.2749055027961731, "26226": 0.0752234235405922, "26462": 0.1994270235300064, "26642": 0.1212492436170578, "27144": 0.9591107368469238, "27204": 0.08961215615272522, "28093": 0.18573370575904846, "28139": 0.791648268699646, "28207": 0.06886265426874161, "28309": 0.04953393340110779, "28591": 0.1221139207482338} | 7613033 | Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrial follow-up of nearly 14,000 patients from four randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about five years was associated with a 34% reduction in 20-year CRC mortality. A separate metaanalysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in four randomized adenoma prevention trials showed that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least two years, there was a 50% or more reduction in the risk of CRC commencing five years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation. | Aspirin in the chemoprevention of colorectal neoplasia: an overview. |
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"28014": 0.7836518287658691, "29206": 0.7370892763137817, "29248": 0.10731173306703568} | 7621534 | Although chemokines are well established to function in immunity and endothelial cell activation and proliferation, a rapidly growing literature suggests that CXC Chemokine receptors CXCR3, CXCR4 and CXCR7 are critical in the development and progression of solid tumors. The effect of these chemokine receptors in tumorigenesis is mediated via interactions with shared ligands I-TAC (CXCL11) and SDF-1 (CXCL12). Over the last decade, CXCR4 has been extensively reported to be overexpressed in most human solid tumors and has earned considerable attention toward elucidating its role in cancer metastasis. To enrich the existing armamentarium of anti-cancerous agents, many inhibitors of CXCL12-CXCR4 axis have emerged as additional or alternative agents for neo-adjuvant treatments and even many of them are in preclinical and clinical stages of their development. However, the discovery of CXCR7 as another receptor for CXCL12 with rather high binding affinity and recent reports about its involvement in cancer progression, has questioned the potential of "selective blockade" of CXCR4 as cancer chemotherapeutics. Interestingly, CXCR7 can also bind another chemokine CXCL11, which is an established ligand for CXCR3. Recent reports have documented that CXCR3 and their ligands are overexpressed in different solid tumors and regulate tumor growth and metastasis. Therefore, it is important to consider the interactions and crosstalk between these three chemokine receptors and their ligand mediated signaling cascades for the development of effective anti-cancer therapies. Emerging evidence also indicates that these receptors are differentially expressed in tumor endothelial cells as well as in cancer stem cells, suggesting their direct role in regulating tumor angiogenesis and metastasis. In this review, we will focus on the signals mediated by this receptor trio via their shared ligands and their role in tumor growth and progression. | Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12. |
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"23616": 0.015504186972975731, "23750": 0.0029254043474793434, "23900": 0.07341018319129944, "24054": 0.7210738658905029, "24394": 0.05970508232712746, "24455": 0.6471850275993347, "24635": 0.8748174905776978, "24707": 0.28082266449928284, "25456": 0.6369074583053589, "25549": 1.185243844985962, "25714": 0.05786345899105072, "25778": 0.38441169261932373, "25950": 0.06703783571720123, "26351": 0.9045027494430542, "26396": 0.05694137513637543, "26402": 0.9878844022750854, "26520": 1.0768938064575195, "26874": 0.3381449282169342, "27099": 0.13755162060260773, "27673": 0.06246116757392883, "28179": 0.2026219218969345, "28180": 0.026976587250828743, "28314": 0.22079704701900482, "28406": 0.2918238639831543, "29105": 0.8780695199966431, "29391": 0.025073638185858727, "29494": 0.24859806895256042} | 7622767 | We have used microinjection and time-lapse video microscopy to study the role of cyclin A in mitosis. We have injected purified, active cyclin A/cyclin-dependent kinase 2 (CDK2) into synchronized cells at specific points in the cell cycle and assayed its effect on cell division. We find that cyclin A/CDK2 will drive G2 phase cells into mitosis within 30 min of microinjection, up to 4 h before control cells enter mitosis. Often this premature mitosis is abnormal; the chromosomes do not completely condense and daughter cells fuse. Remarkably, microinjecting cyclin A/CDK2 into S phase cells has no effect on progress through the following G2 phase or mitosis. In complementary experiments we have microinjected the amino terminus of p21Cip1/Waf1/Sdi1 (p21N) into cells to inhibit cyclin A/CDK2 activity. We find that p21N will prevent S phase or G2 phase cells from entering mitosis, and will cause early prophase cells to return to interphase. These results suggest that cyclin A/CDK2 is a rate-limiting component required for entry into mitosis, and for progress through mitosis until late prophase. They also suggest that cyclin A/CDK2 may be the target of the recently described prophase checkpoint. | Human Cyclin a Is Required for Mitosis until Mid Prophase |
