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25737507
|
Feline Immunodeficiency Virus (FIV) is a Lentivirus responsible for an immunodeficiency like disease in domestic cats. Based on the genetic diversity of the V3-V5 region of env gene FIV is divided in five phylogenetic subtypes (A, B, C, D and E) with a world-wide distribution. To understand the subtype diversity of FIV in Portugal a serological survey was conducted during 1 year in the Veterinary Faculty Hospital, Lisbon, Portugal to identify seropositive animals. Two viral genomic regions were amplified by a nested PCR, sequenced and the phylogenetic relationships between 24 new Portuguese FIV sequences and other previously published FIV isolates were assessed. The introduction of these sequences induced a subclustering in subtype B including most of the new Portuguese sequences. Moreover, a new cluster emerged, with two highly divergent new sequences that might represent a new subtype. The study of these new FIV isolates showed the presence in Portugal of a unique viral population subclustering within subtype B and of sequences clearly divergent from the five known subtypes, providing a contribution for the understanding of FIV's genetic diversity.
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Phylogenetic analysis of Portuguese Feline Immunodeficiency Virus sequences reveals high genetic diversity.
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25738896
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The thymic transcription factor autoimmune regulator (Aire) prevents autoimmunity in part by promoting expression of tissue-specific self-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to cancer and provide insights into how such responses might be triggered. In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1-specific T cells without affecting thymic numbers of regulatory T cells. Aire-deficient mice displayed elevated T-cell immune responses that were associated with suppression of melanoma outgrowth. Furthermore, transplantation of Aire-deficient thymic stroma was sufficient to confer more effective immune rejection of melanoma in an otherwise Aire wild-type host. Together, our work showed how Aire deficiency can enhance immune responses against melanoma and how manipulating TRP-1-specific T-cell negative selection may offer a logical strategy to enhance immune rejection of melanoma.
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Aire deficiency promotes TRP-1-specific immune rejection of melanoma.
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"29070": 0.018384648486971855, "29536": 0.08961215615272522}
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25742130
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With respect to cervical cancer management, Finland and the Netherlands are comparable in relevant characteristics, e.g., fertility rate, age-of-mother at first birth and a national screening programme for several years. The aim of this study is to compare trends in incidence of and mortality from cervical cancer in Finland and the Netherlands in relation to the introduction and intensity of the screening programmes. Therefore, incidence and mortality rates were calculated using the Cancer Registries of Finland and the Netherlands. Data on screening intensity were obtained from the Finnish Cancer Registry and the Dutch evaluation centre at ErasmusMC-Rotterdam. Women aged 30-60 have been screened every 5 years, in Finland since 1992 and in the Netherlands since 1996. Screening protocols for smear taking and referral to the gynaecologist are comparable. Incidence and mortality rates have declined more in Finland. In 2003, age-adjusted incidence and mortality in Finland were 4.0 and 0.9 and in the Netherlands 4.9 and 1.4 per 100,000 woman-years, respectively. Excess smear use in the Netherlands was estimated to be 24 per 1,000 women during a 5-year interval compared to 121 in Finland. The decline in mortality in Finland seems to be almost completely related to the screening programme whereas in the Netherlands it was initially considered to be a natural decline. Differences in risk factors might also play a role: the Netherlands has higher population density and higher percentages of immigrants and (female) smokers. The greater excess smear use in Finland might also have affected incidence.
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Mass screening programmes and trends in cervical cancer in Finland and the Netherlands.
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25742205
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RanBP type proteins have been reported to increase the catalytic efficiency of the RanGAP-mediated GTPase reaction on Ran. Since the structure of the Ran-RanBP1-RanGAP complex showed RanBP1 to be located away from the active site, we reinvestigated the reaction using fluorescence spectroscopy under pre-steady-state conditions. We can show that RanBP1 indeed does not influence the rate-limiting step of the reaction, which is the cleavage of GTP and/or the release of product P(i). It does, however, influence the dynamics of the Ran-RanGAP interaction, its most dramatic effect being the 20-fold stimulation of the already very fast association reaction such that it is under diffusion control (4.5 x 10(8) M(-1) s(-1)). Having established a valuable kinetic system for the interaction analysis, we also found, in contrast to previous findings, that the highly conserved acidic C-terminal end of RanGAP is not required for the switch-off reaction. Rather, genetic experiments in Saccharomyces cerevisiae demonstrate a profound effect of the acidic tail on microtubule organization during mitosis. We propose that the acidic tail of RanGAP is required for a process during mitosis.
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Biochemical characterization of the Ran-RanBP1-RanGAP system: are RanBP proteins and the acidic tail of RanGAP required for the Ran-RanGAP GTPase reaction?
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25747721
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Type 1 cell-mediated immunity might play an important role in protection from typhoid fever. We evaluated whether immunization with Salmonella enterica serovar Typhi (S. Typhi) strain CVD 908-htrA (a Delta aroC Delta aroD Delta htrA mutant), a leading live oral typhoid vaccine candidate, elicits specific CD4(+) and CD8(+) S. Typhi immune responses. Potent CTL responses and IFN-gamma secretion by CD8(+) T cells were detected following immunization with CVD 908-htrA in high (4.5 x 10(8) CFU) and low (5 x 10(7) CFU) dosages. S. Typhi-specific CTL were observed in six of eight vaccinees (four high and two low dose) after immunization. Mean increases in the frequency of IFN-gamma spot-forming cells (SFC) in the presence of S. Typhi-infected targets were 221 +/- 41 SFC/10(6) PBMC and 233 +/- 87 SFC/10(6) PBMC, in the high and low dose groups, respectively. Strong CD4(+) T cell responses were also observed. Increases in the IFN-gamma production to soluble S. Typhi flagella (STF) occurred in 82 and 38% of the volunteers who received the high and low doses, respectively. Robust correlations were observed between volunteers that responded with IFN-gamma SFC to stimulation with S. Typhi-infected cells and IFN-gamma released in response to stimulation with STF Ags (r = 0.822, p < 0.001) and between CTL and IFN-gamma production to STF (r = 0.818, p = 0.013). These data demonstrating the concomitant induction of both CD4- and CD8-mediated CMI are consistent with a significant role for type 1 immunity in controlling typhoid infection and support the continuing evaluation of CVD 908-htrA as a typhoid vaccine candidate.
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Concomitant induction of CD4+ and CD8+ T cell responses in volunteers immunized with Salmonella enterica serovar typhi strain CVD 908-htrA.
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"28835": 1.2693654298782349}
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25748308
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Multiple roles for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) have been recently appreciated. In addition to the cytoplasm where the majority of GAPDH is located under the basal condition, GAPDH is also found in the particulate fractions, such as the nucleus, the mitochondria, and the small vesicular fractions. When cells are exposed to various stressors, dynamic subcellular re-distribution of GAPDH occurs. Here we review these multifunctional properties of GAPDH, especially linking them to its oligomerization, posttranslational modification, and subcellular localization. This includes mechanistic descriptions of how S-nitrosylation of GAPDH under oxidative stress may lead to cell death/dysfunction via nuclear translocation of GAPDH, which is counteracted by a cytosolic GOSPEL. GAPDH is also involved in various diseases, especially neurodegenerative disorders and cancers. Therapeutic strategies to these conditions based on molecular understanding of GAPDH are discussed.
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The diverse functions of GAPDH: views from different subcellular compartments.
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25761154
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Exercise-induced asthma is defined as an intermittent narrowing of the airways, demonstrated by a decrease in some measure of flow, that the patient experiences as wheezing, chest tightness, coughing, and difficulty breathing that is triggered by exercise. Exercise will trigger asthma in most individuals who have chronic asthma, as well as in some who do not otherwise have asthma. Definitive diagnosis requires demonstration of a drop in flow rate, typically > or = 13-15% for forced expiratory volume in one second (FEV1) and > or = 15-20% for peak expiratory flow rate (PEFR), after exercise, associated with symptoms. Prevalence data indicate that this disorder is very common in those who participate in recreational sports as well as in highly competitive athletes, with at least 12-15% of unselected athletes having positive exercise challenges. Treatment of exercise induced asthma involves use of nonpharmacological measures (such as the use of the refractory period after exercise and prewarming air) as well as use of medications (beta-agonists, cromolyn, and nedocromil). With treatment, those who suffer from exercise-induced asthma may be able to participate and compete at the highest levels of performance.
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Exercise-induced asthma: a practical guide to definitions, diagnosis, prevalence, and treatment.
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25786167
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BACKGROUND The quality of histopathology slides of endoscopic biopsies from different laboratories varies, but the effect of biopsy quality on outcome is unknown. HYPOTHESIS The ability to demonstrate a histologic lesion in the stomach or duodenum of a dog or cat is affected by the quality of endoscopic biopsy samples submitted. More endoscopic samples are needed to find a lesion in poor-quality tissue specimens. ANIMALS Tissues from 99 dogs and 51 cats were examined as clinical cases at 8 veterinary institutions or practices in 5 countries. METHODS Histopathology slides from sequential cases that underwent endoscopic biopsy were submitted by participating institutions. Quality of the histologic section of tissue (inadequate, marginal, adequate), type of lesion (lymphangiectasia, crypt lesion, villus blunting, cellular infiltrate), and severity of lesion (normal, mild, moderate, severe) were determined. Sensitivity of different quality tissue samples for finding different lesions was determined. RESULTS Fewer samples were required from dogs for diagnosis as the quality of the sample improved from inadequate to marginal to adequate. Duodenal lesions in cats displayed the same trend except for moderate duodenal infiltrates for which quality of tissue sample made no difference. Gastric lesions in dogs and mild gastric lesions in cats had the same trend, whereas the number of tissue samples needed to diagnose moderately severe gastric lesions in cats was not affected by the quality of tissue sample. CONCLUSIONS AND CLINICAL IMPORTANCE The quality of endoscopically obtained tissue samples has a profound effect on their sensitivity for identifying certain lesions, and there are differences between biopsies of canine and feline tissues.
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Effect of sample quality on the sensitivity of endoscopic biopsy for detecting gastric and duodenal lesions in dogs and cats.
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25787749
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The evolutionarily conserved G-quadruplexes (G4s) are faithfully inherited and serve a variety of cellular functions such as telomere maintenance, gene regulation, DNA replication initiation, and epigenetic regulation. Different from the Watson-Crick base-pairing found in duplex DNA, G4s are formed via Hoogsteen base pairing and are very stable and compact DNA structures. Failure of untangling them in the cell impedes DNA-based transactions and leads to genome instability. Cells have evolved highly specific helicases to resolve G4 structures. We used a recombinant nuclear form of Saccharomyces cerevisiae Pif1 to characterize Pif1-mediated DNA unwinding with a substrate mimicking an ongoing lagging strand synthesis stalled by G4s, which resembles a replication origin and a G4-structured flap in Okazaki fragment maturation. We find that the presence of G4 may greatly stimulate the Pif1 helicase to unwind duplex DNA. Further studies reveal that this stimulation results from G4-enhanced Pif1 dimerization, which is required for duplex DNA unwinding. This finding provides new insights into the properties and functions of G4s. We discuss the observed activation phenomenon in relation to the possible regulatory role of G4s in the rapid rescue of the stalled lagging strand synthesis by helping the replicator recognize and activate the replication origin as well as by quickly removing the G4-structured flap during Okazaki fragment maturation.
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G-quadruplexes significantly stimulate Pif1 helicase-catalyzed duplex DNA unwinding.
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25789730
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Both axon and myelin degeneration have significant impact on the long-term disability of patients with white matter disorder. However, the clinical manifestations of the neurological dysfunction caused by white matter disorders are not sufficient to determine the origin of neurological deficits. A noninvasive biological marker capable of detecting and differentiating axon and myelin degeneration would be a significant addition to currently available tools. Directional diffusivities derived from diffusion tensor imaging (DTI) have been previously proposed by this group as potential biological markers to detect and differentiate axon and myelin degeneration. To further test the hypothesis that axial (lambdaparallel) and radial (lambdaperpendicular) diffusivities reflect axon and myelin pathologies, respectively, the optic nerve was examined serially using DTI in a mouse model of retinal ischemia. A significant decrease of lambdaparallel, the putative DTI axonal marker, was observed 3 days after ischemia without concurrently detectable changes in lambdaperpendicular, the putative myelin marker. This result is consistent with histological findings of significant axonal degeneration with no detectable demyelination at 3 days after ischemia. The elevation of lambdaperpendicular observed 5 days after ischemia is consistent with histological findings of myelin degeneration at this time. These results support the hypothesis that lambdaparallel and lambdaperpendicular hold promise as specific markers of axonal and myelin injury, respectively, and, further, that the coexistence of axonal and myelin degeneration does not confound this utility.
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Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia.
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"23797": 0.04394211992621422, "24051": 1.0855059623718262, "24184": 1.4236729145050049, "24558": 0.4203280806541443, "24580": 0.07341018319129944, "24958": 0.3409265875816345, "25262": 0.08782484382390976, "25354": 1.2181298732757568, "25524": 0.4794800877571106, "25644": 0.5903874635696411, "25969": 0.9613537192344666, "26083": 0.11256109178066254, "26223": 0.034552380442619324, "26512": 1.6447447538375854, "26534": 0.36494144797325134, "26563": 0.009718249551951885, "26610": 0.29473719000816345, "26616": 0.2607102394104004, "26773": 0.4568560719490051, "26775": 0.5860490798950195, "26872": 0.3177432417869568, "26944": 0.6543170213699341, "27152": 0.7163142561912537, "27263": 1.3499990701675415, "27343": 0.5110208988189697, "27422": 0.06795065850019455, "27606": 0.04860413447022438, "28295": 0.10026945173740387, "28424": 0.5517725944519043, "28848": 0.33675122261047363, "29206": 0.1064341589808464, "29290": 0.012615402229130268, "29490": 0.06886265426874161}
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25799020
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Transcriptional regulatory elements play essential roles in gene expression during animal development and cellular response to environmental signals, but our knowledge of these regions in the human genome is limited despite the availability of the complete genome sequence. Promoters mark the start of every transcript and are an important class of regulatory elements. A large, complex protein structure known as the pre-initiation complex (PIC) is assembled on all active promoters, and the presence of these proteins distinguishes promoters from other sequences in the genome. Using components of the PIC as tags, we isolated promoters directly from human cells as protein-DNA complexes and identified the resulting DNA sequences using genomic tiling microarrays. Our experiments in four human cell lines uncovered 252 PIC-binding sites in 44 semirandomly selected human genomic regions comprising 1% (30 megabase pairs) of the human genome. Nearly 72% of the identified fragments overlap or immediately flank 5' ends of known cDNA sequences, while the remainder is found in other genomic regions that likely harbor putative promoters of unannotated transcripts. Indeed, molecular analysis of the RNA isolated from one cell line uncovered transcripts initiated from over half of the putative promoter fragments, and transient transfection assays revealed promoter activity for a significant proportion of fragments when they were fused to a luciferase reporter gene. These results demonstrate the specificity of a genome-wide analysis method for mapping transcriptional regulatory elements and also indicate that a small, yet significant number of human genes remains to be discovered.
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Direct isolation and identification of promoters in the human genome.
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0.06886265426874161, "12010": 0.0752234235405922, "12222": 0.04953393340110779, "12269": 0.007782140281051397, "12331": 0.9900637865066528, "12429": 0.3554046154022217, "12520": 0.4679262638092041, "12540": 0.0174254160374403, "12765": 0.5427330136299133, "12808": 0.2026219218969345, "12876": 0.06246116757392883, "12878": 0.6714286804199219, "12881": 0.1384023278951645, "12908": 0.0058422754518687725, "13013": 0.7009293437004089, "13180": 0.029824240133166313, "13186": 0.15023678541183472, "13203": 0.16110190749168396, "13263": 0.011650617234408855, "13356": 0.06703783571720123, "13433": 0.1221139207482338, "13481": 0.3864043951034546, "13561": 0.10026945173740387, "13649": 0.07431721687316895, "13900": 0.1229778528213501, "13915": 0.1064341589808464, "14126": 0.28597161173820496, "14155": 0.520350456237793, "14235": 0.02792670577764511, "14261": 0.011650617234408855, "14286": 0.15860503911972046, "14289": 0.9287132620811462, "14358": 0.14686977863311768, "14454": 0.7881022095680237, "14759": 0.13243216276168823, "14972": 0.1889725625514984, "15071": 0.1358480453491211, "15157": 0.14264501631259918, "15396": 0.19622190296649933, "15410": 0.18654440343379974, "15734": 0.034552380442619324, "15816": 0.20977331697940826, "15928": 0.28450319170951843, "15978": 0.14939609169960022, "15982": 0.15023678541183472, "15995": 0.18978065252304077, "16134": 0.27934664487838745, "16149": 1.022197961807251, "16150": 0.0058422754518687725, "16311": 0.23015019297599792, "16343": 0.21922965347766876, "16367": 0.9287132620811462, "16452": 0.2184450328350067, "17128": 0.15359249711036682, "17660": 0.09761575609445572, "17672": 0.25088030099868774, "17785": 0.669430673122406, "17895": 0.14179791510105133, "18655": 0.030771657824516296, "18949": 0.6155022978782654, "19219": 0.31560876965522766, "19329": 0.755608320236206, "19739": 0.11691460013389587, "20272": 0.6369074583053589, "20612": 0.07341018319129944, "20704": 0.11430477350950241, "20999": 0.22079704701900482, "21179": 0.9317949414253235, "21604": 0.5197699069976807, "21752": 0.9987343549728394, "22423": 0.19622190296649933, "22637": 1.034073829650879, "22641": 0.35677260160446167, "22698": 0.7258110046386719, "22787": 0.018384648486971855, "22822": 0.14349138736724854, "23565": 0.3346569836139679, "23980": 0.04113444685935974, "24390": 0.034552380442619324, "25121": 0.2983669638633728, "25394": 0.0797421783208847, "26094": 1.1350497007369995, "26257": 0.0797421783208847, "26458": 0.848413348197937, "26629": 0.04207121208310127, "26641": 0.47463157773017883, "26702": 0.26446542143821716, "27082": 0.11343330889940262, "28093": 0.07612881064414978, "28648": 0.48430517315864563, "29073": 0.06703783571720123, "29148": 0.0029254043474793434}
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25806385
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The World Health Organization/EURO Multicentre Project on Parasuicide is part of the action to implement target 12 of the WHO programme, "Health for All by the Year 2000', for the European region. Sixteen centres in 13 European countries are participating in the monitoring aspect of the project, in which trends in the epidemiology of suicide attempts are assessed. The highest average male age-standardized rate of suicide attempts was found for Helsinki, Finland (314/100,000), and the lowest rate (45/100,000) was for Guipuzcoa, Spain, representing a sevenfold difference. The highest average female age-standardized rate was found for Cergy-Pontoise, France (462/100,000), and the lowest (69/100,000) again for Guipuzcoa, Spain. With only one exception (Helsinki), the person-based suicide attempt rates were higher among women than among men. In the majority of centres, the highest person-based rates were found in the younger age groups. The rates among people aged 55 years or over were generally the lowest. For the majority of the centres, the rates for individuals aged 15 years or over decreased between 1989 and 1992. The methods used were primarily "soft' (poisoning) or cutting. More than 50% of the suicide attempters made more than one attempt, and nearly 20% of the second attempts were made within 12 months after the first attempt. Compared with the general population, suicide attempters more often belong to the social categories associated with social destabilization and poverty.
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Attempted suicide in Europe: rates, trends and sociodemographic characteristics of suicide attempters during the period 1989-1992. Results of the WHO/EURO Multicentre Study on Parasuicide.
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25811797
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In recent years infection caused by Salmonella serotype Enteritidis (SE) phage type 4 has spread through Europe but has been uncommon in the USA. The first recognized outbreak of this strain in the USA occurred in a Chinese restaurant in EI Paso, Texas, in April 1993; no source was identified. In September 1993, a second outbreak caused by SE phage type 4 was associated with the same restaurant. To determine the cause of the second outbreak, we compared food exposures of the 19 patients with that of two control groups. Egg rolls were the only item significantly associated with illness in both analyses (first control group: odds ratio [OR] 8.2, 95% confidence interval [CI] 2.3-31.6; second control group: OR 13.1, 95% CI 2.1-97.0). Retrospective analysis of the April outbreak also implicated egg rolls (OR 32.4, 95% CI 9.1-126.6). Egg roll batter was made from pooled shell eggs and was left at room temperature throughout the day. These two outbreaks of SE phage type 4 likely could have been prevented by using pasteurized eggs and safe food preparation practices.
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Recurrent outbreaks of Salmonella Enteritidis infections in a Texas restaurant: phage type 4 arrives in the United States.
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25813706
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Nuclear extracts derived from HeLa and Drosophila melanogaster KC cell lines have been found to correct single base-base mispairs within open circular DNA heteroduplexes containing a strand-specific, site-specific incision located 808 base pairs from the mismatch. Correction in both extract systems is strand specific, being highly biased to the incised DNA strand. Different mispairs within a homologous set of heteroduplexes were processed with different efficiencies (G.T greater than G.G approximately equal to A.C greater than C.C), and correction was accompanied by mismatch-dependent DNA synthesis localized to the region spanning the mispair and the strand break, thus demonstrating that mismatch recognition is associated with the repair reaction. Correction of each of these heteroduplexes was abolished by aphidicolin but was relatively insensitive to the presence of high concentrations of ddTTP, indicating probable involvement of alpha and/or delta class DNA polymerase(s). These findings suggest that higher eukaryotic cells possess a general, strand-specific mismatch repair system analogous to the Escherichia coli mutHLS and the Streptococcus pneumoniae hexAB pathways, systems that contribute in a major way to the genetic stability of these bacterial species.
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Strand-specific mismatch correction in nuclear extracts of human and Drosophila melanogaster cell lines.
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25816994
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BACKGROUND Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. METHODS The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. FINDINGS 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril. INTERPRETATION In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.
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Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.
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"29516": 0.1221139207482338}
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25817686
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BACKGROUND Prolonged hypothermia, as occurs during solid organ transplantation, negatively influences transplantation outcome. Proteolysis is one of the deleterious events implicated in preservation injury of organ allografts. This strongly affects graft quality and hence immediate organ function. Since donor catecholamine treatment improves transplantation outcome after renal transplantation, the present study was conducted to examine the influence of dopamine (DA) pretreatment on hypothermia induced proteolysis in endothelial cells subjected to prolonged cold storage. MATERIALS AND METHODS Lactate dehydrogenase (LDH) assay, two-dimensional electrophoresis, ubiquitination analysis, intracellular calcium measurement, and Western blot analysis were performed on human umbilical vein endothelial cells (HUVEC) subjected to hypothermic preservation or not. RESULTS HUVEC were highly susceptible to cold storage, which was reflected by morphological changes, loss of viability, and by significant changes in cellular proteome. DA pretreatment prevented cell death during cold storage. Western blot analysis demonstrated a time dependent up-regulation of calpain 1 and 2 during cold storage, which could be prevented by addition of EDTA. DA pretreatment abolished autoproteolysis of calpain 1. Analysis of ubiquitination revealed a significant increase in ubiquitinated conjugates after cold storage. This was not prevented by DA pretreatment. Neither proteasome nor calpain inhibitors prevented cell death during cold storage. CONCLUSION In endothelial cells subjected to cold preservation, activation of the calpain pathway and the ubiquitin proteasome system occur. Although DA pretreatment inhibits the former, calpain inhibition did not protect endothelial cells during cold storage. DA pretreatment might influence proteolysis, but proteolysis is not the major cause of endothelial cell death.
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Hypothermic preservation up-regulates calpain expression and increases ubiquitination in cultured vascular endothelial cells: influence of dopamine pretreatment.
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25821556
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Transcription regulation in higher eukaryotes is controlled by regulatory elements such as enhancers that are recognized by transcription factors. In many cases regulatory elements can be located at distances up to several megabases from their target genes. Recent evidence shows that long-range control of gene expression can be mediated through direct physical interactions between genes and these regulatory elements. Such looping interactions can be detected using the chromosome conformation capture (3C) methodology. Although 3C is experimentally straightforward, to draw meaningful conclusions one must carefully design 3C experiments and implement the conscientious use of controls. The general guidelines presented here should help experimental design and minimize misinterpretation of 3C experiments.
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The three 'C' s of chromosome conformation capture: controls, controls, controls
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25822299
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Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and has been proposed as having antiatherosclerotic property. Vascular endothelial cells also produce endothelin-1 (ET-1), which is a potent vasoconstrictor peptide and has potent proliferating activity on vascular smooth muscle cells. Therefore, ET-1 has been implicated in the progression of atheromatous vascular disease. Because exercise training has been reported to produce an alteration in the function of vascular endothelial cells in animals, we hypothesized that exercise training influences the production of NO and ET-1 in humans. The purpose of the present study was to examine whether chronic exercise could influence the plasma levels of NO (measured as the stable end product of NO, i.e., nitrite/nitrate [NOx]) and ET-1 in humans. Eight healthy young subjects (20.3 +/- 0.5 yr old) participated in the study and exercised by cycling on a leg ergometer (70% VO2max for 1 hour, 3-4 days/week) for 8 weeks. Venous plasma concentrations of NOx and ET-1 were measured before and after (immediately before the end of 8-week exercise training) the exercise training, and also after the 4th and 8th week after the cessation of training. The VO2max significantly increased after exercise training. After the exercise training, the plasma concentration of NOx significantly increased (30.69 +/- 3.20 vs. 48.64 +/- 8.16 micromol/L, p < 0.05), and the plasma concentration of ET-1 significantly decreased (1.65 +/- 0.14 vs. 1.23 +/- 0.12 pg/mL, p < 0.05). The increase in NOx level and the decrease in ET-1 level lasted to the 4th week after the cessation of exercise training and these levels (levels of NOx and ET-1) returned to the basal levels (the levels before the exercise training) in the 8th week after the cessation of exercise training. There was a significant negative correlation between plasma NOx concentration and plasma ET-1 concentration. The present study suggests that chronic exercise causes an increase in production of NO and a decrease in production of ET-1 in humans, which may produce beneficial effects (i.e., vasodilative and antiatherosclerotic) on the cardiovascular system.
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Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans.
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"23130": 0.08782484382390976, "23150": 0.04674193635582924, "23247": 0.07250232994556427, "23306": 0.5773153901100159, "23476": 0.0019512200960889459, "23586": 0.03266380727291107, "23737": 0.4002431631088257, "23858": 0.19541899859905243, "23892": 0.15442965924739838, "23900": 0.10467668622732162, "23924": 0.1485546976327896, "24054": 0.18004031479358673, "24137": 0.05786345899105072, "24269": 0.25694093108177185, "24278": 0.38174858689308167, "24340": 0.1485546976327896, "24552": 0.009718249551951885, "24983": 0.13755162060260773, "25006": 0.5871354341506958, "25284": 0.42608439922332764, "25357": 0.22782009840011597, "25499": 0.07341018319129944, "25761": 0.0606246218085289, "26117": 0.15275461971759796, "26118": 0.1064341589808464, "26287": 0.21214580535888672, "26402": 0.1619328260421753, "26451": 0.3949938118457794, "26512": 0.732405424118042, "26601": 0.058784693479537964, "26616": 0.45870962738990784, "26651": 0.015504186972975731, "26702": 0.1221139207482338, "26741": 0.14349138736724854, "27169": 0.8682814836502075, "27511": 0.018384648486971855, "27572": 0.025073638185858727, "27641": 0.13414156436920166, "28046": 0.06429435312747955, "28156": 0.6149744987487793, "28290": 0.13925230503082275, "28479": 1.3809088468551636, "28562": 0.22157983481884003, "28696": 0.9147270321846008, "28767": 0.09761575609445572, "28964": 0.21530038118362427, "29494": 0.5640701055526733}
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25827024
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Deletion of copper-zinc superoxide dismutase (CuZnSOD) in Sod1(-/-) mice leads to accelerated loss of muscle mass and force during aging, but the losses do not occur with muscle-specific deletion of CuZnSOD. To determine the role of motor neurons in the muscle decline, we generated transgenic Sod1(-/-) mice in which CuZnSOD was expressed under control of the synapsin 1 promoter (SynTgSod1(-/-) mice). SynTgSod1(-/-) mice expressed CuZnSOD in brain, spinal cord, and peripheral nerve, but not in other tissues. Sciatic nerve CuZnSOD content in SynTgSod1(-/-) mice was ~20% that of control mice, but no reduction in muscle mass or isometric force was observed in SynTgSod1(-/-) mice compared with control animals, whereas muscles of age-matched Sod1(-/-) mice displayed 30-40% reductions in mass and force. In addition, increased oxidative damage and adaptations in stress responses observed in muscles of Sod1(-/-) mice were absent in SynTgSod1(-/-) mice, and degeneration of neuromuscular junction (NMJ) structure and function occurred in Sod1(-/-) mice but not in SynTgSod1(-/-) mice. Our data demonstrate that specific CuZnSOD expression in neurons is sufficient to preserve NMJ and skeletal muscle structure and function in Sod1(-/-) mice and suggest that redox homeostasis in motor neurons plays a key role in initiating sarcopenia during aging.
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Neuron-specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD-knockout mice.
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25830701
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The cytokine erythropoietin (Epo) promotes erythropoietic progenitor cell proliferation and is required for erythropoietic differentiation. We have found that the Epo gene is a direct transcriptional target gene of retinoic acid signaling during early erythropoiesis (prior to embryonic day E12.5) in the fetal liver. Mouse embryos lacking the retinoic acid receptor gene RXR alpha have a morphological and histological phenotype that is comparable with embryos in which the Epo gene itself has been mutated, and flow cytometric analysis indicates that RXR alpha-deficient embryos are deficient in erythroid differentiation. Epo mRNA levels are reduced substantially in the fetal livers of RXR alpha(-/-) embryos at E10.25 and E11.25, and genetic analysis shows that the RXR alpha and Epo genes are coupled in the same pathway. We furthermore show that the Epo gene is retinoic acid inducible in embryos, and that the Epo gene enhancer contains a DR2 sequence that represents a retinoic acid receptor-binding site and a retinoic acid receptor transcriptional response element. However, unlike Epo-deficient embryos that die from anemia, the erythropoietic deficiency in RXR alpha(-/-) embryos is transient; Epo mRNA is expressed at normal levels by E12.5, and erythropoiesis and liver morphology are normal by E14.5. We show that HNF4, like RXR alpha a member of the nuclear receptor family, is abundantly expressed in fetal liver hepatocytes, and is competitive with retinoic acid receptors for occupancy of the Epo gene enhancer DR2 element. We propose that Epo expression is regulated during the E9.5--E11.5 phase of fetal liver erythropoiesis by RXR alpha and retinoic acid, and that expression then becomes dominated by HNF4 activity from E11.5 onward. This transition may be responsible for switching regulation of Epo expression from retinoic acid control to hypoxic control, as is found throughout the remainder of life.
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A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4.
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25832301
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BACKGROUND Increased expression of the tetraspanin TSPAN7 has been observed in a number of cancers; however, it is unclear how TSPAN7 plays a role in cancer progression. METHODS We investigated the expression of TSPAN7 in the haematological malignancy multiple myleoma (MM) and assessed the consequences of TSPAN7 expression in the adhesion, migration and growth of MM plasma cells (PC) in vitro and in bone marrow (BM) homing and tumour growth in vivo. Finally, we characterised the association of TSPAN7 with cell surface partner molecules in vitro. RESULTS TSPAN7 was found to be highly expressed at the RNA and protein level in CD138(+) MM PC from approximately 50% of MM patients. TSPAN7 overexpression in the murine myeloma cell line 5TGM1 significantly reduced tumour burden in 5TGM1/KaLwRij mice 4 weeks after intravenous adminstration of 5TGM1 cells. While TSPAN7 overexpression did not affect cell proliferation in vitro, TSPAN7 increased 5TGM1 cell adhesion to BM stromal cells and transendothelial migration. In addition, TSPAN7 was found to associate with the molecular chaperone calnexin on the cell surface. CONCLUSION These results suggest that elevated TSPAN7 may be associated with better outcomes for up to 50% of MM patients.
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Tetraspanin 7 (TSPAN7) expression is upregulated in multiple myeloma patients and inhibits myeloma tumour development in vivo.
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0.06703783571720123, "29299": 0.6522845029830933, "29347": 0.08871890604496002, "29361": 0.25995752215385437, "29458": 0.025073638185858727, "29525": 0.48610860109329224}
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25837950
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Obesity is associated with higher mortality in the general population, but this association is reversed in patients on dialysis. The nature of the relationship of obesity with adverse clinical outcomes in nondialysis-dependent CKD and the putative interaction of the severity of disease with this association are unclear. We analyzed data from a nationally representative cohort of 453,946 United States veterans with eGFR<60 ml/min per 1.73 m(2). The associations of body mass index categories (<20, 20 to <25, 25 to <30, 30 to <35, 35 to <40, 40 to <45, 45 to <50, and ≥50 kg/m(2)) with all-cause mortality and disease progression (using multiple definitions, including incidence of ESRD, doubling of serum creatinine, and the slopes of eGFR) were examined in Cox proportional hazards models and logistic regression models. Multivariable adjustments were made for age, race, comorbidities and medications, and baseline eGFR. Body mass index showed a relatively consistent U-shaped association with clinical outcomes, with the best outcomes observed in overweight and mildly obese patients. Body mass index levels <25 kg/m(2) were associated with worse outcomes in all patients, independent of severity of CKD. Body mass index levels ≥35 kg/m(2) were associated with worse outcomes in patients with earlier stages of CKD, but this association was attenuated in those patients with eGFR<30 ml/min per 1.73 m(2). Thus, until clinical trials establish the ideal body mass index, a cautious approach to weight management is warranted in this patient population.
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Association of body mass index with outcomes in patients with CKD.
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"21081": 0.23402166366577148, "21114": 0.9820492267608643, "21197": 0.6471850275993347, "21213": 0.1011524572968483, "21262": 0.6989894509315491, "21371": 1.0782235860824585, "21395": 0.4419025182723999, "21434": 0.25239890813827515, "21557": 0.06612417846918106, "21575": 0.05046287178993225, "21647": 0.22001366317272186, "21901": 0.11951763927936554, "21903": 0.3588210940361023, "22108": 0.07431721687316895, "22126": 0.6265231370925903, "22207": 0.14518201351165771, "22253": 0.04113444685935974, "22860": 0.11168810725212097, "22958": 0.36900100111961365, "23079": 0.055094651877880096, "23150": 0.2223619967699051, "23277": 1.5023398399353027, "23429": 0.0752234235405922, "23569": 0.5145297050476074, "23797": 0.20022670924663544, "23892": 0.9576126337051392, "24004": 0.8100618124008179, "24287": 0.2674594223499298, "24344": 0.20022670924663544, "24564": 0.014542185701429844, "25194": 0.05786345899105072, "25409": 0.5092619061470032, "25468": 0.1905880719423294, "25874": 0.25467249751091003, "26083": 0.05417001247406006, "26296": 0.9232974052429199, "26305": 0.417115718126297, "26402": 0.08692999184131622, "26524": 0.7610978484153748, "26534": 0.0038986403960734606, "26601": 0.13925230503082275, "26741": 0.1889725625514984, "26773": 0.4425300657749176, "26774": 0.46608972549438477, "26874": 0.18004031479358673, "26994": 0.39367714524269104, "26999": 0.40546512603759766, "27515": 0.2539152204990387, "27605": 0.6553317308425903, "28024": 0.15359249711036682, "28179": 0.46424978971481323, "28227": 0.5313173532485962, "28290": 0.058784693479537964, "28309": 0.06886265426874161, "28424": 0.27044451236724854, "28562": 0.08692999184131622, "28667": 1.061472773551941, "28685": 0.10379679501056671, "28691": 0.20102575421333313, "28767": 0.0009760859538801014, "28774": 0.1229778528213501, "28828": 0.4831010699272156, "28829": 0.77198725938797, "28835": 0.08064348995685577, "28927": 0.3750596046447754, "28964": 0.15275461971759796, "28992": 0.08871890604496002, "29060": 0.23787821829319, "29206": 0.19381128251552582}
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25838286
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Werner syndrome (WS) predisposes patients to cancer and premature aging, owing to mutations in WRN. The WRN protein is a RECQ-like helicase and is thought to participate in DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) or homologous recombination (HR). It has been previously shown that non-homologous DNA ends develop extensive deletions during repair in WS cells, and that this WS phenotype was complemented by wild-type (wt) WRN. WRN possesses both 3' --> 5' exonuclease and 3' --> 5' helicase activities. To determine the relative contributions of each of these distinct enzymatic activities to DSB repair, we examined NHEJ and HR in WS cells (WRN-/-) complemented with either wtWRN, exonuclease-defective WRN (E-), helicase-defective WRN (H-) or exonuclease/helicase-defective WRN (E-H-). The single E-and H- mutants each partially complemented the NHEJ abnormality of WRN-/- cells. Strikingly, the E-H- double mutant complemented the WS deficiency nearly as efficiently as did wtWRN. Similarly, the double mutant complemented the moderate HR deficiency of WS cells nearly as well as did wtWRN, whereas the E- and H- single mutants increased HR to levels higher than those restored by either E-H- or wtWRN. These results suggest that balanced exonuclease and helicase activities of WRN are required for optimal HR. Moreover, WRN appears to play a structural role, independent of its enzymatic activities, in optimizing HR and efficient NHEJ repair. Another human RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting that mammalian RECQ helicases have distinct functions that can finely regulate recombination events.
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WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair.
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0.24325250089168549, "16706": 0.7629209756851196, "16730": 1.3715375661849976, "17146": 0.015504186972975731, "17351": 0.16690383851528168, "17366": 1.0278041362762451, "17367": 0.21530038118362427, "17452": 1.0628231763839722, "17703": 0.417115718126297, "17718": 1.1236859560012817, "17782": 0.2501201331615448, "17993": 0.8559102416038513, "18003": 1.1947507858276367, "18037": 0.004870930220931768, "18139": 0.3283478021621704, "18231": 0.036437395960092545, "18595": 0.18816383183002472, "19137": 0.7881022095680237, "19362": 0.13071982562541962, "19386": 1.2341761589050293, "19395": 0.8707374930381775, "19476": 0.009718249551951885, "19563": 0.15442965924739838, "19739": 1.1689931154251099, "20026": 0.8813109993934631, "20030": 1.0298984050750732, "20363": 0.034552380442619324, "20434": 0.23556606471538544, "20817": 0.304147332906723, "20881": 1.1115491390228271, "21031": 0.07884006202220917, "21101": 0.49626702070236206, "21114": 0.960606575012207, "21472": 0.09228714555501938, "21476": 0.3325583338737488, "21486": 0.1332872211933136, "21531": 0.983511209487915, "21557": 0.1485546976327896, "21608": 0.05970508232712746, "21647": 1.2840756177902222, "21716": 0.2145126610994339, "21755": 0.014542185701429844, "21778": 0.018384648486971855, "22026": 0.23015019297599792, "22184": 0.5295937061309814, "22571": 0.9100211262702942, "22644": 0.7674643993377686, "22863": 0.7969439625740051, "22931": 1.0430610179901123, "22932": 0.31560876965522766, "22974": 0.00875066313892603, "23041": 0.7701805830001831, "23079": 0.030771657824516296, "23150": 0.052318159490823746, "23207": 0.8748174905776978, "23499": 0.06612417846918106, "23563": 0.27934664487838745, "23758": 1.0641717910766602, "23767": 0.20501139760017395, "23777": 0.26146242022514343, "23915": 0.04674193635582924, "23924": 0.0752234235405922, "23943": 0.3381449282169342, "24051": 0.1212492436170578, "24226": 0.2763880789279938, "24269": 1.0437490940093994, "24558": 0.15860503911972046, "24848": 0.01934296265244484, "25022": 0.7610978484153748, "25096": 0.04113444685935974, "25264": 0.018384648486971855, "25458": 0.11604541540145874, "25714": 0.8682814836502075, "25743": 0.38441169261932373, "25957": 0.09228714555501938, "26224": 1.2555493116378784, "26356": 1.035461664199829, "26475": 1.0001721382141113, "26601": 0.9944084882736206, "26632": 0.9936857223510742, "26775": 0.1384023278951645, "26874": 0.34370049834251404, "27094": 0.11604541540145874, "27226": 0.17020416259765625, "27325": 0.09850110858678818, "27642": 0.14179791510105133, "27781": 1.1070401668548584, "27854": 0.1477125883102417, "28024": 0.6649205088615417, "28086": 0.006812678650021553, "28154": 0.12556517124176025, "28184": 0.33115679025650024, "28424": 0.48670899868011475, "28667": 0.5635144114494324, "28689": 1.0207915306091309, "28691": 0.05970508232712746, "28873": 0.10555581003427505, "29060": 0.18978065252304077, "29304": 0.040196798741817474, "29490": 0.06886265426874161}
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25842866
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Most eukaryotic telomeres contain a repeating motif with stretches of guanine residues that form a 3'-terminal overhang extending beyond the telomeric duplex region. The telomeric repeat of hypotrichous ciliates, d(T(4)G(4)), forms a 16-nucleotide 3'-overhang. Such sequences can adopt parallel-stranded as well as antiparallel-stranded quadruplex conformations in vitro. Although it has been proposed that guanine-quadruplex conformations may have important cellular roles including telomere function, recombination, and transcription, evidence for the existence of this DNA structure in vivo has been elusive to date. We have generated high-affinity single-chain antibody fragment (scFv) probes for the guanine-quadruplex formed by the Stylonychia telomeric repeat, by ribosome display from the Human Combinatorial Antibody Library. Of the scFvs selected, one (Sty3) had an affinity of K(d) = 125 pM for the parallel-stranded guanine-quadruplex and could discriminate with at least 1,000-fold specificity between parallel or antiparallel quadruplex conformations formed by the same sequence motif. A second scFv (Sty49) bound both the parallel and antiparallel quadruplex with similar (K(d) = 3--5 nM) affinity. Indirect immunofluorescence studies show that Sty49 reacts specifically with the macronucleus but not the micronucleus of Stylonychia lemnae. The replication band, the region where replication and telomere elongation take place, was also not stained, suggesting that the guanine-quadruplex is resolved during replication. Our results provide experimental evidence that the telomeres of Stylonychia macronuclei adopt in vivo a guanine-quadruplex structure, indicating that this structure may have an important role for telomere functioning.