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effectiveness of a brief, 4-session cognitive behavioral, group psychotherapy for binge eating among bariatric surgery candidates at an academic medical center. Binge eating behaviors have been linked to poorer outcomes among bariatric surgery patients, and binge eating disorder have be considered a contraindication in surgery programs, some of which have mandated preoperative binge eating treatment. However, no previous studies have examined whether a preoperative binge eating intervention could successfully reduce binge eating behaviors among severely obese bariatric surgery candidates. METHODS A total of 243 bariatric surgery candidates completed a brief cognitive behavioral group treatment for binge eating behaviors and were administered the Binge Eating Scale and reported the number of weekly binge eating episodes at the initial psychological evaluation and again after the group sessions. The study used a pre-post intervention design. RESULTS The results suggested significant reductions in both binge eating behaviors and cognitions and binge eating episodes after the group intervention. The intervention's effectiveness did not differ according to gender or ethnicity (black versus white). CONCLUSION A brief cognitive behavioral intervention can reduce binge eating behaviors among bariatric surgery candidates. Given the potential influence of binge eating on outcomes, bariatric surgery programs could benefit by treating binge eating before surgery. | Brief, four-session group CBT reduces binge eating behaviors among bariatric surgery candidates. |
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"25022": 0.6254787445068359, "25346": 0.6043586730957031, "25409": 0.9037119746208191, "25468": 0.12470348179340363, "25481": 0.176772341132164, "25778": 0.14433705806732178, "26022": 0.036437395960092545, "26179": 0.08961215615272522, "26180": 0.02316705882549286, "26319": 0.3485364317893982, "26462": 0.5795059204101562, "26745": 0.8989537954330444, "26906": 0.18329764902591705, "27144": 0.12556517124176025, "27794": 0.010684899985790253, "27881": 0.19862671196460724, "28093": 0.7898768186569214, "28207": 0.1913948506116867, "28297": 0.1477125883102417, "28667": 0.8500841856002808, "28794": 0.08513788133859634, "29191": 0.1685553640127182, "29251": 0.24171993136405945, "29264": 0.17922431230545044, "29336": 0.013579257763922215, "29458": 0.1510767638683319, "29486": 0.34508460760116577} | 7639744 | OBJECTIVE To systematically review the evidence that smoking cessation after diagnosis of a primary lung tumour affects prognosis. DESIGN Systematic review with meta-analysis. DATA SOURCES CINAHL (from 1981), Embase (from 1980), Medline (from 1966), Web of Science (from 1966), CENTRAL (from 1977) to December 2008, and reference lists of included studies. STUDY SELECTION Randomised controlled trials or observational longitudinal studies that measured the effect of quitting smoking after diagnosis of lung cancer on prognostic outcomes, regardless of stage at presentation or tumour histology, were included. DATA EXTRACTION Two researchers independently identified studies for inclusion and extracted data. Estimates were combined by using a random effects model, and the I(2) statistic was used to examine heterogeneity. Life tables were used to model five year survival for early stage non-small cell lung cancer and limited stage small cell lung cancer, using death rates for continuing smokers and quitters obtained from this review. RESULTS In 9/10 included studies, most patients studied were diagnosed as having an early stage lung tumour. Continued smoking was associated with a significantly increased risk of all cause mortality (hazard ratio 2.94, 95% confidence interval 1.15 to 7.54) and recurrence (1.86, 1.01 to 3.41) in early stage non-small cell lung cancer and of all cause mortality (1.86, 1.33 to 2.59), development of a second primary tumour (4.31, 1.09 to 16.98), and recurrence (1.26, 1.06 to 1.50) in limited stage small cell lung cancer. No study contained data on the effect of quitting smoking on cancer specific mortality or on development of a second primary tumour in non-small cell lung cancer. Life table modelling on the basis of these data estimated 33% five year survival in 65 year old patients with early stage non-small cell lung cancer who continued to smoke compared with 70% in those who quit smoking. In limited stage small cell lung cancer, an estimated 29% of continuing smokers would survive for five years compared with 63% of quitters on the basis of the data from this review. CONCLUSIONS This review provides preliminary evidence that smoking cessation after diagnosis of early stage lung cancer improves prognostic outcomes. From life table modelling, the estimated number of deaths prevented is larger than would be expected from reduction of cardiorespiratory deaths after smoking cessation, so most of the mortality gain is likely to be due to reduced cancer progression. These findings indicate that offering smoking cessation treatment to patients presenting with early stage lung cancer may be beneficial. | Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis |