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In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei.
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25853741
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The incidence of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) was analyzed separately in all 764 patients who received a renal allograft between 1966 and 1988 at the Leiden University Hospital. The mean follow-up period was 8.7 posttransplant years (range 1-21 years). During this time period 176 skin cancers were diagnosed in 47 patients. The overall risk to develop a first tumor increased from 10% after 10 years to 40% after 20 years of graft survival. The overall incidence of SCC was 250 times higher and that of BCC 10 times higher when compared with the general Dutch population. Moreover the localization of SCCs and BCCs differed considerably. Solar radiation is thought to be an important risk factor for the development of skin cancer. However, the occurrence of skin cancer in long-term graft survivors forms also a major problem in a country with a higher geographical latitude and a moderate amount of sun-exposure, such as the Netherlands.
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Incidence of skin cancer after renal transplantation in The Netherlands.
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"21903": 0.3241194784641266, "22291": 0.04953393340110779, "22311": 0.7755908370018005, "22330": 0.6624060273170471, "22375": 0.14349138736724854, "22602": 0.15943801403045654, "22694": 0.21765978634357452, "22822": 0.8772575259208679, "22935": 0.57457035779953, "23217": 0.006812678650021553, "23737": 0.37371641397476196, "23777": 0.043007105588912964, "23892": 0.6410312056541443, "23924": 0.960606575012207, "24098": 0.07250232994556427, "24191": 0.7601850032806396, "24278": 0.8550800085067749, "24374": 0.3304552733898163, "24714": 0.9425065517425537, "24755": 0.6734226942062378, "25070": 0.5404602885246277, "25147": 0.015504186972975731, "25206": 0.05786345899105072, "25930": 1.3054782152175903, "25972": 0.9878844022750854, "26305": 0.06886265426874161, "26520": 0.1602703034877777, "26524": 0.3127557039260864, "27166": 0.03925827145576477, "27297": 0.1064341589808464, "27321": 0.4412745535373688, "27381": 0.0606246218085289, "27480": 0.33115679025650024, "27554": 0.6759096384048462, "27678": 0.11081436276435852, "28031": 0.8083226680755615, "28086": 1.2522047758102417, "28283": 0.5903874635696411, "28286": 0.029824240133166313, "28353": 0.10026945173740387, "28685": 0.0354953333735466, "28712": 0.02412080205976963, "28788": 0.0009760859538801014, "28828": 0.3995884954929352}
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25858295
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The murine homeo box gene Nkx2-5 is expressed in precardiac mesoderm and in the myocardium of embryonic and fetal hearts. Targeted interruption of Nkx2-5 resulted in abnormal heart morphogenesis, growth retardation and embryonic lethality at approximately 9-10 days postcoitum (p.c.). Heart tube formation occurred normally in mutant embryos, but looping morphogenesis, a critical determinant of heart form, was not initiated at the linear heart tube stage (8.25-8.5 days p.c.). Commitment to the cardiac muscle lineage, expression of most myofilament genes and myofibrillogenesis were not compromised. However, the myosin light-chain 2V gene (MLC2V) was not expressed in mutant hearts nor in mutant ES cell-derived cardiocytes. MLC2V expression normally occurs only in ventricular cells and is the earliest known molecular marker of ventricular differentiation. The regional expression in mutant hearts of two other ventricular markers, myosin heavy-chain beta and cyclin D2, indicated that not all ventricle-specific gene expression is dependent on Nkx2-5. The data demonstrate that Nkx2-5 is essential for normal heart morphogenesis, myogenesis, and function. Furthermore, this gene is a component of a genetic pathway required for myogenic specialization of the ventricles.
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Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5.
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"17463": 0.04207121208310127, "17537": 0.007782140281051397, "17728": 0.19220098853111267, "17808": 0.4311734735965729, "17819": 0.8649974465370178, "17886": 0.34370049834251404, "17975": 0.34300774335861206, "18249": 0.4794800877571106, "18321": 0.304147332906723, "18345": 0.03360854089260101, "18447": 0.791648268699646, "18513": 0.10555581003427505, "18701": 0.2852376699447632, "18723": 0.8715548515319824, "18935": 0.6853039860725403, "18949": 0.8057082891464233, "19009": 0.055094651877880096, "19126": 0.57457035779953, "19132": 0.11951763927936554, "19205": 0.010684899985790253, "19281": 0.040196798741817474, "19515": 0.21687394380569458, "19548": 1.6303123235702515, "19801": 0.3547199070453644, "19960": 0.2822965085506439, "20014": 0.38905516266822815, "20187": 1.1917895078659058, "20272": 0.21530038118362427, "20467": 0.18167030811309814, "20528": 0.034552380442619324, "20569": 0.1358480453491211, "20662": 0.2719337046146393, "20792": 0.13414156436920166, "20828": 0.2837681770324707, "20868": 0.176772341132164, "20942": 0.32270604372024536, "21102": 0.469759464263916, "21162": 0.07250232994556427, "21307": 1.1573970317840576, "21685": 0.2089812457561493, "21733": 0.7845434546470642, "21759": 0.23633737862110138, "21923": 0.037378571927547455, "22571": 0.5957841277122498, "22634": 0.011650617234408855, "22647": 0.38574060797691345, "22863": 0.03925827145576477, "23041": 0.06795065850019455, "23072": 0.8941729068756104, "23087": 0.5376120805740356, "23606": 0.10731173306703568, "23614": 0.3777405619621277, "23633": 0.014542185701429844, "23900": 0.2852376699447632, "24286": 0.2394166737794876, "24479": 0.09761575609445572, "24615": 0.2763880789279938, "24757": 0.1889725625514984, "24952": 0.3443928062915802, "25031": 0.15526613593101501, "25090": 0.304147332906723, "25480": 0.495672345161438, "26282": 0.17840765416622162, "26591": 0.41389304399490356, "26721": 0.0174254160374403, "26835": 0.45251765847206116, "27441": 0.4196864068508148, "27815": 0.14518201351165771, "28032": 0.08782484382390976, "28055": 0.1064341589808464, "28896": 0.3588210940361023, "29347": 0.46608972549438477, "29464": 0.036437395960092545}
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25878014
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The hygiene hypothesis is thought to be a significant contributor to the growing incidence of inflammatory bowel disease (IBD) around the world, although the evidence for specific factors that underlie the hygiene hypothesis in IBD is unclear. We aimed to systematically review the literature to determine which hygiene-related factors are associated with the development of IBD. Publications identified from a broad based MEDLINE and Current Contents search between 1966 and 2007 on key terms relevant to the 'hygiene hypothesis' and IBD including H pylori exposure, helminths, cold chain hypothesis, measles infection and vaccination, antibiotic use, breastfeeding, family size, sibship, urban upbringing, day care attendance and domestic hygiene were reviewed. The literature suggests that the hygiene hypothesis and its association with decreased microbial exposure in childhood probably plays an important role in the development of IBD, although the strength of the supporting data for each of the factors varies considerably. The most promising factors that may potentially be associated with development of IBD include H pylori exposure, helminths, breastfeeding and sibship. However, the vast majority of studies in this area are plagued by serious methodological shortcomings, particularly the reliance on retrospective recall of information making it difficult to truly ascertain the importance of a 'hygiene hypothesis' in IBD. The 'hygiene hypothesis' in IBD is an important area of research that may give clues to the aetiology of this disease. Directions for future research are recommended.
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Hygiene hypothesis in inflammatory bowel disease: a critical review of the literature.
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25886725
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BACKGROUND Dual eligibles, persons who qualify for both Medicare and Medicaid coverage, often receive poorer quality care relative to other Medicare beneficiaries. OBJECTIVES To determine whether dual eligibles are discharged to lower quality post-acute skilled nursing facilities (SNFs) compared with Medicare-only beneficiaries. RESEARCH DESIGN Following the random utility maximization model, we specified a discharge function using a conditional logit model and tested how this discharge rule varied by dual-eligibility status. SUBJECTS A total of 692,875 Medicare fee-for-service patients (22% duals) who were discharged for Medicare paid SNF care between July 2004 and June 2005. MEASURES Medicare enrollment and the Medicaid Analytic Extract files were used to determine dual eligibility. The proportion of Medicaid patients and nursing staff characteristics provided measures of SNF quality. RESULTS Duals are more likely to be discharged to SNFs with a higher share of Medicaid patients and fewer nurses. These results are robust to estimation with an alternative subsample of patients based on primary diagnoses, propensity of being dual eligible, and likelihood of remaining in the nursing home. CONCLUSIONS Disparities exist in access to quality SNF care for duals. Strategies to improve discharge planning processes are required to redirect patients to higher quality providers, regardless of Medicaid eligibility.
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Are dual eligibles admitted to poorer quality skilled nursing facilities?
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25895285
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Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance. SIGNIFICANCE Pazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy.
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Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib
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25897733
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PURPOSE OF REVIEW The 2009 pandemic HIN1 influenza strain (H1N12009) produced more severe disease and increased risk for mortality. As an at-risk population for more severe influenza illness, particular concern regarding HIV patients triggered a focused effort to evaluate disease burden and vaccine efficacy in these populations. RECENT FINDINGS As with other immune-compromised individuals, most HIV-infected individuals recovered without major consequence. Although HIV infection was assumed to be a risk factor for more severe disease and death, the published literature does not indicate this to be so. Neuraminadase inhibitors were well tolerated by this population and there was no evidence of clinically significant pharmacokinetic interactions with antiretroviral therapy. Immunogenicity was increased with H1N12009 vaccine compared to the historical results of nonpandemic vaccines and optimized by the use of adjuvants. Booster dosing was also of benefit. H1N12009 vaccine was generally well tolerated without evidence of detrimental effect on HIV status. SUMMARY The worse case scenario was not realized for H1N12009 in the general population or in those with HIV. Immunization with adjuvant represents a key measure to protect this population from H1N12009 and other future novel influenza strains.
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Pandemic H1N12009 influenza and HIV: a review of natural history, management and vaccine immunogenicity.
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"25403": 0.9310253858566284, "25700": 0.4132472574710846, "26083": 0.5278670787811279, "26157": 0.49626702070236206, "26305": 0.5882205963134766, "26741": 0.4067663550376892, "26773": 0.47402387857437134, "26874": 0.08064348995685577, "27000": 0.2231435477733612, "27084": 0.05786345899105072, "27086": 0.13157635927200317, "27226": 0.8699195384979248, "27295": 0.1873544454574585, "27330": 0.255429208278656, "27352": 0.06977381557226181, "27511": 0.11081436276435852, "27556": 0.1602703034877777, "27605": 0.1619328260421753, "28086": 0.053244512528181076, "28239": 0.12470348179340363, "28424": 0.015504186972975731, "28442": 0.020300358533859253, "29206": 0.23633737862110138}
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25900857
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Most theories used to explain the evolution of eusociality rest upon two key assumptions: mutations affecting the phenotype of sterile workers evolve by positive selection if the resulting traits benefit fertile kin, and that worker traits provide the primary mechanism allowing social insects to adapt to their environment. Despite the common view that positive selection drives phenotypic evolution of workers, we know very little about the prevalence of positive selection acting on the genomes of eusocial insects. We mapped the footprints of positive selection in Apis mellifera through analysis of 40 individual genomes, allowing us to identify thousands of genes and regulatory sequences with signatures of adaptive evolution over multiple timescales. We found Apoidea- and Apis-specific genes to be enriched for signatures of positive selection, indicating that novel genes play a disproportionately large role in adaptive evolution of eusocial insects. Worker-biased proteins have higher signatures of adaptive evolution relative to queen-biased proteins, supporting the view that worker traits are key to adaptation. We also found genes regulating worker division of labor to be enriched for signs of positive selection. Finally, genes associated with worker behavior based on analysis of brain gene expression were highly enriched for adaptive protein and cis-regulatory evolution. Our study highlights the significant contribution of worker phenotypes to adaptive evolution in social insects, and provides a wealth of knowledge on the loci that influence fitness in honey bees.
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Population genomics of the honey bee reveals strong signatures of positive selection on worker traits.
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0.6254787445068359, "20544": 0.791648268699646, "20766": 0.10993985831737518, "20817": 0.49030399322509766, "20858": 0.053244512528181076, "20868": 0.18004031479358673, "21466": 0.35334911942481995, "21471": 0.25088030099868774, "21472": 0.129004567861557, "21477": 0.2674594223499298, "21575": 0.6000806093215942, "21618": 0.6482070088386536, "21755": 0.3070250153541565, "21903": 0.35745587944984436, "21919": 0.2516399025917053, "21967": 0.14518201351165771, "22026": 0.0174254160374403, "22203": 0.2034190446138382, "22248": 0.2837681770324707, "22275": 1.426491141319275, "22307": 0.06154331564903259, "22394": 0.1718502640724182, "22415": 0.04953393340110779, "22422": 0.3283478021621704, "22644": 0.9021284580230713, "22939": 0.4311734735965729, "22953": 1.0802149772644043, "23068": 0.6517757177352905, "23216": 0.32199856638908386, "23217": 0.47584590315818787, "23586": 0.5871354341506958, "23758": 0.03266380727291107, "23777": 0.2184450328350067, "23943": 0.05694137513637543, "24051": 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25901598
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Posttranslational modifications mediate important regulatory functions in biology. The acetylation of the p53 transcription factor, for example, promotes transcriptional activation of target genes including p21. Here we show that the acetylation of two lysine residues in p53 promotes recruitment of the TFIID subunit TAF1 to the p21 promoter through its bromodomains. UV irradiation of cells diacetylates p53 at lysines 373 and 382, which in turn recruits TAF1 to a distal p53-binding site on the p21 promoter prior to looping to the core promoter. Disruption of acetyl-p53/bromodomain interaction inhibits TAF1 recruitment to both the distal p53-binding site and the core promoter. Further, the TFIID subunits TAF4, TAF5, and TBP are detected on the core promoter prior to TAF1, suggesting that, upon DNA damage, distinct subunits of TFIID may be recruited separately to the p21 promoter and that the transcriptional activation depends on posttranslational modification of the p53 transcription factor.
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An acetylation switch in p53 mediates holo-TFIID recruitment.
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25915873
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PURPOSE Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. RESULTS Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. EXPERIMENTAL DESIGN We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. CONCLUSION Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases.
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Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation.
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"22678": 0.012615402229130268, "22694": 0.08154398202896118, "22731": 0.05139094591140747, "22822": 0.9886114001274109, "22863": 0.4228905141353607, "22922": 0.3464667797088623, "22930": 0.1477125883102417, "23216": 0.2800849378108978, "23245": 1.0927356481552124, "23340": 0.034552380442619324, "23346": 1.1469062566757202, "23389": 0.3084607720375061, "23586": 0.6664261221885681, "23737": 0.41389304399490356, "23892": 0.08244366943836212, "23924": 0.9842413663864136, "24054": 0.6456501483917236, "24169": 0.22937409579753876, "24176": 0.5045560002326965, "24203": 0.010684899985790253, "24269": 0.9317949414253235, "24278": 0.37907835841178894, "24471": 1.2250384092330933, "24759": 0.5197699069976807, "25125": 1.1846466064453125, "25147": 0.2478361576795578, "25194": 0.04953393340110779, "25320": 0.02412080205976963, "25370": 0.4709797203540802, "25423": 0.33325836062431335, "25456": 0.5057345628738403, "25502": 0.12986256182193756, "25644": 0.1808556467294693, "25714": 0.9194108247756958, "26243": 0.13071982562541962, "26288": 0.16607704758644104, "26305": 0.09228714555501938, "26402": 1.0001721382141113, "26734": 1.1262223720550537, "26773": 0.7845434546470642, "27431": 0.01934296265244484, "27703": 0.09317722171545029, "27822": 0.010684899985790253, "27854": 0.38374659419059753, "28086": 0.26146242022514343, "28121": 0.1873544454574585, "28156": 0.417115718126297, "28227": 0.3930181860923767, "28251": 0.3416208028793335, "28344": 0.9147270321846008, "28691": 0.06520967930555344, "28828": 0.3910386264324188, "29217": 0.013579257763922215, "29290": 0.09672962874174118}
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25928548
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The molecular signals that regulate growth and branching of the ureteric bud during formation of the renal collecting system are largely undefined. Members of the bone morphogenetic protein (BMP) family signal through the type I BMP receptor ALK3 to inhibit ureteric bud and collecting duct cell morphogenesis in vitro. We investigated the function of the BMP signaling pathway in vivo by generating a murine model of ALK3 deficiency restricted to the ureteric bud lineage (Alk3(UB-/-) mice). At the onset of branching morphogenesis, Alk3(UB-/-) kidneys are characterized by an abnormal primary (1 degrees ) ureteric bud branch pattern and an increased number of ureteric bud branches. However, during later stages of renal development, Alk3(UB-/-) kidneys have fewer ureteric bud branches and collecting ducts than wild-type kidneys. Postnatal Alk3(UB-/-) mice exhibit a dysplastic renal phenotype characterized by hypoplasia of the renal medulla, a decreased number of medullary collecting ducts, and abnormal expression of beta-catenin and c-MYC in medullary tubules. In summary, normal kidney development requires ALK3-dependent BMP signaling, which controls ureteric bud branching.
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BMP receptor ALK3 controls collecting system development.