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0.026025565341114998, "28405": 0.3070250153541565, "28577": 0.029824240133166313, "28667": 0.26296505331993103, "28788": 0.8699195384979248, "29206": 1.0361549854278564, "29290": 0.6244332790374756} | 7640058 | The cloning of animals from adult cells has demonstrated that the developmental state of adult cells can be reprogrammed into that of embryonic cells by uncharacterized factors within the oocyte. More recently, transcription factors have been identified that can induce pluripotency in somatic cells without the use of oocytes, generating induced pluripotent stem (iPS) cells. iPS cells provide a unique platform to dissect the molecular mechanisms that underlie epigenetic reprogramming. Moreover, iPS cells can teach us about principles of normal development and disease, and might ultimately facilitate the treatment of patients by custom-tailored cell therapy. | Epigenetic reprogramming and induced pluripotency. |
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"26226": 0.2822965085506439, "26237": 0.15860503911972046, "26261": 0.2837681770324707, "26319": 0.02792670577764511, "26404": 0.4113073945045471, "26698": 0.175953671336174, "26786": 0.029824240133166313, "26819": 0.010684899985790253, "27065": 0.08064348995685577, "27339": 0.22782009840011597, "27697": 0.083342544734478, "27790": 0.25694093108177185, "27794": 1.0444365739822388, "27833": 0.013579257763922215, "27894": 0.5197699069976807, "28093": 0.1718502640724182, "28141": 0.5318912267684937, "28309": 0.12470348179340363, "28321": 0.06886265426874161, "28353": 0.46302130818367004, "28436": 0.3034266233444214, "28697": 0.09584271162748337, "28739": 0.29255300760269165, "28915": 0.24859806895256042, "29166": 0.24171993136405945, "29237": 0.28082266449928284, "29295": 0.17267228662967682, "29299": 0.021256839856505394, "29427": 0.06429435312747955, "29458": 0.1332872211933136} | 7640792 | CONTEXT Conflicting information exists about whether sex differences modulate short-term mortality following acute coronary syndromes (ACS). OBJECTIVES To investigate the relationship between sex and 30-day mortality in ACS, and to determine whether this relationship was modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates. DESIGN, SETTING, AND PARTICIPANTS A convenience sample of patients pooled from 11 independent, international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained at the Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) were women; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29% women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina. MAIN OUTCOME MEASURE Thirty-day mortality following ACS. RESULTS Thirty-day mortality was 9.6% in women and 5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95% CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI, 30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI (adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women (adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, women more often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel (23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (P for interaction = .70). CONCLUSIONS Sex-based differences existed in 30-day mortality among patients with ACS and vary depending on clinical presentation. However, these differences appear to be largely explained by clinical differences at presentation and severity of angiographically documented disease. | Sex differences in mortality following acute coronary syndromes. |
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"25100": 0.011650617234408855, "26309": 0.28890204429626465, "26591": 0.0019512200960889459, "27058": 0.5838727951049805, "27169": 0.371698260307312, "27178": 0.1221139207482338, "27441": 1.2856967449188232, "27717": 1.1487655639648438, "28166": 0.030771657824516296, "28283": 0.5849615335464478, "28314": 0.07159364968538284, "28613": 0.8583967685699463, "28835": 0.2160874605178833, "29053": 0.25995752215385437, "29297": 1.0601204633712769} | 7643848 | We have characterized the membrane topology of a 60-kDa inner membrane protein from Escherichia coli that is homologous to the recently identified Oxa1p protein in Saccharomyces cerevisiae mitochondria implicated in the assembly of mitochondrial inner membrane proteins. Hydrophobicity and alkaline phosphatase fusion analyses suggest a membrane topology with six transmembrane segments, including an N-terminal signal-anchor sequence not present in mitochondrial Oxa1p. In contrast to partial N-terminal fusion protein constructs, the full-length protein folds into a protease-resistant conformation, suggesting that important folding determinants are present in the C-terminal part of the molecule. | Membrane topology of the 60-kDa Oxa1p homologue from Escherichia coli. |
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"26646": 0.1889725625514984, "26773": 0.12038381397724152, "26775": 0.3750596046447754, "26807": 0.1718502640724182, "26835": 0.12642613053321838, "26874": 0.6400018334388733, "27295": 0.11256109178066254, "27642": 0.24018502235412598, "27989": 0.12728634476661682, "28024": 0.47584590315818787, "28389": 1.56877863407135, "28712": 0.44566190242767334, "28848": 0.007782140281051397, "28873": 0.4437839686870575, "29060": 0.1401015669107437} | 7645565 | Hepatitis B X protein (HBx) plays an essential role in the hepatitis B virus (HBV) replication cycle, but the function of HBx has been elusive until recently. It was recently shown that transcription from the HBV genome (covalently-closed circular DNA, cccDNA) is inhibited by the structural maintenance of chromosome 5/6 complex (Smc5/6), and that a key function of HBx is to redirect the DNA-damage binding protein 1 (DDB1) E3 ubiquitin ligase to target this complex for degradation. By doing so, HBx alleviates transcriptional repression by Smc5/6 and stimulates HBV gene expression. In this review, we discuss in detail how the interplay between HBx and Smc5/6 was identified and characterized. We also discuss what is known regarding the repression of cccDNA transcription by Smc5/6, the timing of HBx expression, and the potential role of HBx in promoting hepatocellular carcinoma (HCC). | Identifying and Characterizing Interplay between Hepatitis B Virus X Protein and Smc5/6 |
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"26163": 0.2018241584300995, "26226": 0.09584271162748337, "26236": 0.2852376699447632, "26305": 0.8989537954330444, "26708": 0.10731173306703568, "26835": 0.37907835841178894, "26957": 0.11081436276435852, "27162": 0.151916041970253, "27216": 0.21372433006763458, "27312": 0.0913962796330452, "27672": 0.009718249551951885, "27794": 0.7889899015426636, "27815": 0.41065993905067444, "28023": 0.11256109178066254, "28207": 0.1358480453491211, "28389": 1.533164143562317, "28578": 0.8941729068756104, "28848": 0.5376120805740356, "28873": 0.13071982562541962, "28879": 1.0560526847839355, "29098": 0.6435998678207397} | 7647224 | Background. Hepatitis C virus (HCV) is an underappreciated cause of pediatric liver disease, most frequently acquired by vertical transmission (VT). Current guidelines that include the option of screening infants for HCV RNA at 1-2 months are based on data prior to current real-time polymerase chain reaction (PCR)-based testing. Previous studies have demonstrated VT rates of 4%-15% and an association with high maternal viral load. We evaluated HCV RNA in infants with HCV VT and assessed maternal risk factors in a prospective cohort in Cairo, Egypt. Methods. Pregnant women were screened for HCV from December 2012 to March 2014. For those with HCV viremia, their infants were tested at 12 months for HCV RNA using real-time PCR. Maternal risk factors assessed for HCV VT association included HCV RNA levels, mode of delivery, and maternal IL28B genotype. Results. Of 2514 women screened, a total of 54 women were viremic (2.1%) and delivered 56 infants. Of those, 51 infants of 49 women were tested at 12 months of age. Only 7 infants were viremic, with an HCV VT rate of 14.3% (7 of 49). Median HCV RNA in the infants was 2100 IU/mL. None of the maternal risk factors analyzed were associated with transmission. Conclusions. In Egypt where HCV is highly endemic, we observed an overall 12-month HCV VT rate of 14.3%. Further studies should focus on better identification of pregnant women more likely to vertically transmit HCV and earlier testing of infants to identify those likely to develop chronicity. | Hepatitis C Virus (HCV) Vertical Transmission in 12-Month-Old Infants Born to HCV-Infected Women and Assessment of Maternal Risk Factors |
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0.9710156321525574, "25090": 0.05970508232712746, "25437": 0.3824150264263153, "25714": 0.04113444685935974, "25765": 0.2105647772550583, "26013": 0.3949938118457794, "26163": 0.7995813488960266, "26236": 0.1619328260421753, "26305": 0.056018441915512085, "26308": 0.12470348179340363, "26462": 0.11168810725212097, "26492": 0.6244332790374756, "26520": 0.010684899985790253, "26572": 0.33115679025650024, "26835": 0.3824150264263153, "27354": 0.11778303235769272, "28389": 0.21372433006763458, "28436": 0.34922540187835693, "28711": 0.5483922958374023, "28762": 0.08871890604496002, "28873": 0.1485546976327896, "29458": 0.5712664127349854, "29490": 0.11256109178066254} | 7650066 | BACKGROUND Several studies have shown that testing for high-risk human papillomavirus (HPV) types results in an improved sensitivity for CIN2+, compared with cytology, although with a somewhat lower specificity. METHODS We obtained follow-up results, with at least one smear after participation in the HART study, which compared HPV testing (HC-II) with cytology as a primary screening modality. RESULTS With a median follow-up of 6 years, 42 additional cases of CIN2+ were identified; women who were HPV positive at baseline were more likely to develop CIN2+ than those who were HPV negative (hazard ratio (HR) 17.2; 95% confidence interval (CI) (9.3-31.6)) and the risk increased with increasing viral load. Compared with HPV-negative women (relative light unit (RLU) <1), the HR (95% CI) was 5.4 (1.6, 18.2) for 1-10 RLU and 25.5 (13.6, 47.9) for RLU > or = 10. Positive cytology (borderline or worse compared with negative) was also predictive of developing CIN2, although to a lesser extent (HR 8.7; 95% CI (4.5-17.1)). Only one case of CIN3 and three cases of CIN2 were found in women who showed a positive cytology result but were HPV negative at baseline. CONCLUSION After 5 years of follow-up, CIN2+ occurred in 0.23% of women who were HPV negative at baseline compared with 0.48% of women who showed a negative cytology result, indicating a much longer low-risk interval for CIN2+ after HPV testing. | Long-term follow-up of cervical disease in women screened by cytology and HPV testing: results from the HART study |
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0.09495500475168228, "28093": 0.35060185194015503, "28190": 0.11256109178066254, "28279": 0.04394211992621422, "28297": 0.18492233753204346, "28321": 0.034552380442619324, "28472": 0.1602703034877777, "28685": 0.255429208278656, "28774": 0.2576959431171417, "28836": 0.37640097737312317, "29107": 0.18329764902591705, "29361": 0.06429435312747955, "29461": 0.11168810725212097} | 7655029 | BACKGROUND Blindness due to trachoma is avoidable through Surgery, Antibiotics, Facial hygiene and Environmental improvements (SAFE). Recent surveys have shown trachoma to be a serious cause of blindness in Southern Sudan. We conducted this survey in Ayod County of Jonglei State to estimate the need for intervention activities to eliminate blinding trachoma. METHODOLOGY AND FINDINGS A cross-sectional two-stage cluster random survey was conducted in November 2006. All residents of selected households were clinically assessed for trachoma using the World Health Organization (WHO) simplified grading scheme. A total of 2,335 people from 392 households were examined, of whom 1,107 were over 14 years of age. Prevalence of signs of active trachoma in children 1-9 years of age was: trachomatous inflammation follicular (TF) = 80.1% (95% confidence interval [CI], 73.9-86.3); trachomatous inflammation intense (TI) = 60.7% (95% CI, 54.6-66.8); and TF and/or TI (active trachoma) = 88.3% (95% CI, 83.7-92.9). Prevalence of trachomatous trichiasis (TT) was 14.6% (95% CI, 10.9-18.3) in adults over 14 years of age; 2.9% (95% CI, 0.4-5.3) in children 1-14 years of age; and 8.4% (95% CI, 5.5-11.3) overall. The prevalence of corneal opacity in persons over 14 years of age with TT was 6.4% (95% CI, 4.5-8.3). No statistically significant difference was observed in the prevalence of trachoma signs between genders. Trachoma affected almost all households surveyed: 384/392 (98.0%) had at least one person with active trachoma and 130 (33.2%) had at least one person with trichiasis. CONCLUSIONS Trachoma is an unnecessary public health problem in Ayod. The high prevalence of active trachoma and trichiasis confirms the severe burden of blinding trachoma found in other post-conflict areas of Southern Sudan. Based on WHO recommended thresholds, all aspects of the SAFE strategy are indicated to eliminate blinding trachoma in Ayod. | The Burden of Trachoma in Ayod County of Southern Sudan |
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A century of research has revealed the essential causative agent: cholesterol-carrying low-density lipoprotein (LDL). LDL is controlled by specific receptors (LDLRs) in liver that remove it from blood. Mutations that eliminate LDLRs raise LDL and cause heart attacks in childhood, whereas mutations that raise LDLRs reduce LDL and diminish heart attacks. If we are to eliminate coronary disease, lowering LDL should be the primary goal. Effective means to achieve this goal are currently available. The key questions are: who to treat, when to treat, and how long to treat. | A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins |
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DESIGN Retrospective cohort study. Pregnancies in a cohort of women followed from registration of pregnancy to outcome of infant seven days after birth. SETTING Routine family planning records in 20 rural townships in eastern China. SUBJECTS 3697 pregnancies registered by the local family planning system during 1999. MAIN OUTCOME MEASURES Abortions, stillbirths, early neonatal mortality, perinatal mortality. RESULTS Only three cases were lost to follow up. The average age of the women at pregnancy was 25.9 years. Three hundred and twelve pregnancies were aborted and 240 ended in miscarriage (total 552, 15%). The perinatal mortality rate was 69 per 1000 births, the rate of stillbirth was 24 per 1000 births, and the early neonatal mortality was 46 per 1000 live births. The early neonatal mortality was 29 in boys and 69 in girls per 1000 live births. The perinatal mortality rate increased notably with parity and was higher in townships having lower income per capita. CONCLUSIONS The family planning system at the most local level is a useful data source for studying perinatal mortality in rural China. The perinatal mortality rate in the study county was higher than previously reported for both rural and urban areas in China. The results by parity and sex of the infant raise concern over the impact of the one child policy. | Perinatal mortality in rural China: retrospective cohort study. |