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1.0815403461456299, "25855": 0.5685047507286072, "26180": 0.1873544454574585, "26236": 0.9680526852607727, "26243": 0.026025565341114998, "26244": 0.3588210940361023, "26279": 0.39762192964553833, "26632": 0.9363996982574463, "26858": 0.022212404757738113, "27152": 0.014542185701429844, "27321": 0.1384023278951645, "27833": 0.1808556467294693, "27896": 0.06154331564903259, "28196": 0.05046287178993225, "28204": 0.04394211992621422, "28352": 0.7907629609107971, "28479": 0.14095009863376617, "28788": 0.1808556467294693, "28835": 0.9658246636390686, "29090": 0.19862671196460724, "29197": 0.1384023278951645, "29596": 0.05417001247406006}
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25937484
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The lower respiratory tract of cigarette smokers contains an increased amount of iron that is predominantly sequestered within alveolar macrophages (AM), but is also present in alveolar epithelial fluid. Extracellular ferritin-bound iron could potentially be released by reductants present in cigarette smoke and catalyze generation of highly reactive hydroxyl radicals capable of causing oxidant injury. To determine whether AM are a source of alveolar extracellular ferritin and iron, we assessed in vitro release of iron, ferritin, and transferrin by AM recovered by bronchoalveolar lavage (BAL) of 27 healthy subjects including nine nonsmokers (NS), nine light smokers (LS), and nine heavy smokers (HS). Release of iron in vitro over 20 h was increased in AM recovered from LS (2.24 +/- 0.21 nmol/10(6) AM/20 h, p < 0.001) and HS (3.11 +/- 0.32 nmol/10(6) AM, p < 0.001) compared with NS (1.28 +/- 0.08 nmol/10(6) AM). Release of ferritin in vitro over 20 h was also increased in AM recovered from LS (71 +/- 24 ng/10(6) AM, p < 0.05) and HS (176 +/- 35 ng/10(6), p < 0.001) compared with NS (18 +/- 3 ng/10(6) AM). AM recovered from 12 smokers (8 HS, 4 LS) contained greater than 10 nmol of iron per 10(6) cells. These iron-loaded AM released a greater percentage of cell ferritin stores in vitro over 4 h (8.4% +/- 1.1, p < 0.01) than did AM from NS (3.2% +/- 0.6). Release of lactate dehydrogenase (LDH) over 4 h was substantially less (2.9% +/- 0.3, p < 0.001) than ferritin release.(ABSTRACT TRUNCATED AT 250 WORDS)
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Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers.
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25938221
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A specific retinopathy has been described in African children with cerebral malaria, but in adults this has not been extensively studied. Since the structure and function of the retinal vasculature greatly resembles the cerebral vasculature, study of retinal changes can reveal insights into the pathophysiology of cerebral malaria. A detailed observational study of malarial retinopathy in Bangladeshi adults was performed using high-definition portable retinal photography. Retinopathy was present in 17/27 adults (63%) with severe malaria and 14/20 adults (70%) with cerebral malaria. Moderate or severe retinopathy was more frequent in cerebral malaria (11/20, 55%) than in uncomplicated malaria (3/15, 20%; P=0.039), bacterial sepsis (0/5, 0%; P=0.038) or healthy controls (0/18, 0%; P<0.001). The spectrum of malarial retinopathy was similar to that previously described in African children, but no vessel discolouration was observed. The severity of retinal whitening correlated with admission venous plasma lactate (P=0.046), suggesting that retinal ischaemia represents systemic ischaemia. In conclusion, retinal changes related to microvascular obstruction were common in adults with severe falciparum malaria and correlated with disease severity and coma, suggesting that a compromised microcirculation has important pathophysiological significance in severe and cerebral malaria. Portable retinal photography has potential as a valuable tool to study malarial retinopathy.
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The spectrum of retinopathy in adults with Plasmodium falciparum malaria
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25938251
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A novel design for intervention studies is presented, the so called PROBE study (Prospective Randomized Open, Blinded End-point). This design is compared to the classical double-blind design. Among the advantages of the PROBE design are lower cost and greater similarity to standard clinical practice, which should make the results more easily applicable in routine medical care. Since end-points are evaluated by a blinded end-point committee it is obvious that there should be no difference between the two types of trials in this regard.
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Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point.
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"28873": 0.3127557039260864, "28976": 0.13157635927200317, "29290": 0.25694093108177185}
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25942757
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The substantial importance of P-selectin glycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initial identification as a selectin ligand. PSGL-1 seemed to be a relatively simple molecule with an extracellular mucin domain extended as a flexible rod, teleologically consistent with its primary role in tethering leukocytes to endothelial selectins. The rolling interaction between leukocyte and endothelium mediated by this selectin-PSGL-1 interaction requires branched O-glycan extensions on specific PSGL-1 amino acid residues. In some cells, such as neutrophils, the glycosyltransferases involved in formation of the O-glycans are constitutively expressed, while in other cells, such as T cells, they are expressed only after appropriate activation. Thus, PSGL-1 supports leukocyte recruitment in both innate and adaptive arms of the immune response. A complex array of amino acids within the selectins engage multiple sugar residues of the branched O-glycans on PSGL-1 and provide the molecular interactions responsible for the velcro-like catch bonds that support leukocyte rolling. Such binding of PSGL-1 can also induce signaling events that influence cell phenotype and function. Scrutiny of PSGL-1 has revealed a better understanding of how it performs as a selectin ligand and yielded unexpected insights that extend its scope from supporting leukocyte rolling in inflammatory settings to homeostasis including stem cell homing to the thymus and mature T-cell homing to secondary lymphoid organs. PSGL-1 has been found to bind homeostatic chemokines CCL19 and CCL21 and to support the chemotactic response to these chemokines. Surprisingly, the O-glycan modifications of PSGL-1 that support rolling mediated by selectins in inflammatory conditions interfere with PSGL-1 binding to homeostatic chemokines and thereby limit responsiveness to the chemotactic cues used in steady state T-cell traffic. The multi-level influence of PSGL-1 on cell traffic in both inflammatory and steady state settings is therefore substantially determined by the orchestrated addition of O-glycans. However, central as specific O-glycosylation is to PSGL-1 function, in vivo regulation of PSGL-1 glycosylation in T cells remains poorly understood. It is our purpose herein to review what is known, and not known, of PSGL-1 glycosylation and to update understanding of PSGL-1 functional scope.
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PSGL-1 function in immunity and steady state homeostasis.
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25946292
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CD46 is a ubiquitous human cell surface receptor for the complement components C3b and C4b and for various pathogens, including the measles virus and human herpes virus 6. Ligand binding to CD46 affects (i) protection of autologous cells from complement attack by breakdown of complement components, (ii) intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv) down-regulation of cell surface CD46. Recent evidence indicates that CD46 signaling can link innate and acquired immune function. The molecular mechanisms for these processes and the importance of intracellular trafficking of the receptor have not yet been elucidated. We demonstrate here that, in nonlymphoid cells, CD46 is constitutively internalized via clathrin-coated pits, traffics to multivesicular bodies, and is recycled to the cell surface. However, cross-linking of CD46 at the cell surface, by either multivalent antibody or by measles virus, induces pseudopodia that engulf the ligand in a process similar to macropinocytosis, and leads to the degradation of cell surface CD46. Thus, we have elucidated two pathways for CD46 internalization, which are regulated by the valence of cross-linking of CD46 and which utilize either clathrin-coated pits or pseudopodial extension. This has important implications for CD46 signaling, antigen presentation, CD46 down-regulation, and engulfment of pathogens.
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Ligand binding determines whether CD46 is internalized by clathrin-coated pits or macropinocytosis.
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25950264
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We established an in vitro 3-D model of metastatic hepatocellular carcinoma (HCC) by culturing MHCC97H cells on molecular scaffolds within a rotating wall vessel bioreactor. Morphological and biochemical analyses revealed that the 3-D HCC model mirrored many clinical pathological features of HCC in vivo, including cancer cell morphology, tissue ultrastructure, protein production and secretion, glucose metabolism, tissue-specific gene expression, and apoptosis. Xenografts into livers of nude mice resulted in tumorigenesis and distant metastasis. This 3-D HCC spheroid is a promising model for HCC tumor biology, anticancer drug screening, and for the establishment of HCC animal models.
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A three-dimensional cell biology model of human hepatocellular carcinoma in vitro
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25953438
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Understanding of the age- and season- dependence of malaria mortality is an important prerequisite for epidemiologic models of malaria immunity. However, most studies of malaria mortality have aggregated their results into broad age groups and across seasons, making it hard to predict the likely impact of interventions targeted at specific age groups of children. We present age-specific mortality rates for children aged < 15 years for the period of 2001-2005 in 7 demographic surveillance sites in areas of sub-Saharan Africa with stable endemic Plasmodium falciparum malaria. We use verbal autopsies (VAs) to estimate the proportion of deaths by age group due to malaria, and thus calculate malaria-specific mortality rates for each site, age-group, and month of the year. In all sites a substantial proportion of deaths (ranging from 20.1% in a Mozambican site to 46.2% in a site in Burkina Faso) were attributed to malaria. The overall age patterns of malaria mortality were similar in the different sites. Deaths in the youngest children (< 3 months old) were only rarely attributed to malaria, but in children over 1 year of age the proportion of deaths attributed to malaria was only weakly age-dependent. In most of the sites all-cause mortality rates peaked during the rainy season, but the strong seasonality in malaria transmission in these sites was not reflected in strong seasonality in the proportion of deaths attributed to malaria, except in the two sites in Burkina Faso. Improvement in the specificity of malaria verbal autopsies would make it easier to interpret the age and season patterns in such data.
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Patterns of age-specific mortality in children in endemic areas of sub-Saharan Africa.
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0.16359257698059082, "25117": 0.13499516248703003, "25604": 0.5816917419433594, "25690": 0.175953671336174, "25708": 1.1906025409698486, "25937": 0.2852376699447632, "26358": 0.0009760859538801014, "27108": 1.149384617805481, "27133": 0.1221139207482338, "27854": 0.22157983481884003, "28177": 0.037378571927547455, "28227": 0.812664806842804, "28228": 0.06429435312747955, "28297": 0.07793712615966797, "28696": 1.0326838493347168, "28993": 0.7220231294631958, "29101": 0.0038986403960734606, "29107": 0.11604541540145874, "29125": 0.41001203656196594, "29160": 0.7086513638496399, "29295": 0.6471850275993347, "29458": 0.4926934838294983, "29486": 0.015504186972975731, "29610": 0.2954642176628113}
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25969485
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CONTEXT Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity. OBJECTIVE The objective of the investigation was to study the somatotroph axis in obese MC4R-deficient patients and equally obese controls. PATIENTS AND METHODS We obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjects and 1392 controls matched for age and severity of obesity. We measured fasting IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficient patients and 36 control subjects. We examined pulsatile GH secretion in six adult MC4R-deficient subjects and six obese controls. RESULTS Height sd score was significantly greater in MC4R-deficient children under 5 yr of age compared with controls (mean ± SEM: 2.3 ± 0.06 vs. 1.8 ± 0.04, P < 0.001), an effect that persisted throughout childhood. Final height (cm) was greater in MC4R-deficient men (mean ± SEM 173 ± 2.5 vs. 168 ± 2.1, P < 0.001) and women (mean 165 ± 2.1 vs. 158 ± 1.9, P < 0.001). Fasting IGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups. GH levels were markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency. The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increased in MC4R deficiency, consistent with increased pulsatile and total GH secretion. Fasting insulin levels were markedly elevated in MC4R-deficient children. CONCLUSIONS In MC4R deficiency, increased linear growth in childhood leads to increased adult final height, greater than predicted by obesity alone. GH pulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role for MC4R in controlling hypothalamic somatostatinergic tone. Fasting insulin levels are significantly higher in children carrying MC4R mutations. Both of these factors may contribute to the accelerated growth phenotype characteristic of MC4R deficiency.
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Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion.
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0.16110190749168396, "22953": 0.9084475636482239, "22963": 0.25239890813827515, "23586": 0.07159364968538284, "23606": 0.9798521995544434, "23713": 0.009718249551951885, "23900": 0.04953393340110779, "23943": 0.02887592278420925, "24054": 0.33115679025650024, "24345": 0.2026219218969345, "24432": 0.0058422754518687725, "24755": 0.04767346754670143, "24806": 0.06795065850019455, "24868": 0.018384648486971855, "25003": 0.7028654217720032, "25344": 0.3784096837043762, "25456": 0.22782009840011597, "26180": 0.176772341132164, "26243": 0.13670019805431366, "26266": 0.5707147121429443, "26402": 0.2837681770324707, "26651": 0.3019835948944092, "26721": 0.034552380442619324, "26942": 0.5816917419433594, "27065": 0.8893690705299377, "27325": 0.04487626627087593, "27833": 0.13670019805431366, "27854": 0.24248650670051575, "27896": 0.28082266449928284, "28139": 1.0172666311264038, "28163": 0.055094651877880096, "28228": 0.15693697333335876, "28309": 0.12470348179340363, "29048": 0.1685553640127182, "29525": 0.3070250153541565}
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25970224
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The beta-adrenoceptor antagonist of propranolol, metoprolol, atenolol and butoxamine in anaesthetized cats has been measured and compared with the activity of four synthetic phenylethanolamine derivatives. The effects of isoprenaline on four parameters in the anaesthetized cat: heart rate, blood pressure, soleus muscle contractility and airway reactance, were measured and the modification of the isoprenaline dose-response relation by each of the antagonist drugs assessed. Parallel shifts in log dose-response curves for isoprenaline were caused by propranolol for all parameters, by metoprolol and atenolol for each parameter except blood pressure, and butoxamine for each except soleus muscle and heart rate. Selectivity of action of the antagonists between different organs was measured by comparing DR10 values, computed from isoprenaline dose-ratios. Propranolol was the most potent antagonist and showed slight selectivity of action on soleus muscle compared with heart. Atenolol and metoprolol were approximately equipotent and were cardioselective at low doses only. Butoxamine was the least potent antagonist and possessed non-beta-adrenoceptor effects on the parameters measured. Each of the new compounds, 4'-bromo-2'-methoxy-N-isopropyl phenylethanolamine, the 4'-chloro- and 4'-methyl analogues, and 4'-methoxy-N-t-butyl phenylethanolamine, was a potent antagonist but did not exhibit any selectivity of action. The results suggest no clear separation of beta-adrenoceptors into beta 1- and beta 2-subclasses in organs of the cat. There is no apparent separation of beta-adrenoceptor-mediated effects on skeletal muscle and airways.
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The selectivity of beta-adrenoceptor antagonists on isoprenaline-induced changes in heart rate, blood pressure, soleus muscle contractility and airways function in anaesthetized cats.
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25973484
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Obesity has a complicated relationship to both breast cancer risk and the clinical behavior of the established disease. In postmenopausal women, particularly the elderly, various measures of obesity have been positively associated with risk. However, before menopause increased body weight is inversely related to breast cancer risk. In both premenopausal and postmenopausal breast cancer, the mechanisms by which body weight and obesity affect risk have been related to estrogenic activity. Obesity has also been related to advanced disease at diagnosis and with a poor prognosis in both premenopausal and postmenopausal breast cancer. Breast cancer in African-American women, considering its relationship to obesity, exhibits some important differences from those described in white women, although the high prevalence of obesity in African-American women may contribute to the relatively poor prognosis compared with white American women. Despite the emphasis on estrogens to explain the effects of obesity on breast cancer, other factors may prove to be equally or more important, particularly as they relate to expression of an aggressive tumor phenotype. Among these, this review serves to stress insulin, insulin-like growth factor-I, and leptin, and their relationship to angiogenesis, and transcriptional factors.
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Breast cancer and obesity: an update.
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25974070
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The amount and type of dietary fat have long been associated with the risk of CVD. Arterial stiffness and endothelial dysfunction are important risk factors in the aetiology of CHD. A range of methods exists to assess vascular function that may be used in nutritional science, including clinic and ambulatory blood pressure monitoring, pulse wave analysis, pulse wave velocity, flow-mediated dilatation and venous occlusion plethysmography. The present review focuses on the quantity and type of dietary fat and effects on blood pressure, arterial compliance and endothelial function. Concerning fat quantity, the amount of dietary fat consumed habitually appears to have little influence on vascular function independent of fatty acid composition, although single high-fat meals postprandially impair endothelial function compared with low-fat meals. The mechanism is related to increased circulating lipoproteins and NEFA which may induce pro-inflammatory pathways and increase oxidative stress. Regarding the type of fat, cross-sectional data suggest that saturated fat adversely affects vascular function whereas polyunsaturated fat (mainly linoleic acid (18 : 2n-6) and n-3 PUFA) are beneficial. EPA (20 : 5n-3) and DHA (22 : 6n-3) can reduce blood pressure, improve arterial compliance in type 2 diabetics and dyslipidaemics, and augment endothelium-dependent vasodilation. The mechanisms for this vascular protection, and the nature of the separate physiological effects induced by EPA and DHA, are priorities for future research. Since good-quality observational or interventional data on dietary fatty acid composition and vascular function are scarce, no further recommendations can be suggested in addition to current guidelines at the present time.
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Dietary saturated and unsaturated fats as determinants of blood pressure and vascular function.
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25985964
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Very small embryonic-like stem cells (VSELs) are possibly lost during cord blood banking and bone marrow (BM) processing for autologus stem cell therapy mainly because of their small size. The present study was conducted on human umbilical cord blood (UCB, n=6) and discarded red blood cells (RBC) fraction obtained after separation of mononuclear cells from human BM (n=6), to test this hypothesis. The results show that VSELs, which are pluripotent stem cells with maximum regenerative potential, settle along with the RBCs during Ficoll-Hypaque density separation. These cells are very small in size (3-5 μm), have high nucleo-cytoplasmic ratio, and express nuclear Oct-4, cell surface protein SSEA-4, and other pluripotent markers such as Nanog, Sox-2, Rex-1, and Tert as indicated by immunolocalization and quantitative polymerase chain reaction (Q-PCR) studies. Interestingly, a distinct population of slightly larger, round hematopoietic stem cells (HSCs) with cytoplasmic Oct-4 were detected in the "buffy" coat, which usually gets banked or used during autologus stem cell therapy. Immunohistochemical studies on the umbilical cord tissue (UCT) sections (n=3) showed the presence of nuclear Oct-4-positive VSELs and many fibroblast-like mesenchymal stem cells (MSCs) with cytoplasmic Oct-4. These VSELs with nuclear Oct-4, detected in UCB, UCT, and discarded RBC fraction obtained after BM processing, may persist throughout life, maintain tissue homeostasis, and undergo asymmetric cell division to self-renew as well as produce larger progenitor stem cells, viz. HSCs or MSCs, which follow differentiation trajectories depending on the somatic niche. Hence, it can be concluded that the true stem cells in adult body tissues are the VSELs, whereas the HSCs and MSCs are actually progenitor stem cells that arise by asymmetric cell division of VSELs. The results of the present study may help explain low efficacy reported during adult autologous stem cell trials, wherein unknowingly progenitor stem cells are injected rather than the pluripotent stem cells with maximum regenerative potential.
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Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy.
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25988622
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Monocyte-derived macrophages (mo-MΦs) and T cells have been shown to contribute to spinal cord repair. Recently, the remote brain choroid plexus epithelium (CP) was identified as a portal for monocyte recruitment, and its activation for leukocyte trafficking was found to be IFN-γ-dependent. Here, we addressed how the need for effector T cells can be reconciled with the role of inflammation-resolving immune cells in the repair process. Using an acute spinal cord injury model, we show that in mice deficient in IFN-γ-producing T cells, the CP was not activated, and recruitment of inflammation-resolving mo-MΦ to the spinal cord parenchyma was limited. We further demonstrate that mo-MΦ locally regulated recruitment of thymic-derived Foxp3(+) regulatory T (Treg) cells to the injured spinal cord parenchyma at the subacute/chronic phase. Importantly, an ablation protocol that resulted in reduced Tregs at this stage interfered with tissue remodeling, in contrast to Treg transient ablation, restricted to the 4 d period before the injury, which favored repair. The enhanced functional recovery observed following such a controlled decrease of Tregs suggests that reduced systemic immunosuppression at the time of the insult can enhance CNS repair. Overall, our data highlight a dynamic immune cell network needed for repair, acting in discrete compartments and stages, and involving effector and regulatory T cells, interconnected by mo-MΦ. Any of these populations may be detrimental to the repair process if their level or activity become dysregulated. Accordingly, therapeutic interventions must be both temporally and spatially controlled.
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CNS repair requires both effector and regulatory T cells with distinct temporal and spatial profiles.