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7666498 | Mitosis is controlled by multiple kinases that drive cell cycle progression and prevent chromosome mis-segregation. Aurora kinase B interacts with survivin, borealin and incenp to form the chromosomal passenger complex (CPC), which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. Whereas genetic ablation of survivin, borealin or incenp results in early lethality at the morula stage, we show here that aurora B is dispensable for CPC function during early cell divisions and aurora B-null embryos are normally implanted. This is due to a crucial function of aurora C during these early embryonic cycles. Expression of aurora C decreases during late blastocyst stages resulting in post-implantation defects in aurora B-null embryos. These defects correlate with abundant prometaphase figures and apoptotic cell death of the aurora B-deficient inner cell mass. Conditional deletion of aurora B in somatic cells that do not express aurora C results in chromosomal misalignment and lack of chromosome segregation. Re-expression of wild-type, but not kinase-dead, aurora C rescues this defect, suggesting functional overlap between these two kinases. Finally, aurora B-null cells partially arrest in the presence of nocodazole, suggesting that this kinase is not essential for the spindle assembly checkpoint. | Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development. |
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RanGTP regulates the latter process by releasing microtubule-associated proteins from inhibitory complexes. NuSAP, a microtubule- and DNA-binding protein, is a target of RanGTP and promotes the formation of microtubules near chromosomes. However, the contribution of NuSAP to cell proliferation in vivo is unknown. Here, we demonstrate that the expression of NuSAP highly correlates with cell proliferation during embryogenesis and adult life, making it a reliable marker of proliferating cells. Additionally, we show that NuSAP deficiency in mice leads to early embryonic lethality. Spindle assembly in NuSAP-deficient cells is highly inefficient and chromosomes remain dispersed in the mitotic cytoplasm. As a result of sustained spindle checkpoint activity, the cells are unable to progress through mitosis, eventually leading to caspase activation and apoptotic cell death. Together, our findings demonstrate that NuSAP is essential for proliferation of embryonic cells and, simultaneously, they underscore the importance of chromatin-induced spindle assembly. | NuSAP is essential for chromatin-induced spindle formation during early embryogenesis. |
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"25644": 0.23787821829319, "25708": 0.037378571927547455, "25714": 0.7898768186569214, "25761": 1.0087559223175049, "26083": 0.2034190446138382, "26244": 0.06612417846918106, "26402": 0.8796916007995605, "26512": 0.8699195384979248, "26520": 0.06612417846918106, "26534": 0.3615458607673645, "26773": 0.6118015646934509, "26775": 0.5795059204101562, "27295": 0.034552380442619324, "27554": 0.176772341132164, "27598": 0.2983669638633728, "27673": 0.0913962796330452, "27854": 0.21372433006763458, "28517": 0.0019512200960889459, "29206": 0.15860503911972046, "29290": 0.7333439588546753, "29347": 0.15860503911972046} | 7688110 | The E2F family of transcription factors are essential for the regulation of genes required for appropriate progression through the cell cycle. Five members of the E2F family have been previously reported, namely E2F1-5. All five are key elements in transcriptional regulation of essential genes, and they can be divided into two functional groups, those that induce S-phase progression when overexpressed in quiescent cells (E2Fs 1–3), and those that do not (E2Fs 4–5). Here, we describe the identification of a novel member of this family, which we refer to as E2F-6. E2F-6 shares significant homology with E2Fs 1–5, especially within the DNA binding, heterodimerization and marked box domains. Unlike E2Fs 1–5, E2F-6 lacks a transactivation and a pocket protein binding domain, hence, forms a unique third group within the E2F family. E2F-6 is a nuclear protein that can form heterodimers with the DP proteins (both DP-1 and DP-2) in vitro and in vivo. Our results show that the complex formed between E2F-6 and the DP proteins, possesses high DNA binding activity, displaying a preference for a TTTCCCGC E2F recognition site, which is slightly different to the E2F consensus site derived from the E2 promoter (TTTCGCGC). In contrast to the other members of the E2F family, ectopic expression of E2F-6 inhibits transcription from promoters possessing E2F recognition sites rather than activating transcription. In addition, overexpression of E2F-6 suppresses the transactivational effects of co-expression of E2F-1 and DP-1. The inhibitory effect of E2F-6 is dependent on its DNA binding activity and its ability to form heterodimers with the DPs. Interestingly, ectopic expression of E2F-6 leads to accumulation of cells in S-phase. Our data suggest that E2F-6 expression delays the exit from S-phase rather than inducing S-phase, which further emphasizes the functional difference between E2F-6 and the previously known E2F family members. | E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription |
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"25194": 0.2689530849456787, "25362": 0.013579257763922215, "25456": 0.9687942266464233, "25609": 0.42608439922332764, "25714": 0.846739649772644, "25761": 0.2034190446138382, "26243": 0.9531047344207764, "26402": 0.659380316734314, "26468": 1.2494091987609863, "26514": 0.803087055683136, "26721": 0.11517547070980072, "26755": 0.05786345899105072, "26773": 0.3070250153541565, "27166": 0.47402387857437134, "27292": 0.7629209756851196, "27854": 0.3554046154022217, "28173": 0.823009729385376, "28228": 0.175953671336174, "28282": 0.22626367211341858, "28767": 0.15943801403045654, "29076": 0.11604541540145874, "29222": 0.1913948506116867, "29577": 0.11343330889940262, "29598": 0.6400018334388733} | 7708803 | The slow afterhyperpolarization (sAHP) in hippocampal neurons has been implicated in learning and memory. However, its precise role in cell excitability and central nervous system function has not been explicitly tested for 2 reasons: 1) there are, at present, no selective inhibitors that effectively reduce the underlying current in vivo or in intact in vitro tissue preparations, and 2) although it is known that a small conductance K(+) channel that activates after a rise in [Ca(2+)](i) underlies the sAHP, the exact molecular identity remains unknown. We show that 3-(triphenylmethylaminomethyl)pyridine (UCL2077), a novel compound, suppressed the sAHP present in hippocampal neurons in culture (IC(50) = 0.5 microM) and in the slice preparation (IC(50) approximately 10 microM). UCL2077 was selective, having minimal effects on Ca(2+) channels, action potentials, input resistance and the medium afterhyperpolarization. UCL2077 also had little effect on heterologously expressed small conductance Ca(2+)-activated K(+) (SK) channels. Moreover, UCL2077 and apamin, a selective SK channel blocker, affected spike firing in hippocampal neurons in different ways. These results provide further evidence that SK channels are unlikely to underlie the sAHP. This study also demonstrates that UCL2077, the most potent, selective sAHP blocker described so far, is a useful pharmacological tool for exploring the role of sAHP channels in the regulation of cell excitability in intact tissue preparations and, potentially, in vivo. | Enhancement of hippocampal pyramidal cell excitability by the novel selective slow-afterhyperpolarization channel blocker 3-(triphenylmethylaminomethyl)pyridine (UCL2077). |
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0.06703783571720123} | 7711685 | This review will reconsider the current paradigm for understanding the critical, final steps in the progression of atherosclerotic lesions. That scheme, largely an outgrowth of observations of autopsy tissues by Davies and colleagues,1 2 asserts that the cause of death in atherosclerotic coronary artery disease is rupture of an advanced atherosclerotic lesion. Although this assumption may be partially true, recent autopsy studies suggest that it is incomplete. To reconsider this paradigm, we reexamined the morphological classification scheme for lesions proposed by the American Heart Association (AHA).3 4 This scheme is difficult to use for 2 reasons. First, it uses a very long list of roman numerals modified by letter codes that are difficult to remember. Second, it implies an orderly, linear pattern of lesion progression. This tends to be ambiguous, because it is not clear whether there is a single sequence of events during the progression of all lesions. We have therefore tried to devise a simpler classification scheme that is consistent with the AHA categories but is easier to use, able to deal with a wide array of morphological variations, and not overly burdened by mechanistic implications. The current paradigm is based on the belief that type IV lesions, or “atheromas,” described by the AHA are stable because the fatty, necrotic core is contained by a smooth muscle cell–rich fibrous cap. Virchow’s analysis5 in 1858 pointed out that historically, the term “atheroma” refers to a dermal cyst (“Grutzbalg”), a fatty … | Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. |