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25993718
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Traditionally, the diagnosis of male infertility has depended upon a descriptive evaluation of human semen with emphasis on the number of spermatozoa that are present in the ejaculate, their motility and their morphology. The fundamental tenet underlying this approach is that male fertility can be defined by reference to a threshold concentration of motile, morphologically normal spermatozoa that must be exceeded in order to achieve conception. Many independent studies have demonstrated that this fundamental concept is flawed and, in reality, it is not so much the absolute number of spermatozoa that determines fertility, but their functional competence. In the light of this conclusion, a range of in vitro tests have been developed to monitor various aspects of sperm function including their potential for movement, cervical mucus penetration, capacitation, zona recognition, the acrosome reaction and sperm-oocyte fusion. Such functional assays have been found to predict the fertilizing capacity of human spermatozoa in vitro and in vivo with some accuracy. Recent developments in this field include the introduction of tests to assess the degree to which human spermatozoa have suffered oxidative stress as well as the integrity of their nuclear and mitochondrial DNA. Such assessments not only yield information on the fertilizing capacity of human spermatozoa but also their ability to support normal embryonic development.
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Sperm function tests and fertility.
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|
25994317
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CACCC boxes are among the critical sequences present in regulatory elements of genes expressed in erythroid cells, as well as in selected other cell types. While an erythroid cell-specific CACCC-box-binding protein, EKLF, has been shown to be required in vivo for proper expression of the adult beta-globin gene, it is dispensable for the regulation of several other globin and nonglobin erythroid cell-expressed genes. In the work described here, we searched for additional CACCC-box transcription factors that might be active in murine erythroid cells. We identified a major gel shift activity (termed BKLF), present in yolk sac and fetal liver erythroid cells, that could be distinguished from EKLF by specific antisera. Through relaxed-stringency hybridization, we obtained the cDNA encoding BKLF, a highly basic, novel zinc finger protein that is related to EKLF and other Krüppel-like members in its DNA-binding domain but unrelated elsewhere. BKLF, which is widely but not ubiquitously expressed in cell lines, is highly expressed in the midbrain region of embryonic mice and appears to correspond to the gel shift activity TEF-2, a transcriptional activator implicated in regulation of the simian virus 40 enhancer and other CACCC-box-containing regulatory elements. Because BKLF binds with high affinity and preferentially over Sp1 to many CACCC sequences of erythroid cell expressed genes, it is likely to participate in the control of many genes whose expression appears independent of the action of EKLF.
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Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box-binding protein in erythroid cells and selected other cells.
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26000593
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Most osteoporosis treatments have proven efficacy in reducing the risk of vertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures. Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention to treat (ITT) population rather than on exploratory subgroup analyses; however, non-vertebral anti-fracture efficacy has been largely derived by post-hoc subgroup analyses. This review and meta-analysis was performed to assess non-vertebral anti-fracture efficacy of several osteoporosis therapies, including a more stringent assessment of the ITT populations. Data on non-vertebral anti-fracture efficacy, a defined endpoint of the ITT analyses and confirmed by radiographs, were obtained from randomized, placebo-controlled, phase III clinical trials of at least 3-year duration. Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate. Relative risks (RR), 95% confidence intervals (CI) and statistical significance for active treatment compared with placebo were calculated. Eleven clinical trials met the criteria for review, three of which showed statistically significant ( P ≤0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials with risedronate and one trial with strontium. A meta-analysis showed significant reductions in the relative risk of non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76–0.97, P =0.012) and risedronate (RR=0.81; 95% CI: 0.71–0.92, P =0.001). Risedronate and strontium ranelate were the only treatments to show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy of osteoporosis therapy using ITT populations in trials of 3 years or more in duration. Risedronate was the only agent shown to demonstrate efficacy in more than one trial. Meta-analysis showed that both alendronate and risedronate provide non-vertebral anti-fracture efficacy.
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Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies
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0.6553317308425903, "16783": 0.004870930220931768, "17441": 0.0019512200960889459, "17869": 0.2711893916130066, "17926": 0.07793712615966797, "17996": 0.8247235417366028, "18128": 0.034552380442619324, "18275": 0.036437395960092545, "18419": 0.4002431631088257, "18462": 1.259437084197998, "18479": 0.9037119746208191, "18714": 0.36290550231933594, "18757": 0.030771657824516296, "18804": 0.7314660549163818, "18888": 0.2990913391113281, "19470": 0.6107416749000549, "19500": 0.026976587250828743, "19539": 0.3923587501049042, "19554": 0.034552380442619324, "19653": 0.1384023278951645, "20415": 0.14264501631259918, "20467": 0.6950984001159668, "20624": 0.841701865196228, "20626": 0.13670019805431366, "20806": 0.07431721687316895, "20960": 0.012615402229130268, "21183": 0.42735910415649414, "21262": 0.2719337046146393, "21297": 0.011650617234408855, "21425": 0.026025565341114998, "21446": 0.5145297050476074, "21618": 0.022212404757738113, "21648": 0.26146242022514343, "21890": 0.0913962796330452, "21903": 0.3077431619167328, "22318": 0.09584271162748337, "22332": 0.02412080205976963, "22571": 0.7258110046386719, "22694": 0.06154331564903259, "22863": 0.0797421783208847, "23150": 0.07793712615966797, "23245": 0.7370892763137817, "23346": 0.8893690705299377, "23376": 0.3374483287334442, "23737": 0.11951763927936554, "23974": 0.24325250089168549, "24176": 1.004473328590393, "24269": 0.11691460013389587, "24471": 1.12938392162323, "25125": 0.9302552938461304, "25206": 0.15943801403045654, "25339": 0.8065804839134216, "25354": 1.0116009712219238, "25449": 0.11517547070980072, "25932": 0.0354953333735466, "26014": 0.015504186972975731, "26179": 0.9922385215759277, "26305": 0.3141832649707794, "26356": 1.034073829650879, "26534": 0.24401791393756866, "26734": 1.1230508089065552, "26741": 0.21530038118362427, "26775": 0.07431721687316895, "27169": 0.45251765847206116, "27208": 0.672426164150238, "27287": 0.6517757177352905, "27480": 0.5444341897964478, "28086": 0.24554696679115295, "28102": 0.0606246218085289, "28156": 0.21687394380569458, "28290": 0.5010119676589966, "28327": 0.8869584798812866, "28685": 0.38905516266822815, "28828": 0.7969439625740051, "28873": 0.05046287178993225, "29333": 0.08961215615272522}
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26008063
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Islet1 (Isl1) is a transcription factor transiently expressed in a subset of heart and limb progenitors. During studies of limb development, conditional Isl1 deletion produced unexpected kidney abnormalities. Here, we studied the renal expression of Isl1 and whether it has a role in kidney development. In situ hybridization revealed Isl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditional deletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT). The absence of Isl1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The abnormal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia. Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, Isl1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud. These observations call for further studies to investigate whether Isl1 may be a causative gene for human CAKUT.
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Islet1 deletion causes kidney agenesis and hydroureter resembling CAKUT.
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0.04953393340110779, "17261": 0.6744182109832764, "17702": 0.6000806093215942, "18077": 0.37974658608436584, "18260": 0.18411032855510712, "18340": 0.17759032547473907, "18516": 0.4349733293056488, "18549": 0.2493593990802765, "18796": 0.04207121208310127, "18903": 0.0009760859538801014, "18969": 0.619189441204071, "19444": 0.15359249711036682, "19686": 0.08244366943836212, "19723": 0.0058422754518687725, "19780": 0.10555581003427505, "19783": 0.043007105588912964, "19817": 0.07068414986133575, "19872": 0.151916041970253, "19882": 0.2800849378108978, "20045": 0.4196864068508148, "20187": 0.6400018334388733, "20350": 0.0752234235405922, "20567": 0.755608320236206, "20655": 0.3248254358768463, "20679": 0.19381128251552582, "20752": 0.06520967930555344, "20806": 0.15610189735889435, "20817": 0.23092569410800934, "21471": 0.12470348179340363, "21520": 0.39762192964553833, "21575": 0.417115718126297, "21618": 0.31132611632347107, "21718": 0.05046287178993225, "21733": 0.6553317308425903, "21903": 0.22001366317272186, "21935": 0.34023189544677734, "22311": 0.9340999722480774, "22318": 0.06886265426874161, "23150": 0.11604541540145874, "23296": 1.176850438117981, "23316": 0.24401791393756866, "23572": 0.47402387857437134, "23746": 0.30558720231056213, "23797": 0.026976587250828743, "23943": 0.20102575421333313, "23969": 0.5882205963134766, "24054": 0.021256839856505394, "24169": 0.2089812457561493, "24203": 0.6664261221885681, "24454": 0.22157983481884003, "24501": 0.08064348995685577, "24529": 0.2800849378108978, "24587": 0.6054253578186035, "24848": 1.1312761306762695, "25002": 0.27786844968795776, "25117": 0.09228714555501938, "25343": 0.026976587250828743, "25394": 0.012615402229130268, "25643": 0.1510767638683319, "25644": 0.07884006202220917, "25708": 0.009718249551951885, "26117": 0.2830325961112976, "26210": 0.14349138736724854, "26279": 0.11778303235769272, "26296": 1.0382318496704102, "26435": 0.4041621685028076, "26633": 0.1384023278951645, "26773": 0.4932899475097656, "27170": 0.5871354341506958, "27287": 0.06886265426874161, "27697": 0.9248477816581726, "27790": 1.0628231763839722, "27854": 0.013579257763922215, "27989": 0.8161250352859497, "28024": 0.23324857652187347, "28038": 1.0775588750839233, "28696": 0.0752234235405922, "28715": 1.1185935735702515, "28835": 0.34300774335861206}
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26008462
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Repair of tissue after injury depends on a series of concerted but overlapping events including, inflammation, re-epithelialization, neovascularization and synthesis and stabilization of a fibrous extracellular matrix (ECM) that is remodeled to emulate normal tissue over time. Particular members of the transglutaminase (TG) family are upregulated during wound healing and act as a novel class of wound-healing mediators during the repair process. This group of enzymes which crosslink proteins via epsilon(gamma-glutamyl) lysine bridges are involved in wound healing through their ability to stabilize proteins and also by regulating the behavior of a wide variety of cell types that are recruited to the damaged area in order to carry out tissue repair. In this article we discuss the function of the most widely expressed member of the TG family "tissue transglutaminase" (TG2) in wound repair. Using both early and recent evidence from the literature we demonstrate how the multifunctional TG2 affects the stability of the ECM, cell-ECM interactions and as a consequence cell behavior within the different phases of wound healing, and highlight how TG2 itself might be exploited for therapeutic use.
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Tissue transglutaminase (TG2)--a wound response enzyme.
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26011884
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Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory synaptic neurotransmission in the central nervous system. The selective assembly of iGluRs into AMPA, kainate, and N-methyl-d-aspartic acid (NMDA) receptor subtypes is regulated by their extracellular amino-terminal domains (ATDs). Kainate receptors are further classified into low-affinity receptor families (GluK1-GluK3) and high-affinity receptor families (GluK4-GluK5) based on their affinity for the neurotoxin kainic acid. These two families share a 42% sequence identity for the intact receptor but only a 27% sequence identity at the level of ATD. We have determined for the first time the high-resolution crystal structures of GluK3 and GluK5 ATDs, both of which crystallize as dimers but with a strikingly different dimer assembly at the R1 interface. By contrast, for both GluK3 and GluK5, the R2 domain dimer assembly is similar to those reported previously for other non-NMDA iGluRs. This observation is consistent with the reports that GluK4-GluK5 cannot form functional homomeric ion channels and require obligate coassembly with GluK1-GluK3. Our analysis also reveals that the relative orientation of domains R1 and R2 in individual non-NMDA receptor ATDs varies by up to 10°, in contrast to the 50° difference reported for the NMDA receptor GluN2B subunit. This restricted domain movement in non-NMDA receptor ATDs seems to result both from extensive intramolecular contacts between domain R1 and domain R2 and from their assembly as dimers, which interact at both R1 and R2 domains. Our results provide the first insights into the structure and function of GluK4-GluK5, the least understood family of iGluRs.
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Crystal structures of the glutamate receptor ion channel GluK3 and GluK5 amino-terminal domains.
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26016929
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OBJECTIVE To assess whether population screening for impaired vision among older people in the community leads to improvements in vision. DESIGN Systematic review of randomised controlled trials of population screening in the community that included any assessment of vision or visual function with at least 6 months' follow up. SUBJECTS Adults aged 65 or over. MAIN OUTCOME MEASURE Proportions with visual impairment in intervention and control groups with any method of assessing visual impairment. RESULTS There were no trials that primarily assessed visual screening. Outcome data on vision were available for 3494 people in five trials of multiphasic assessment. All the trials used self reported measures for vision impairment, both as screening tools and as outcome measures. The inclusion of a visual screening component in the assessment did not result in improvements in self reported visual problems (pooled odds ratio 1.04:95% confidence interval 0.89 to 1.22). A small reduction (11%) in the number of older people with self reported visual problems cannot be excluded. CONCLUSIONS Screening of asymptomatic older people in the community is not justified on present evidence. Visual impairment in this age group can usually be reduced with treatment. It is unclear why no benefit was seen. Further work is needed to clarify what interventions are appropriate for older people with unreported impairment of vision.
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Effectiveness of screening older people for impaired vision in community setting: systematic review of evidence from randomised controlled trials.
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26019505
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The Hippo pathway regulates organ size and tissue homeostasis in response to multiple stimuli, including cell density and mechanotransduction. Pharmacological inhibition of phosphatases can also stimulate Hippo signaling in cell culture. We defined the Hippo protein-protein interaction network with and without inhibition of serine and threonine phosphatases by okadaic acid. We identified 749 protein interactions, including 599 previously unrecognized interactions, and demonstrated that several interactions with serine and threonine phosphatases were phosphorylation-dependent. Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK (striatin-interacting phosphatase and kinase complex). Deletion of the amino-terminal forkhead-associated domain of SLMAP (sarcolemmal membrane-associated protein), a component of the STRIPAK complex, prevented its association with MST1 and MST2. Phosphatase inhibition produced temporally distinct changes in proteins that interacted with MOB1A and MOB1B (Mps one binder kinase activator-like 1A and 1B) and promoted interactions with upstream Hippo pathway proteins, such as MST1 and MST2, and with the trimeric protein phosphatase 6 complex (PP6). Mutation of three basic amino acids that are part of a phospho-serine- and phospho-threonine-binding domain in human MOB1B prevented its interaction with MST1 and PP6 in cells treated with okadaic acid. Collectively, our results indicated that changes in phosphorylation orchestrate interactions between kinases and phosphatases in Hippo signaling, providing a putative mechanism for pathway regulation.
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Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions.
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"27487": 0.36290550231933594, "27598": 0.9379299283027649, "27790": 0.056018441915512085, "27895": 0.06337817758321762, "28041": 0.24554696679115295, "28093": 1.138809084892273, "28096": 0.014542185701429844, "28156": 0.2969166338443756, "28228": 0.022212404757738113, "28413": 0.9455460906028748, "28516": 0.1212492436170578, "28715": 0.1602703034877777, "29167": 0.12384103983640671, "29170": 0.6629094481468201, "29181": 1.0257055759429932, "29290": 0.7124901413917542, "29595": 0.9348671436309814}
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26025370
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Background: Vasoconstriction and reactive oxygen species (ROS) accumulation following contrast media (CM) injection are the key factors triggering CM-induced nephropathy. We compared the effects of N-acetylcysteine (NAC), theophylline or sodium bicarbonate on intrarenal vasoconstriction and ROS generation in a rat model of CM-induced nephropathy. Methods: Following a 3-day dehydration, Sprague-Dawley rats received CM (Telebrix) or sham ‘CM’ injection of 0.9% saline. Part of them received NAC, theophylline or bicarbonate prior to CM. Medullar renal blood flow was estimated by laser Doppler. The animals were sacrificed 1, 15 or 30 min after the respective treatments, their kidneys allocated and intrarenal STAT-8 isoprostane, PGE2 and NO assessed. Results: Vasoconstriction was significantly attenuated by NAC. Theophylline only mildly attenuated the perfusion drop at 15 min, and was ineffective following 30 min. Unlike theophylline or bicarbonate, NAC significantly augmented intrarenal PGE2. NAC, theophylline but not bicarbonate, gradually increased intrarenal NO. In all experimental variables, CM-induced ROS accumulation, represented by STAT-8 isoprostane estimation, progressed undisturbed. Conclusions: (1) CM-induced intrarenal vasoconstriction was efficiently prohibited by NAC but not bicarbonate or theophylline; (2) the vasodilatory effect of NAC was mediated via increased PGE2 synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected by any pharmacologic manipulations.
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Differential Effects of N-Acetylcysteine, Theophylline or Bicarbonate on Contrast-Induced Rat Renal Vasoconstriction
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"15909": 0.14686977863311768, "15911": 0.5936289429664612, "15946": 1.187628984451294, "16014": 0.15860503911972046, "16081": 0.8161250352859497, "16157": 0.11604541540145874, "16185": 0.17267228662967682, "16221": 0.1946154683828354, "16228": 0.053244512528181076, "16330": 0.440646231174469, "16341": 0.5027855634689331, "16381": 0.6048921346664429, "16389": 0.08064348995685577, "16463": 0.1477125883102417, "16483": 0.02412080205976963, "16487": 0.29109421372413635, "16519": 0.42225050926208496, "16599": 0.6921701431274414, "16670": 0.1384023278951645, "16705": 1.0382318496704102, "16820": 0.03925827145576477, "16940": 0.981317400932312, "17146": 0.29036402702331543, "17261": 0.5495203733444214, "17350": 0.045809537172317505, "17441": 0.0029254043474793434, "17738": 0.997294545173645, "17820": 0.13499516248703003, "17890": 0.11778303235769272, "17913": 0.32199856638908386, "17996": 0.4500300884246826, "18089": 0.7333439588546753, "18276": 0.1221139207482338, "18340": 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26025820
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The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa). As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system. We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model. We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.
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Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease.
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"16778": 0.8845420479774475, "16853": 0.574020504951477, "16902": 0.966567873954773, "16921": 0.7445381283760071, "16940": 0.36086538434028625, "16983": 0.029824240133166313, "17011": 0.9576126337051392, "17034": 0.02412080205976963, "17076": 0.17020416259765625, "17208": 0.347847044467926, "17464": 0.15526613593101501, "17503": 0.33605360984802246, "17547": 0.19220098853111267, "17815": 0.0019512200960889459, "17908": 0.08154398202896118, "18075": 0.23556606471538544, "18133": 0.18978065252304077, "18422": 0.3963087201118469, "18478": 0.0317181795835495, "18491": 0.37907835841178894, "18539": 0.1734936386346817, "18609": 0.06795065850019455, "18613": 0.0019512200960889459, "18622": 0.11430477350950241, "19037": 0.1751343309879303, "19064": 1.1121915578842163, "19198": 0.151916041970253, "19875": 0.956112265586853, "19879": 0.23247487843036652, "19968": 0.06246116757392883, "20077": 0.4067663550376892, "20167": 0.35334911942481995, "20201": 0.24554696679115295, "20389": 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"24582": 0.10555581003427505, "24806": 0.27342069149017334, "24848": 0.0354953333735466, "24895": 0.18004031479358673, "25006": 0.3903779089450836, "25086": 0.09317722171545029, "25320": 0.48670899868011475, "25708": 0.1905880719423294, "25714": 0.4580921530723572, "25896": 0.04674193635582924, "25918": 0.14518201351165771, "25937": 0.15777134895324707, "26189": 0.025073638185858727, "26210": 0.2852376699447632, "26226": 1.0628231763839722, "26384": 0.04953393340110779, "26535": 0.07068414986133575, "26715": 0.129004567861557, "26721": 1.0471819639205933, "26745": 0.011650617234408855, "26886": 0.036437395960092545, "26989": 0.5517725944519043, "27011": 0.7500885725021362, "27144": 0.04487626627087593, "27312": 0.3248254358768463, "27354": 0.04860413447022438, "27404": 0.5021947622299194, "27532": 0.026025565341114998, "27846": 0.5495203733444214, "28141": 0.3683255612850189, "28329": 0.2954642176628113, "28375": 0.11691460013389587, "28436": 0.5909284353256226, "28472": 0.25239890813827515, "28578": 0.034552380442619324, "28808": 0.04860413447022438, "28879": 0.27712854743003845, "29160": 0.11430477350950241, "29454": 0.1808556467294693, "29458": 0.14686977863311768, "29610": 1.2829933166503906}
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26026009
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As a result of increasing interest in non-surgical treatment for the reduction of goitre size the use of magnetic resonance (MR) imaging for volume estimation of large multinodular goitres was evaluated in 20 patients (three males and 17 females; age 61 +/- 21 years) with a multinodular goitre larger than 100 ml. In addition, MR measurements were compared with scintigraphic (SC) volume estimations. Intraobserver coefficient of variation (CV) of MR measurements was 2.2 +/- 2.0% (Observer 1) and interobserver CV 4.1 +/- 2.2% (Observers 1 and 2). In all 20 patients signs of mechanical complications were shown on MR images. For SC measurements intraobserver CV was 7.5 +/- 5.7% (Observer 3) and 5.4 +/- 5.1% (Observer 4). Interobserver CV was 10.1 +/- 6.1%. The correlation between measurements with both methods was not strong (r = 0.665) and the resulting CV was 17.3 +/- 14.2%. Underestimation of SC volumes could not be explained by the presence of cysts on the surface of the thyroid. It is concluded that MR imaging can be used for in vivo thyroid volume estimation in large multinodular goitres. The high precision of MR measurements makes this technique potentially useful for the evaluation of thyroid growth and non-surgical treatment for reducing goitre size. Scintigraphic volume measurements do not suffice for this purpose. An additional advantage of MR imaging is the detailed anatomical information it provides with regard to mechanical complications of large goitres.