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from host defense mechanisms. The human-pathogenic fungus Cryptococcus neoformans undergoes phenotypic switching in vivo that promotes persistence in tissue. By microarray and real-time PCR analyses, the allergen 1 gene (ALL1) was found to be downregulated in the hypervirulent mucoid switch variant, both during logarithmic growth and during intracellular growth in macrophages. The ALL1 gene encodes a small cytoplasmic protein that is involved in capsule formation. Growth of an all1Delta gene deletion mutant was normal. Similar to cells of the mucoid switch variant, all1Delta cells produced a larger polysaccharide capsule than cells of the smooth parent and the complemented strain produced, and the enlarged capsule inhibited macrophage phagocytosis. The mutant exhibited a modest defect in capsule induction compared to all of the other variants. In animal models the phenotype of the all1Delta mutant mimicked the hypervirulent phenotype of the mucoid switch variant, which is characterized by decreased host survival and elevated intracranial pressure. Decreased survival is likely the result of both an ineffective cell-mediated immune response and impaired phagocytosis by macrophages. Consequently, we concluded that, unlike loss of most virulence-associated genes, where loss of gene function results in attenuated virulence, loss of the ALL1 gene enhances virulence by altering the host-pathogen interaction and thereby impairing clearance. Our data identified the first cryptococcal gene associated with elevated intracranial pressure and support the hypothesis that an environmental opportunistic pathogen has modified its virulence in vivo by epigenetic downregulation of gene function. | Loss of allergen 1 confers a hypervirulent phenotype that resembles mucoid switch variants of Cryptococcus neoformans. |
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These receptors play an important role for the development and function of the nervous system, and are essential in learning and memory. However, iGluRs are also implicated in or have causal roles for several brain disorders, e.g. epilepsy, Alzheimer's disease, Parkinson's disease and schizophrenia. Their involvement in neurological diseases has stimulated widespread interest in their structure and function. Since the first publication in 1998 of the structure of a recombinant soluble protein comprising the ligand-binding domain of GluA2 extensive studies have afforded numerous crystal structures of wildtype and mutant proteins including different ligands. The structural information obtained combined with functional data have led to models for receptor activation and desensitization by agonists, inhibition by antagonists and block of desensitization by positive allosteric modulators. Furthermore, the structural and functional studies have formed a powerful platform for the design of new selective compounds. | Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators. |
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"26657": 0.14602625370025635, "26775": 0.8057082891464233, "27651": 0.1384023278951645, "27989": 0.5398913025856018, "28024": 0.6296497583389282, "28156": 0.6492279767990112, "28413": 1.0560526847839355, "28466": 1.0375399589538574, "28685": 0.304147332906723, "28828": 0.8981585502624512, "28868": 0.12814582884311676, "28927": 0.022212404757738113, "29048": 1.1350497007369995, "29160": 0.680370569229126, "29181": 1.19829261302948, "29290": 0.6286086440086365, "29458": 0.10026945173740387} | 7734150 | Pulmonary hypertension (PH) causes loss of body weight and inspiratory (diaphragm) muscle dysfunction. A model of PH induced by drug (monocrotaline, MCT) has been extensively used in mice to examine the etiology of PH. However, it is unclear if PH induced by MCT in mice reproduces the loss of body weight and diaphragm muscle dysfunction seen in patients. This is a pre-requisite for widespread use of mice to examine mechanisms of cachexia and diaphragm abnormalities in PH. Thus, we measured body and soleus muscle weight, food intake, and diaphragm contractile properties in mice after 6-8 weeks of saline (control) or MCT (600 mg/kg) injections. Body weight progressively decreased in PH mice, while food intake was similar in both groups. PH decreased (P<0.05) diaphragm maximal isometric specific force, maximal shortening velocity, and peak power. Protein carbonyls in whole-diaphragm lysates and the abundance of select myofibrillar proteins were unchanged by PH. Our findings show diaphragm isometric and isotonic contractile abnormalities in a murine model of PH induced by MCT. Overall, the murine model of PH elicited by MCT mimics loss of body weight and diaphragm muscle weakness reported in PH patients. | Diaphragm Atrophy and Contractile Dysfunction in a Murine Model of Pulmonary Hypertension |
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