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Magnetic resonance imaging for volume estimation of large multinodular goitres: a comparison with scintigraphy.
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"28788": 0.6059582233428955, "28848": 0.6773988008499146, "28873": 0.2689530849456787, "29090": 0.0354953333735466, "29290": 0.5947071313858032, "29477": 0.19782574474811554}
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26030079
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Respiratory epithelial cells play an active part in the host response to respiratory pathogens, such as Streptococcus pneumoniae, by releasing chemokines responsible for neutrophil recruitment. In order to investigate the role of specific pneumococcal virulence factors in eliciting CXC chemokine responses, type II pneumocytes (A549) and nasopharyngeal cells (Detroit-562) were infected with S. pneumoniae D39 or mutants lacking choline-binding protein A (CbpA), pneumococcal surface protein A (PspA), or specific domains thereof. In response to wild-type D39, both A549 and Detroit-562 cells showed a significant increase in CXC chemokine mRNA and interleukin-8 protein. This response was increased twofold when a cbpA deletion mutant (DeltaCbpA) was used, suggesting that CbpA inhibits CXC chemokine induction. All three N-terminal domains of CbpA are required for this effect, as in-frame deletion of the respective region of cbpA had the same effect on the CXC chemokine response as deletion of cbpA altogether. Infection with a pspA deletion mutant (DeltaPspA) led to a twofold decrease in the CXC chemokine response of A549 but not Detroit-562 cells, compared to infection with D39 at 2 h. Thus, PspA appears to have the ability to stimulate early CXC chemokine release from A549 cells. Deletion of the region of pspA encoding the first N-terminal alpha-helical domain reduced the ability of S. pneumoniae to elicit a chemokine response to the same degree as deletion of pspA altogether. Thus, the N termini of CbpA and PspA exert differential effects on CXC chemokine induction in epithelial cells infected with S. pneumoniae.
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Differential role of CbpA and PspA in modulation of in vitro CXC chemokine responses of respiratory epithelial cells to infection with Streptococcus pneumoniae.
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26038789
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3BNC117 is a broad and potent neutralizing antibody to HIV-1 that targets the CD4 binding site on the viral envelope spike. When administered passively, this antibody can prevent infection in animal models and suppress viremia in HIV-1–infected individuals. Here we report that HIV-1 immunotherapy with a single injection of 3BNC117 affects host antibody responses in viremic individuals. In comparison to untreated controls that showed little change in their neutralizing activity over a 6-month period, 3BNC117 infusion significantly improved neutralizing responses to heterologous tier 2 viruses in nearly all study participants. We conclude that 3BNC117-mediated immunotherapy enhances host humoral immunity to HIV-1.
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HIV-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1
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26045237
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BACKGROUND Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).
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Safety and efficacy of RNAi therapy for transthyretin amyloidosis.
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1.018678069114685, "24731": 0.030771657824516296, "24774": 0.5568217039108276, "24848": 0.040196798741817474, "24868": 0.04487626627087593, "24872": 0.9178520441055298, "25090": 0.7951818704605103, "25117": 0.9944084882736206, "25194": 0.08692999184131622, "25456": 0.9944084882736206, "25458": 0.04487626627087593, "25502": 0.319873183965683, "25619": 0.6950984001159668, "25714": 0.4950772523880005, "25969": 0.7239188551902771, "26058": 0.2160874605178833, "26089": 0.012615402229130268, "26402": 1.1561684608459473, "26524": 0.0029254043474793434, "26591": 0.3127557039260864, "26651": 0.3554046154022217, "27292": 0.8289952278137207, "27325": 0.20501139760017395, "27465": 0.036437395960092545, "27846": 1.057410478591919, "27854": 0.34023189544677734, "28177": 1.0802149772644043, "28295": 0.8039615154266357, "28370": 0.45251765847206116, "28406": 0.08513788133859634, "28688": 0.11951763927936554, "29458": 0.3683255612850189, "29490": 0.4349733293056488}
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26047921
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Cells can respond to mechanical stress by gating mechanosensitive ion channels (MSCs). The cloning of Piezo1, a eukaryotic cation selective MSC, defines a new system for studying mechanical transduction at the cellular level. Because Piezo1 has electrophysiological properties similar to those of endogenous cationic MSCs that are selectively inhibited by the peptide GsMTx4, we tested whether the peptide targets Piezo1 activity. Extracellular GsMTx4 at micromolar concentrations reversibly inhibited ∼80% of the mechanically induced current of outside-out patches from transfected HEK293 cells. The inhibition was voltage insensitive, and as seen with endogenous MSCs, the mirror image d enantiomer inhibited like the l. The rate constants for binding and unbinding based on Piezo1 current kinetics provided association and dissociation rates of 7.0 × 10(5) M(-1) s(-1) and 0.11 s(-1), respectively, and a K(D) of ∼155 nM, similar to values previously reported for endogenous MSCs. Consistent with predicted gating modifier behavior, GsMTx4 produced an ∼30 mmHg rightward shift in the pressure-gating curve and was active on closed channels. In contrast, streptomycin, a nonspecific inhibitor of cationic MSCs, showed the use-dependent inhibition characteristic of open channel block. The peptide did not block currents of the mechanical channel TREK-1 on outside-out patches. Whole-cell Piezo1 currents were also reversibly inhibited by GsMTx4, and although the off rate was nearly identical to that of outside-out patches, differences were observed for the on rate. The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports the use of this channel in high-throughput screens for pharmacological agents and diagnostic assays.
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The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.
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0.02412080205976963, "16748": 0.8383291959762573, "16834": 0.021256839856505394, "16902": 0.6128603219985962, "16923": 0.0009760859538801014, "17042": 0.021256839856505394, "17190": 0.058784693479537964, "17214": 0.055094651877880096, "17350": 1.0271050930023193, "17404": 0.14518201351165771, "17473": 0.11865071207284927, "17596": 0.11604541540145874, "17696": 0.04487626627087593, "17815": 0.11430477350950241, "17864": 0.6563454270362854, "17913": 0.13499516248703003, "17920": 0.2983669638633728, "18089": 0.09495500475168228, "18178": 0.13755162060260773, "18423": 0.9769153594970703, "18622": 0.24631060659885406, "18639": 0.175953671336174, "18647": 0.05417001247406006, "18714": 0.34922540187835693, "18791": 0.020300358533859253, "18856": 0.5767669677734375, "19037": 0.0058422754518687725, "19064": 0.09938567131757736, "19163": 0.3883931338787079, "19242": 0.16359257698059082, "19362": 0.1930064558982849, "19653": 0.5186077356338501, "19872": 0.8901712894439697, "20162": 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0.14686977863311768, "27144": 0.10291612148284912, "27266": 0.053244512528181076, "27313": 0.24401791393756866, "27511": 0.15442965924739838, "27606": 0.997294545173645, "27704": 0.045809537172317505, "27764": 0.016465263441205025, "27833": 0.15693697333335876, "27854": 0.07884006202220917, "27922": 0.05694137513637543, "28225": 0.33115679025650024, "28370": 0.2105647772550583, "28426": 0.08513788133859634, "28475": 0.08871890604496002, "28687": 0.21922965347766876, "28696": 0.2317005842924118, "28774": 0.0029254043474793434, "28835": 0.2089812457561493, "29235": 0.08961215615272522, "29290": 0.14433705806732178, "29299": 0.36426326632499695}
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26058927
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Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved beta-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P<0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7 (PIO+drug-naïve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2 (ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.
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Thiazolidinediones improve beta-cell function in type 2 diabetic patients.
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"21472": 0.40611594915390015, "21733": 0.8332487344741821, "21799": 0.07612881064414978, "21823": 0.020300358533859253, "21903": 0.46363574266433716, "21967": 0.058784693479537964, "22203": 0.24248650670051575, "22275": 1.3960126638412476, "22330": 0.6233867406845093, "22401": 1.0389231443405151, "22422": 0.20580662786960602, "22471": 0.06703783571720123, "22543": 0.46486347913742065, "22571": 0.5381823778152466, "22597": 0.17840765416622162, "22648": 0.8143964409828186, "22907": 0.16442140936851501, "22932": 0.015504186972975731, "23316": 0.08871890604496002, "23352": 0.5209306478500366, "23393": 1.0881409645080566, "23586": 0.0842406153678894, "23737": 0.1677299439907074, "23777": 0.4311734735965729, "23892": 0.6170841455459595, "24054": 0.006812678650021553, "24269": 0.9900637865066528, "24278": 0.09317722171545029, "24335": 0.6558387279510498, "24587": 0.6244332790374756, "24755": 0.6709295511245728, "24759": 0.6502478122711182, "25172": 0.42353010177612305, "25409": 0.16359257698059082, "25642": 0.9131608605384827, "25714": 0.4041621685028076, "25778": 0.07793712615966797, "25874": 0.38374659419059753, "25950": 1.1573970317840576, "26187": 0.417115718126297, "26209": 0.129004567861557, "26305": 0.4126010537147522, "26402": 0.4944818615913391, "26520": 0.0009760859538801014, "26565": 0.6317287683486938, "26601": 0.0038986403960734606, "27009": 0.25694093108177185, "27531": 0.22937409579753876, "27697": 0.7333439588546753, "27790": 0.6118015646934509, "27821": 0.23247487843036652, "27989": 0.05694137513637543, "28156": 0.5472630262374878, "28227": 0.603290855884552, "28503": 0.9531047344207764, "28685": 0.02316705882549286, "28696": 0.9379299283027649, "28715": 0.996573805809021, "28756": 0.4624064862728119, "28828": 0.38441169261932373, "28873": 0.0913962796330452, "28919": 0.022212404757738113, "29206": 0.9409833550453186, "29535": 0.036437395960092545}
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26059876
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Ku70, a known nonhomologous end-joining (NHEJ) factor, also functions in tumor suppression, although this molecular mechanism remains uncharacterized. Previously, we showed that mice deficient for DNA ligase IV (Lig4), another key NHEJ factor, succumbed to aggressive lymphoma in the absence of tumor suppressor p53. However, the tumor phenotype is abrogated by the introduction of a hypomorphic mutant p53R172P, which impaired p53-mediated apoptosis but not cell-cycle arrest. However, Lig4−/−p53R172P mice succumbed to severe diabetes. To further elucidate the role of NHEJ and p53-mediated apoptosis in vivo, we bred Ku70−/− p53R172P mice. Unexpectedly, these mice were free of diabetes, although 80% of the mutant mice had abnormally enlarged colons with pronounced inflammation. Remarkably, most of these mutant mice progressed to dysplasia, adenoma and adenocarcinoma; this is in contrast to the Lig4−/−p53R172P phenotype, strongly suggesting an NHEJ-independent function of Ku70. Significantly, our analyses of Ku70−/−p53R172P colonic epithelial cells show nuclear stabilization of β-catenin accompanied by higher expression of cyclin D1 and c-Myc in affected colon sections than in control samples. This is not due to the p53 mutation, as Ku70−/− mice share this phenotype. Our results not only unravel a novel function of Ku70 essential for colon homeostasis, but also establish an excellent in vivo model in which to study how chronic inflammation and abnormal cellular proliferation underlie tumorigenesis and tumor progression in the colon.
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A novel Ku70 function in colorectal homeostasis separate from nonhomologous end joining
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26064662
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Importance Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Exposures Presence of SCT. Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons). Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.
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Association of Sickle Cell Trait With Hemoglobin A1c in African Americans
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"29489": 0.17840765416622162}
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26064942
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Recently, mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor have been identified in a new subclass of congenital disorders of glycosylation (CDGs) with a distinct spectrum of clinical features. To date, mutations have been identified in six genes (PIGA, PIGL, PIGM, PIGN, PIGO, and PIGV) encoding proteins in the GPI-anchor-synthesis pathway in individuals with severe neurological features, including seizures, muscular hypotonia, and intellectual disability. We developed a diagnostic gene panel for targeting all known genes encoding proteins in the GPI-anchor-synthesis pathway to screen individuals matching these features, and we detected three missense mutations in PGAP2, c.46C>T, c.380T>C, and c.479C>T, in two unrelated individuals with hyperphosphatasia with mental retardation syndrome (HPMRS). The mutations cosegregated in the investigated families. PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus and is required for stable association between GPI-anchored proteins and the cell-surface membrane rafts. Transfection of the altered protein constructs, p. Arg16Trp (NP_001243169.1), p. Leu127Ser, and p. Thr160Ile, into PGAP2-null cells showed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface. In this work, we show that an impairment of GPI-anchor remodeling also causes HPMRS and conclude that targeted sequencing of the genes encoding proteins in the GPI-anchor-synthesis pathway is an effective diagnostic approach for this subclass of CDGs.
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PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome.
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The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without related signs or symptoms. It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment. The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms. Summary of Recommendation and Evidence The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) See the Clinical Considerations section for suggestions for implementation in practice. See the Figure for a summary of the recommendation and suggestions for clinical practice. Figure. Screening for lung cancer: clinical summary of U.S. Preventive Services Task Force recommendation. Appendix Table 1 describes the USPSTF grades, and Appendix Table 2 describes the USPSTF classification of levels of certainty about net benefit. Appendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice Appendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit Supplement. Consumer Fact Sheet. Rationale Importance Lung cancer is the third most common cancer and the leading cause of cancer-related death in the United States (1). The most important risk factor for lung cancer is smoking, which results in approximately 85% of all U.S. lung cancer cases (2). Although the prevalence of smoking has decreased, approximately 37% of U.S. adults are current or former smokers (2). The incidence of lung cancer increases with age and occurs most commonly in persons aged 55 years or older. Increasing age and cumulative exposure to tobacco smoke are the 2 most common risk factors for lung cancer. Lung cancer has a poor prognosis, and nearly 90% of persons with lung cancer die of the disease. However, early-stage nonsmall cell lung cancer (NSCLC) has a better prognosis and can be treated with surgical resection. Detection Most lung cancer cases are NSCLC, and most screening programs focus on the detection and treatment of early-stage NSCLC. Although chest radiography and sputum cytologic evaluation have been used to screen for lung cancer, LDCT has greater sensitivity for detecting early-stage cancer (3). Benefits of Detection and Early Treatment Although lung cancer screening is not an alternative to smoking cessation, the USPSTF found adequate evidence that annual screening for lung cancer with LDCT in a defined population of high-risk persons can prevent a substantial number of lung cancerrelated deaths. Direct evidence from a large, well-conducted, randomized, controlled trial (RCT) provides moderate certainty of the benefit of lung cancer screening with LDCT in this population (4). The magnitude of benefit to the person depends on that person's risk for lung cancer because those who are at highest risk are most likely to benefit. Screening cannot prevent most lung cancerrelated deaths, and smoking cessation remains essential. Harms of Detection and Early Intervention and Treatment The harms associated with LDCT screening include false-negative and false-positive results, incidental findings, overdiagnosis, and radiation exposure. False-positive LDCT results occur in a substantial proportion of screened persons; 95% of all positive results do not lead to a diagnosis of cancer. In a high-quality screening program, further imaging can resolve most false-positive results; however, some patients may require invasive procedures. The USPSTF found insufficient evidence on the harms associated with incidental findings. Overdiagnosis of lung cancer occurs, but its precise magnitude is uncertain. A modeling study performed for the USPSTF estimated that 10% to 12% of screen-detected cancer cases are overdiagnosedthat is, they would not have been detected in the patient's lifetime without screening. Radiation harms, including cancer resulting from cumulative exposure to radiation, vary depending on the age at the start of screening; the number of scans received; and the person's exposure to other sources of radiation, particularly other medical imaging. USPSTF Assessment The USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT is of moderate net benefit in asymptomatic persons who are at high risk for lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking. The moderate net benefit of screening depends on limiting screening to persons who are at high risk, the accuracy of image interpretation being similar to that found in the NLST (National Lung Screening Trial), and the resolution of most false-positive results without invasive procedures (4). Clinical Considerations Patient Population Under Consideration The risk for lung cancer increases with age and cumulative exposure to tobacco smoke and decreases with time since quitting smoking. The best evidence for the benefit of screening comes from the NLST, which enrolled adults aged 55 to 74 years who had at least a 30 pack-year smoking history and were current smokers or had quit within the past 15 years. As with all screening trials, the NLST tested a specific intervention over a finite period. Because initial eligibility extended through age 74 years and participants received 3 annual screening computed tomographic scans, the oldest participants in the trial were aged 77 years. The USPSTF used modeling studies to predict the benefits and harms of screening programs that use different screening intervals, age ranges, smoking histories, and times since quitting. A program that annually screens adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years is projected to have a reasonable balance of benefits and harms. The model assumes that persons who achieve 15 years of smoking cessation during the screening program discontinue screening. This model predicts the outcomes of continuing the screening program used in the NLST through age 80 years. Screening may not be appropriate for patients with substantial comorbid conditions, particularly those at the upper end of the screening age range. The NLST excluded persons who were unlikely to complete curative lung cancer surgery and those with medical conditions that posed a substantial risk for death during the 8-year trial. The baseline characteristics of the NLST showed a relatively healthy sample, and fewer than 10% of enrolled participants were older than 70 years (5). Persons with serious comorbid conditions may experience net harm, no net benefit, or at least substantially less net benefit. Similarly, persons who are unwilling to have curative lung surgery are unlikely to benefit from a screening program. Assessment of Risk Age, total exposure to tobacco smoke, and years since quitting smoking are important risk factors for lung cancer and were used to determine eligibility in the NLST. Other risk factors include specific occupational exposures, radon exposure, family history, and history of pulmonary fibrosis or chronic obstructive lung disease. The incidence of lung cancer is relatively low in persons younger than 50 years but increases with age, especially after age 60 years. In current and former smokers, age-specific incidence rates increase with age and cumulative exposure to tobacco smoke. Smoking cessation substantially reduces a person's risk for developing and dying of lung cancer. Among persons enrolled in the NLST, those who were at highest risk because of additional risk factors or a greater cumulative exposure to tobacco smoke experienced most of the benefit (6). A validated multivariate model showed that persons in the highest 60% of risk accounted for 88% of all deaths preventable by screening. Screening Tests Low-dose computed tomography has shown high sensitivity and acceptable specificity for the detection of lung cancer in high-risk persons. Chest radiography and sputum cytologic evaluation have not shown adequate sensitivity or specificity as screening tests. Therefore, LDCT is currently the only recommended screening test for lung cancer. Treatment Surgical resection is the current standard of care for localized NSCLC. This type of cancer is treated with surgical resection when possible and also with radiation and chemotherapy. Annual LDCT screening may not be useful for patients with life-limiting comorbid conditions or poor functional status who may not be candidates for surgery. Other Approaches to Prevention Smoking cessation is the most important intervention to prevent NSCLC. Advising smokers to stop smoking and preventing nonsmokers from being exposed to tobacco smoke are the most effective ways to decrease the morbidity and mortality associated with lung cancer. Current smokers should be informed of their continuing risk for lung cancer and offered cessation treatments. Screening with LDCT should be viewed as an adjunct to tobacco cessation interventions. Useful Resources Clinicians have many resources to help patients stop smoking. The Centers for Disease Control and Prevention has developed a Web site with many such resources, including information on tobacco quit lines, available in several languages (www.cdc.gov/tobacco/campaign/tips). Quit l
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Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement
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26068103
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RSV lower respiratory tract infections (LRTI) are among the most common diseases necessitating hospital admission in children. In addition to causing acute respiratory failure, RSV infections are associated with sequelae such as secondary bacterial infections and reactive airway disease. One characteristic host response observed in severe RSV-induced LRTI and/or subsequent development of asthma is increased expression of interleukin (IL)-10. However, contradictory results have been reported regarding whether IL-10 inhibits asthmatic responses or intensifies the disease. We aimed to reconcile these discordant observations by elucidating the role of IL-10 in regulating the host response to RSV LRTI. In this study, we used a lung-specific, inducible IL-10 over-expression (OE) transgenic mouse model to address this question. Our results showed that the presence of IL-10 at the time of RSV infection not only attenuated acute inflammatory process (i.e. 24 h post-infection), but also late inflammatory changes [characterized by T helper type 2 (Th2) cytokine and chemokine expression]. While this result appears contradictory to some clinical observations where elevated IL-10 levels are observed in asthmatic patients, we also found that delaying IL-10 OE until the late immune response to RSV infection, additive effects rather than inhibitory effects were observed. Importantly, in non-infected, IL-10 OE mice, IL-10 OE alone induced up-regulation of Th2 cytokine (IL-13 and IL-5) and Th2-related chemokine [monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif) ligand 3 (CCL3) and regulated upon activation normal T cell expressed and secreted (RANTES)] expression. We identified a subset of CD11b(+)CD11c(+)CD49b(+)F4/80(-)Gr-1(-) myeloid cells as a prinicipal source of IL-10-induced IL-13 production. Therefore, the augmented pathological responses observed in our 'delayed' IL-10 over-expression model could be attributed to IL-10 OE alone. Taken together, our study indicated dual roles of IL-10 on RSV-induced lung inflammation which appear to depend upon the timing of when elevated IL-10 is expressed in the lung.
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Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation.
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26071782
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Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein–Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by the CD40 receptor and has been implicated in regulating proliferation, survival, or both properties of EBV-infected cells. We established a conditional LMP1 allele in the context of the intact EBV genome to define the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions to infected human B cells. The functional analysis of this conditional system indicated that LMP1 specifically induces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its direct role in upregulating expression of multiple genes with opposing activities involved in cell survival. LMP1's signals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signals are cell cycle arrested and survive quiescently. LMP1's activities are therefore not required to maintain survival in nonproliferating cells. LMP1 does induce both pro- and antiapoptotic genes whose balance seems to permit survival during LMP1's induction and maintenance of proliferation.
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Latent membrane protein 1 of Epstein–Barr virus coordinately regulates proliferation with control of apoptosis
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"26702": 0.11343330889940262, "26832": 0.07612881064414978, "26874": 0.36967599391937256, "27001": 0.08782484382390976, "27144": 0.2954642176628113, "27216": 0.347847044467926, "27292": 0.6038249135017395, "27354": 0.04207121208310127, "27642": 0.8625272512435913, "27673": 0.0317181795835495, "27794": 0.9092346429824829, "27814": 0.4728073179721832, "27854": 0.23402166366577148, "28518": 0.026976587250828743, "28794": 0.08603433519601822, "29490": 0.34508460760116577}
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26079071
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BACKGROUND Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. RESULTS The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
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Crizotinib in ROS1-rearranged non-small-cell lung cancer.
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0.28670501708984375}
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26083387
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The Saccharomyces cerevisiae DNA helicase Rrm3p is needed for normal fork progression through >1000 discrete sites scattered throughout the genome. Here we show that replication of all yeast chromosomes was markedly delayed in rrm3 cells. Delayed replication was seen even in a region that lacks any predicted Rrm3p-dependent sites. Based on the pattern of replication intermediates in two-dimensional gels, the rate of fork movement in rrm3 cells appeared similar to wild-type except at known Rrm3p-dependent sites. These data suggest that although Rrm3p has a global role in DNA replication, its activity is needed only or primarily at specific, difficult-to-replicate sites. By the criterion of chromatin immunoprecipitation, Rrm3p was associated with both Rrm3p-dependent and -independent sites, and moved with the replication fork through both. In addition, Rrm3p interacted with Pol2p, the catalytic subunit of DNA polymerase epsilon, in vivo. Thus, rather than being recruited to its sites of action when replication forks stall at these sites, Rrm3p is likely a component of the replication fork apparatus.
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The S. cerevisiae Rrm3p DNA helicase moves with the replication fork and affects replication of all yeast chromosomes.
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26089649
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Alterations in glomerular function and structure were studied in protein-overload nephrosis in the rat induced by intraperitoneal administration of bovine serum albumin (BSA). Fractional clearance (C/GFR) studies using inulin and tracer proteins of different molecular size and charge revealed in proteinuric rats 1) unchanged glomerular filtration rate and renal plasma flow; 2) a 34-fold increase in C/GFR of rat serum albumin, reaching values similar to BSA; 3) a 2-fold increase in C/GFR for anionic horse radish peroxidase (HRP), but normal values for neutral and cationic HRP, and 4) an 11- and 3-fold increase for heterologous IgG and IgM, respectively. Glomerular epithelial cells showed degenerative changes, but the distribution of anionic sites in the glomerular basement membrane was found to be unaltered, as determined by polyethyleneimine binding studies. In summary, an elevation of serum albumin concentration resulted in an increased transcapillary albumin transport. This was found to lead to degenerative changes of glomerular epithelial cells with development of large pore defects, which were completely reversible.
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The pathophysiology of protein-overload proteinuria.
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26099680
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Circadian organization changes with age, but we do not know the extent to which age-related changes are the result of alterations in the central pacemakers, the peripheral oscillators, or the coupling mechanisms that hold the system together. By using transgenic rats with a luciferase (luc) reporter, we assessed the effects of aging on the rhythm of expression of the Period 1 (Per1) gene in the suprachiasmatic nucleus (SCN) and in peripheral tissues. Young (2 months) and aged (24-26 months) Per1-luc transgenic rats, entrained to light-dark cycles, were killed, and tissues were removed and cultured. Per1-luc expression was measured from 10 tissues. In the SCN, the central mammalian pacemaker, Per1-luc expression was robustly rhythmic for more than 7 weeks in culture. The only difference between SCN rhythmicity in young and old rats was a small but significant age-related shortening of the free-running period. Circadian rhythmicity in some peripheral tissues was unaffected by aging, whereas rhythmicity in other tissues was either phase advanced relative to the light cycle or absent. Those tissues that were arrhythmic could be induced to oscillate by application of forskolin, suggesting that they retained the capacity to oscillate but were not being appropriately driven in vivo. Overall, the results provide new insights into the effects of aging on the mammalian circadian system. Aging seems to affect rhythms in some but not in all tissues and may act primarily on interactions among circadian oscillators, perhaps attenuating the ability of the SCN to drive damped oscillators in the periphery.
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Effects of aging on central and peripheral mammalian clocks.
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"19496": 0.40806588530540466, "19570": 0.12642613053321838, "19601": 0.23324857652187347, "19653": 0.06337817758321762, "19872": 0.839173436164856, "20214": 0.08871890604496002, "20467": 0.7755908370018005, "20817": 0.5307431221008301, "20960": 0.2719337046146393, "21208": 0.029824240133166313, "21252": 1.0979610681533813, "21266": 0.5662899017333984, "21618": 0.0019512200960889459, "21823": 0.14433705806732178, "21903": 0.4770587682723999, "21926": 0.09228714555501938, "22123": 0.846739649772644, "22330": 0.1212492436170578, "22644": 0.07068414986133575, "22930": 0.04207121208310127, "23079": 0.2447827309370041, "23725": 0.8169882297515869, "23943": 0.8247235417366028, "24054": 0.31560876965522766, "24269": 1.1249549388885498, "24278": 0.06337817758321762, "24312": 0.3956514894962311, "24345": 0.11343330889940262, "24701": 0.17759032547473907, "24879": 0.11691460013389587, "24972": 1.102510929107666, "25117": 0.24631060659885406, "25456": 0.05417001247406006, "25714": 0.5898461937904358, "25950": 0.08782484382390976, "26394": 0.0317181795835495, "26402": 0.19220098853111267, "26520": 0.10818854719400406, "26773": 0.1808556467294693, "27235": 1.108330488204956, "27521": 1.8136534690856934, "27777": 0.045809537172317505, "27846": 0.04767346754670143, "27854": 0.3499138653278351, "28424": 0.48430517315864563, "28691": 0.2741633653640747, "29197": 0.9958525896072388}
|
26104554
|
Membrane fission is a fundamental step in membrane transport. So far, the only fission protein machinery that has been implicated in in vivo transport involves dynamin, and functions in several, but not all, transport pathways. Thus, other fission machineries may exist. Here, we report that carboxy-terminal binding protein 3/brefeldin A-ribosylated substrate (CtBP3/BARS) controls fission in basolateral transport from the Golgi to the plasma membrane and in fluid-phase endocytosis, whereas dynamin is not involved in these steps. Conversely, CtBP3/BARS protein is inactive in apical transport to the plasma membrane and in receptor-mediated endocytosis, both steps being controlled by dynamin. This indicates that CtBP3/BARS controls membrane fission in endocytic and exocytic transport pathways, distinct from those that require dynamin.
|
CtBP3/BARS drives membrane fission in dynamin-independent transport pathways
|
{"1037": 0.6543170213699341, "2002": 0.4500300884246826, "2003": 0.10993985831737518, "2005": 0.022212404757738113, "2007": 0.016465263441205025, "2012": 0.2852376699447632, "2018": 0.022212404757738113, "2026": 1.0382318496704102, "2031": 0.03925827145576477, "2033": 0.2223619967699051, "2034": 0.5990082025527954, "2040": 0.006812678650021553, "2043": 0.02887592278420925, "2044": 0.151916041970253, "2050": 0.05139094591140747, "2064": 0.22079704701900482, "2065": 0.018384648486971855, "2071": 0.23479416966438293, "2076": 0.6254787445068359, "2089": 0.10993985831737518, "2096": 0.13670019805431366, "2111": 0.013579257763922215, "2114": 0.12986256182193756, "2124": 0.2105647772550583, "2138": 0.08513788133859634, "2152": 0.10993985831737518, "2161": 0.48610860109329224, "2217": 0.12642613053321838, "2302": 0.07068414986133575, "2313": 0.04113444685935974, "2339": 0.4190443754196167, "2363": 0.6603899002075195, "2445": 0.02316705882549286, "2483": 0.004870930220931768, "2515": 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0.27044451236724854, "7539": 0.27786844968795776, "7654": 0.04394211992621422, "7799": 1.0788878202438354, "7865": 0.9568626880645752, "7870": 0.5762182474136353, "8030": 0.08064348995685577, "8146": 0.007782140281051397, "8171": 0.42225050926208496, "8211": 0.9470623731613159, "8267": 0.24018502235412598, "8319": 0.11430477350950241, "8701": 0.0842406153678894, "8715": 0.08782484382390976, "8729": 0.2918238639831543, "8767": 0.022212404757738113, "8985": 0.9005423784255981, "9016": 0.27342069149017334, "9048": 0.4580921530723572, "9223": 0.03360854089260101, "9280": 0.09406650811433792, "9323": 0.6451379656791687, "9513": 0.15693697333335876, "9740": 0.17431432008743286, "9820": 0.02316705882549286, "9878": 0.5685047507286072, "10047": 0.6275664567947388, "10285": 0.12556517124176025, "10327": 0.11081436276435852, "10372": 0.20421554148197174, "10548": 0.16359257698059082, "10723": 0.058784693479537964, "10831": 0.7201237678527832, "11016": 0.021256839856505394, "11251": 0.0752234235405922, "11290": 1.190008521080017, "11311": 0.2674594223499298, "11595": 0.7047978043556213, "11860": 0.1401015669107437, "11888": 0.8281423449516296, "12353": 0.06337817758321762, "12436": 0.4158279001712799, "12763": 0.8169882297515869, "13047": 0.2539152204990387, "13070": 0.1873544454574585, "13072": 0.18411032855510712, "13075": 0.0019512200960889459, "13191": 0.18167030811309814, "13341": 0.3916989266872406, "13369": 0.12470348179340363, "13434": 0.6902132034301758, "13445": 0.755608320236206, "13706": 0.5718178153038025, "13868": 0.14433705806732178, "14120": 0.18492233753204346, "14234": 0.1693800985813141, "14454": 0.08603433519601822, "14667": 0.2516399025917053, "14693": 1.0423725843429565, "15009": 0.5795059204101562, "15245": 0.7601850032806396, "15403": 0.0842406153678894, "15556": 0.21687394380569458, "15559": 0.09584271162748337, "15900": 0.21135559678077698, "15928": 0.07068414986133575, "15991": 1.02149498462677, "16149": 0.12814582884311676, "16215": 0.083342544734478, "16263": 0.15359249711036682, "16514": 0.6502478122711182, "16670": 0.04860413447022438, "16796": 0.08513788133859634, "17080": 1.0553730726242065, "17252": 0.12986256182193756, "17404": 1.0695481300354004, "17631": 0.05046287178993225, "17678": 0.7172679901123047, "17843": 0.7134475708007812, "18002": 0.5568217039108276, "18130": 0.7067264318466187, "18178": 1.181056022644043, "18191": 0.8941729068756104, "18583": 0.5104349255561829, "18891": 0.2800849378108978, "18906": 0.052318159490823746, "19003": 0.0317181795835495, "19188": 0.24325250089168549, "19340": 0.2954642176628113, "19802": 0.029824240133166313, "19857": 1.2808253765106201, "20110": 0.4812922179698944, "20187": 0.07793712615966797, "20502": 0.00875066313892603, "20523": 0.42225050926208496, "20992": 0.07612881064414978, "21150": 0.015504186972975731, "21281": 0.9178520441055298, "21357": 0.3601844012737274, "21454": 0.16442140936851501, "21557": 1.1185935735702515, "21572": 0.6027565002441406, "21733": 0.043007105588912964, "22160": 0.7791815400123596, "22291": 1.5398868322372437, "22318": 0.0606246218085289, "23041": 0.9621002674102783, "23350": 0.24631060659885406, "23854": 0.23092569410800934, "24093": 0.9432673454284668, "24129": 0.32270604372024536, "24163": 0.0770333781838417, "24260": 0.5301685929298401, "24395": 0.3676496744155884, "24442": 1.4487555027008057, "24479": 0.2741633653640747, "24755": 1.0326838493347168, "24757": 0.24325250089168549, "24952": 0.09406650811433792, "25070": 0.2837681770324707, "25121": 0.05694137513637543, "25360": 0.00875066313892603, "25714": 0.1384023278951645, "25765": 0.347847044467926, "25778": 0.09672962874174118, "25969": 0.21687394380569458, "26013": 0.3262358605861664, "26206": 0.1384023278951645, "26478": 0.0606246218085289, "26778": 0.9052929878234863, "26835": 0.4487839937210083, "27144": 0.969535231590271, "27159": 0.22937409579753876, "27395": 0.0058422754518687725, "27484": 0.8074519634246826, "27528": 0.02412080205976963, "28389": 0.4818955361843109, "28775": 0.045809537172317505, "28804": 0.9994535446166992, "28873": 0.04487626627087593, "28896": 1.0815403461456299, "29361": 0.009718249551951885, "29598": 0.8583967685699463}
|
26105746
|
Solid organ transplant recipients receiving chronic immunosuppressive agents are at increased risk to acquire influenza virus despite vaccination. Myocarditis is a known but rare complication of influenza infection. We present the first adult liver transplant recipient who received prophylactic vaccination but developed influenza A myocarditis. This may occur in solid organ transplant recipients, because they have reduced response to protein vaccines, which may leave them vulnerable to infections. Studies are needed to evaluate if antiviral chemoprophylaxis in solid organ transplant recipients during influenza season would be an effective preventive therapy against influenza in this high-risk population.
|
Influenza A myocarditis developing in an adult liver transplant recipient despite vaccination: a case report and review of the literature.
|
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26107000
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RATIONALE Physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD). COPD has a systemic component that includes significant extrapulmonary effects that may contribute to its severity in individual patients. OBJECTIVES To investigate the association of extrapulmonary effects of the disease and its comorbidities with reduced physical activity in patients with COPD. METHODS In a cross-sectional study, 170 outpatients with COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages I-IV; BODE [body mass index, airway obstruction, dyspnea, and exercise capacity] score 0-10) underwent a series of tests. Physical activity was assessed over 5 to 6 consecutive days by using a multisensor accelerometer armband that records steps per day and the physical activity level (total daily energy expenditure divided by whole-night sleeping energy expenditure). Cardiovascular status was assessed by echocardiography, vascular Doppler sonography, and levels of N-terminal pro-B-type natriuretic peptide. Mental status, metabolic/muscular status, systemic inflammation, and anemia were assessed by Beck Depression Inventory, bioelectrical impedance analysis, handgrip strength, high-sensitivity C-reactive protein/fibrinogen, and hemoglobin, respectively. MEASUREMENTS AND MAIN RESULTS In a multivariate linear regression analysis using either steps per day or physical activity level as a dependent variable, the extrapulmonary parameters that were associated with reduced physical activity in patients with COPD independently of GOLD stages or BODE score were N-terminal pro-B-type natriuretic peptide levels, echocardiographically measured left ventricular diastolic function, and systemic inflammation. CONCLUSIONS Higher values of systemic inflammation and left cardiac dysfunction are associated with reduced physical activity in patients with COPD.
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Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study.
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26108767
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Linking the heavy chain (HC) and light chain (LC) genes required for monoclonal antibodies (mAb) production on a single cassette using 2A peptides allows control of LC and HC ratio and reduces non-expressing cells. Four 2A peptides derived from the foot-and-mouth disease virus (F2A), equine rhinitis A virus (E2A), porcine teschovirus-1 (P2A) and Thosea asigna virus (T2A), respectively, were compared for expression of 3 biosimilar IgG1 mAbs in Chinese hamster ovary (CHO) cell lines. HC and LC were linked by different 2A peptides both in the absence and presence of GSG linkers. Insertion of a furin recognition site upstream of 2A allowed removal of 2A residues that would otherwise be attached to the HC. Different 2A peptides exhibited different cleavage efficiencies that correlated to the mAb expression level. The relative cleavage efficiency of each 2A peptide remains similar for expression of different IgG1 mAbs in different CHO cells. While complete cleavage was not observed for any of the 2A peptides, GSG linkers did enhance the cleavage efficiency and thus the mAb expression level. T2A with the GSG linker (GT2A) exhibited the highest cleavage efficiency and mAb expression level. Stably amplified CHO DG44 pools generated using GT2A had titers 357, 416 and 600 mg/L for the 3 mAbs in shake flask batch cultures. Incomplete cleavage likely resulted in incorrectly processed mAb species and aggregates, which were removed with a chromatin-directed clarification method and protein A purification. The vector and methods presented provide an easy process beneficial for both mAb development and manufacturing.
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Cleavage efficient 2A peptides for high level monoclonal antibody expression in CHO cells.
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26112624
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Mature ribosomal RNAs (rRNAs) are produced from polycistronic precursors following complex processing. Precursor (pre)-rRNA processing has been extensively characterized in yeast and was assumed to be conserved in humans. We functionally characterized 625 nucleolar proteins in HeLa cells and identified 286 required for processing, including 74 without a yeast homolog. For selected candidates, we demonstrated that pre-rRNA processing defects are conserved in different cell types (including primary cells), defects are not due to activation of a p53-dependent nucleolar tumor surveillance pathway, and they precede cell-cycle arrest and apoptosis. We also investigated the exosome's role in processing internal transcribed spacers (ITSs) and report that 3' end maturation of 18S rRNA involves EXOSC10/Rrp6, a yeast ITS2 processing factor. We conclude that human cells adopt unique strategies and recruit distinct trans-acting factors to carry out essential processing steps, posing fundamental implications for understanding ribosomopathies at the molecular level and developing effective therapeutic agents.
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The complexity of human ribosome biogenesis revealed by systematic nucleolar screening of Pre-rRNA processing factors.
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0.08064348995685577, "28847": 0.3381449282169342, "29160": 1.0001721382141113, "29180": 0.23556606471538544, "29347": 0.981317400932312, "29449": 1.035461664199829, "29486": 0.3784096837043762, "29536": 1.3433949947357178}
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26112696
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The purpose of this study was to examine differences in resting, submaximal, and maximal (VO2max) oxygen consumption (VO2) in African-American (n = 44) and Caucasian (n = 31) prepubertal children aged 5-10 yr. Resting VO2 was measured via indirect calorimetry in the fasted state. Submaximal VO2 and VO2max were determined during an all out, progressive treadmill exercise test appropriate for children. Dual-energy X-ray absorptiometry was used to determine total fat mass (FM), soft lean tissue mass (LTM), and leg soft LTM. Doubly labeled water was used to determine total energy expenditure (TEE) and activity energy expenditure (AEE). A significant effect of ethnicity (P < 0.01) was found for VO2max but not resting or submaximal VO2, with African-American children having absolute VO2max approximately 15% lower than Caucasian children (1.21 +/- 0.032 vs. 1.43 +/- 0.031 l/min, respectively). The lower VO2max persisted in African-American children after adjustment for soft LTM (1.23 +/- 0.025 vs. 1.39 +/- 0.031 l/min; P < 0.01), leg soft LTM (1.20 +/- 0.031 vs. 1.43 +/- 0.042 l/min; P < 0.01), and soft LTM and FM (1.23 +/- 0.025 vs. 1.39 +/- 0.031 l/min; P < 0.01). The lower VO2max persisted also after adjustment for TEE (1.20 +/- 0.02 vs. 1.38 +/- 0.0028 l/min P < 0.001) and AEE (1.20 +/- 0.024 vs. 1.38 +/- 0.028 l/min; P < 0.001). In conclusion, our data indicate that African-American and Caucasian children have similar rates of VO2 at rest and during submaximal exercise, but VO2max is approximately 15% lower in African-American children, independent of soft LTM, FM, leg LTM, TEE, and AEE.
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Maximal aerobic capacity in African-American and Caucasian prepubertal children.
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"28727": 1.7956581115722656, "28873": 0.08513788133859634, "28896": 0.23092569410800934, "29003": 0.12642613053321838}
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26117607
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Down syndrome cell adhesion molecule (Dscam) seems likely to play a key role in the "alternative adaptive immunity" that has been reported in invertebrates. Dscam consists of a cytoplasmic tail that is involved in signal transduction and a hypervariable extracellular region that might use a pathogen recognition mechanism similar to that used by the vertebrate antibodies. In our previous paper, we isolated a unique tail-less form of Dscam from Litopenaeus vannamei. In this study, we report the first membrane-bound form of shrimp Dscam: PmDscam was isolated from Penaeus monodon, and it occurred in both membrane-bound and tail-less forms. Phylogenetic analysis showed that while the crustacean Dscams from shrimp and water flea did not share a single subclade, they were distinct from the invertebrate Dscam-like molecules and from the insecta Dscams. In the extracellular region, the variable regions of PmDscam were located in N-terminal Ig2, N-terminal Ig3 and the entire Ig7 domain. The PmDscam extracellular variants and transmembrane domain variants were produced by mutually exclusive alternative splicing events. The cytoplasmic tail variants were produced by exon inclusion/exclusion. Based on the genomic organization of Daphnia Dscam's cytoplasmic tail, we propose a model of how the shrimp Dscam genomic locus might use Type III polyadenylation to generate both the tail-less and membrane-bound forms.
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Penaeus monodon Dscam (PmDscam) has a highly diverse cytoplasmic tail and is the first membrane-bound shrimp Dscam to be reported.
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26118532
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Demonstration of the existence of G-quadruplex structures in telomeres of Stylonychia macronuclei and in the promoter of c-myc in human cells has validated these secondary DNA structures as potential targets for drug design. The next important issue is the selectivity of G-quadruplex-interactive agents for the different types of G-quadruplex structures. In this study, we have taken an important step in associating specific biological effects of these drugs with selective interaction with either intermolecular or intramolecular G-quadruplex structures formed in telomeres. Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor through its G-quadruplex interaction. We have demonstrated that telomestatin interacts preferentially with intramolecular versus intermolecular G-quadruplex structures and also has a 70-fold selectivity for intramolecular G-quadruplex structures over duplex DNA. Telomestatin is able to stabilize G-quadruplex structures that are formed from duplex human telomeric DNA as well as from single-stranded DNA. Importantly, telomestatin stabilizes these G-quadruplex structures in the absence of monovalent cations, which is a unique characteristic among G-quadruplex-interactive compounds. At noncytotoxic concentrations, telomestatin suppresses the proliferation of telomerase-positive cells within several weeks. In contrast, TMPyP4, a compound that preferentially facilitates the formation of intermolecular G-quadruplex structures, suppresses the proliferation of alternative lengthening of telomeres (ALT)-positive cells as well as telomerase-positive cells. We have also demonstrated that TMPyP4 induces anaphase bridges in sea urchin embryos, whereas telomestatin did not have this effect, leading us to conclude that the selectivity of telomestatin for intramolecular G-quadruplex structures and TMPyP4 for intermolecular G-quadruplex structures is important in mediating different biological effects: stabilization of intramolecular G-quadruplex structures produces telomerase inhibition and accelerated telomere shortening, whereas facilitation of the formation of intermolecular G-quadruplex structures induces the formation of anaphase bridges.
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The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures.
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INTRODUCTION Endometriosis affects 10% of women of reproductive age. It is defined as the presence of implanted active endometrial tissue outside the uterine cavity. The exact pathophysiology of endometriosis is still uncertain, although several optional etiological theories have been suggested. Being so common, a novel treatment for endometriosis is widely quested. Recent studies addressing the pathological characteristics of endometriosis have revealed a vicious cycle in which oxidative stress (OS) is generated, which in turn facilitates the implantation of the ectopic endometrium. At the same time, the generation of high amounts of reactive oxygen species further triggers a state of OS. AREAS COVERED The author examined the evidence associating OS and endometriosis. After establishing an association, a search for antioxidant agents that were investigated specifically on endometriosis patients are described including Vitamins C and E, melatonin, resveratrol, xanthohumol and epigallocatechin-3-gallate. A significant effect of all the reviewed antioxidants on endometriosis is reported. EXPERT OPINION Aiming for the reduction of OS as the treatment goal for endometriosis looks promising. However, since most of the studies are either in vitro or are animal based, further studies on human subjects are deemed necessary to elucidate the impact of OS reduction on patients with endometriosis.
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Targeting oxidative stress to treat endometriosis.
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0.46853771805763245, "23900": 0.25088030099868774, "24093": 0.08513788133859634, "24335": 0.5313173532485962, "24396": 0.04394211992621422, "24868": 0.015504186972975731, "24879": 0.0019512200960889459, "24952": 0.2954642176628113, "25229": 0.4531385898590088, "25481": 0.06612417846918106, "25608": 0.7445381283760071, "25714": 0.1358480453491211, "25969": 0.31560876965522766, "26013": 0.30558720231056213, "26163": 0.7408206462860107, "26236": 0.29473719000816345, "26358": 0.848413348197937, "26651": 0.4512746334075928, "26721": 0.0009760859538801014, "26835": 0.29981520771980286, "27144": 0.2447827309370041, "27152": 0.004870930220931768, "27354": 0.06886265426874161, "27709": 0.9739698171615601, "28155": 0.13499516248703003, "28203": 0.13670019805431366, "28389": 1.553198218345642, "28436": 0.0797421783208847, "28578": 0.9769153594970703, "28788": 0.4709797203540802, "28848": 0.3784096837043762, "28873": 0.06429435312747955, "28896": 0.04487626627087593, "29125": 0.9613537192344666, "29251": 0.8366385698318481, "29458": 0.66441810131073, "29494": 0.04394211992621422, "29592": 0.026025565341114998}
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26124606
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Liver disease secondary to hepatitis C virus (HCV) infection is a rising cause of morbidity and mortality among individuals who have been infected parenterally with human immunodeficiency virus (HIV) such as injection drug users, hemophiliacs, and transfused patients. We analyzed both the efficacy of interferon (IFN) alpha therapy in these patients and the predictors of response to this agent. A total of 119 patients with chronic hepatitis C (90 of whom were infected with HIV and 29 of whom were not) were included in a multicenter, prospective, open, nonrandomized observational study. IFN-alpha was given subcutaneously in a dosage of 5 million units three times a week during a 3-month period; those patients who responded received a dose of 3 million units given subcutaneously three times a week for an additional 9 months. One hundred seven patients completed the study; the level of aminotransferases returned to normal and sera became negative (complete response) for HCV RNA in 26 (32.5%) of 80 HIV-infected patients and 10 (37.0%) of 27 non-HIV-infected patients (P = .666) after completion of the treatment. Two variables were independently associated with a response in HIV-infected patients: a CD4+ T lymphocyte count of > 500 x 10(6)/L and a baseline HCV viremia level of < 10(7) copies/mL. In the 12 months following treatment, relapses occurred in 30.8% of the HIV-infected patients and 12.5% of non-HIV-infected patients (P = .403).
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Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Hepatitis-HIV Spanish Study Group.
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0.016465263441205025, "19470": 0.025073638185858727, "19476": 0.19622190296649933, "19699": 0.010684899985790253, "19731": 0.960606575012207, "20166": 0.09938567131757736, "20467": 0.28155985474586487, "20569": 0.3622259199619293, "20792": 0.29255300760269165, "21031": 0.5489565134048462, "21449": 1.4633277654647827, "21700": 1.2732000350952148, "21709": 0.08154398202896118, "21716": 0.004870930220931768, "22014": 0.034552380442619324, "22049": 0.0038986403960734606, "22458": 0.20102575421333313, "22520": 1.3489859104156494, "22574": 0.06520967930555344, "22935": 0.21530038118362427, "23130": 0.03925827145576477, "23150": 0.12470348179340363, "23238": 0.8366385698318481, "23438": 0.16276304423809052, "23496": 0.12642613053321838, "23633": 0.3982778787612915, "23828": 0.015504186972975731, "24117": 0.04487626627087593, "24534": 0.3930181860923767, "24848": 0.24018502235412598, "24979": 0.1889725625514984, "25032": 0.34577593207359314, "25543": 0.2089812457561493, "25887": 0.42225050926208496, "25957": 0.02316705882549286, "25990": 0.0606246218085289, "26456": 1.4283655881881714, "26535": 0.07884006202220917, "26745": 0.2026219218969345, "26835": 0.14264501631259918, "27011": 1.3393092155456543, "27023": 0.06520967930555344, "27109": 0.03831886500120163, "27312": 0.14349138736724854, "27339": 0.0770333781838417, "27404": 0.4067663550376892, "27500": 0.17431432008743286, "27532": 0.07612881064414978, "27843": 0.37035053968429565, "27906": 0.02316705882549286, "28246": 0.18654440343379974, "28487": 0.5027855634689331, "28507": 0.1889725625514984, "28828": 0.22782009840011597, "28879": 0.24248650670051575, "28915": 0.3864043951034546, "29166": 0.12556517124176025, "29212": 0.2969166338443756, "29278": 0.46117570996284485, "29347": 0.9576126337051392, "29477": 0.15526613593101501}
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26132041
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Recent population-based studies have suggested that migraine is a risk factor for the development of infarct-like lesions in the territory of the posterior circulation. These lesions are thought to be true vascular infarcts based on their size, location and magnetic resonance imaging (MRI) characteristics. However, as there are no postmortem studies identifying the pathology of these MRI findings, their true aetiology is unknown. A case patient with migraine is presented, who developed what appeared to be cerebellar infarcts on MRI, but these lesions vanished on repeat imaging 16 days later, questioning their aetiology as vascular ischaemic based infarcts.
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Vanishing cerebellar infarcts in a migraine patient.
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26133404
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Human cytomegalovirus (CMV) establishes latent infections in hematopoietic cells such as granulocyte-macrophage progenitors (GM-Ps). During latency the virus is sequestered in a nonreplicating state, although limited transcriptional activity has been previously reported. In this study we sought to further examine viral gene expression during the latent phase of infection. Using an experimental model of latency, primary human GM-Ps were latently infected with CMV strain Toledo and extracted RNA subjected to reverse transcription-PCR by using CMV gene-specific primers. Using this approach, we detected transcription from the UL111.5A region of the viral genome. This transcription was also detected in GM-Ps latently infected with AD169 and Towne strains, indicating that expression was CMV strain independent. Significantly, we detected UL111.5A-region transcripts in mononuclear cells from healthy bone marrow and mobilized peripheral blood allograft donors, demonstrating expression during natural latent infection. Mapping experiments with RNA extracted from latently infected GM-Ps revealed the expression of a novel UL111.5A region transcript with a splicing pattern that differed from that reported during productive infection of permissive cells. This UL111.5A region transcript expressed during latent infection is predicted to encode a 139-amino-acid protein with homology to the potent immunosuppressor interleukin-10 (IL-10) and to the viral IL-10 homolog that is expressed during productive CMV infection. Expression of a latency-associated cmvIL-10 may confer upon the virus an ability to avoid immune recognition and clearance during the latent phase of infection.
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A novel viral transcript with homology to human interleukin-10 is expressed during latent human cytomegalovirus infection.
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26150367
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Somnambulism, or sleepwalking, is a parasomnia of non-rapid eye movement (NREM) sleep where movement behaviours usually confined to wakefulness are displayed during sleep. Generally, if sleepwalking is causing distress or danger in spite of safety measures, medical or psychological treatment is indicated. Clinicians will need to assess the evidence for treatment options. MEDLINE, EMBASE, PsycINFO and the Ovid Evidence-Based Medicine Reviews (EBM) multifile databases were searched. No properly powered rigorous controlled trials were found for treatment of sleepwalking in adults. Seven reports described small trials with some kind of control arm, or retrospective case series which included 30 or more patients. With no high quality evidence to underpin recommendations for treatments of somnambulism, full discussion with patients is advised. Adequately powered, well-designed clinical trials are now needed, and multi-centre collaborations may be required to obtain the sample sizes required.
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Treatments for somnambulism in adults: assessing the evidence.
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26182390
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Premature chromosome condensation (PCC) was studied in direct preparations of tissues from patients with haematological diseases and carcinomas of various histological types. PCC was found in 6 out of 166 malignancies (128 haematological cases, 35 carcinomas and 3 malignant effusions) analysed with the GTG-technique. Chromosome analysis revealed S-phase and G1-phase PCC in each case; the frequency of PCC varied between 1, 4 and 8.6% of the metaphases analysed. It is suggested that PCC chromosomes, which represent cell fusion in vivo, are not very rare in naturally-occurring human malignancies, and that cell fusion may affect the malignant phenotype. In conjunction with other factors they may also explain the heterogeneity of tumour cell populations.
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Premature chromosome condensation: evidence for in vivo cell fusion in human malignant tumours.
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"18586": 0.0770333781838417, "18622": 0.04767346754670143, "18714": 0.08692999184131622, "18804": 0.8682814836502075, "18809": 0.01934296265244484, "19064": 0.1751343309879303, "19205": 0.9447870850563049, "19209": 0.23092569410800934, "19389": 0.06520967930555344, "19554": 0.10026945173740387, "19804": 0.0058422754518687725, "19960": 0.27342069149017334, "20110": 0.255429208278656, "20118": 0.09495500475168228, "20302": 0.2247048318386078, "20350": 0.040196798741817474, "20409": 0.0174254160374403, "20480": 0.043007105588912964, "20502": 0.06246116757392883, "20704": 0.040196798741817474, "20828": 0.05970508232712746, "20900": 0.03360854089260101, "20939": 0.045809537172317505, "20992": 0.5209306478500366, "21150": 0.39367714524269104, "21903": 0.1485546976327896, "22329": 0.8764448165893555, "22571": 0.06429435312747955, "22597": 0.14939609169960022, "22930": 0.11168810725212097, "22963": 0.2990913391113281, "23208": 0.034552380442619324, "23274": 0.5127768516540527, "23284": 0.0354953333735466, "23467": 0.4374985992908478, "23572": 0.2160874605178833, "23586": 0.6578640341758728, "23683": 0.38041436672210693, "23713": 0.030771657824516296, "23760": 0.7728893756866455, "23900": 0.18978065252304077, "23971": 0.2531573474407196, "24054": 1.2398450374603271, "24096": 0.009718249551951885, "24137": 0.07159364968538284, "24203": 0.4980490207672119, "24353": 0.11081436276435852, "24840": 0.05786345899105072, "25002": 0.02887592278420925, "25185": 0.9225212931632996, "25276": 0.49626702070236206, "25456": 1.1121915578842163, "25604": 0.05970508232712746, "25708": 0.021256839856505394, "25808": 0.7546905279159546, "25947": 0.043007105588912964, "26113": 0.8323994874954224, "26402": 0.6107416749000549, "26462": 0.5255602598190308, "26721": 0.04394211992621422, "26837": 0.05970508232712746, "27484": 0.33675122261047363, "27756": 0.24554696679115295, "27896": 0.20580662786960602, "28163": 0.12038381397724152, "28436": 0.012615402229130268, "28517": 0.28450319170951843, "28648": 0.08064348995685577, "28767": 0.16607704758644104, "28835": 0.06154331564903259, "29048": 0.8989537954330444, "29235": 0.19381128251552582, "29398": 0.04767346754670143}
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26199970
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Objective: It is unclear whether blockade of the angiotensin system has effects on mental health. Our objective was to determine the impact of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor (AT1R) blockers on mental health domain of quality of life. Study design: Meta-analysis of published literature. Data sources: PubMed and clinicaltrials.gov databases. The last search was conducted in January 2017. Study selection: Randomized controlled trials comparing any angiotensin converting enzyme inhibitor or AT1R blocker versus placebo or non-angiotensin converting enzyme inhibitor or non-AT1R blocker were selected. Study participants were adults without any major physical symptoms. We adhered to meta-analysis reporting methods as per PRISMA and the Cochrane Collaboration. Data synthesis: Eleven studies were included in the analysis. When compared with placebo or other antihypertensive medications, AT1R blockers and angiotensin converting enzyme inhibitors were associated with improved overall quality of life (standard mean difference = 0.11, 95% confidence interval = [0.08, 0.14], p < 0.0001), positive wellbeing (standard mean difference = 0.11, 95% confidence interval = [0.05, 0.17], p < 0.0001), mental (standard mean difference = 0.15, 95% confidence interval = [0.06, 0.25], p < 0.0001), and anxiety (standard mean difference = 0.08, 95% confidence interval = [0.01, 0.16], p < 0.0001) domains of QoL. No significant difference was found for the depression domain (standard mean difference = 0.05, 95% confidence interval = [0.02, 0.12], p = 0.15). Conclusions: Use of angiotensin blockers and inhibitors for the treatment of hypertension in otherwise healthy adults is associated with improved mental health domains of quality of life. Mental health quality of life was a secondary outcome in the included studies. Research specifically designed to analyse the usefulness of drugs that block the angiotensin system is necessary to properly evaluate this novel psychiatric target.
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Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials
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0.015504186972975731, "20299": 0.5313173532485962, "20467": 0.04487626627087593, "20506": 1.0587663650512695, "20569": 0.04207121208310127, "20792": 0.8195732831954956, "20806": 0.014542185701429844, "20875": 0.4311734735965729, "21223": 0.036437395960092545, "21346": 0.016465263441205025, "21499": 0.1913948506116867, "21733": 0.8989537954330444, "21901": 0.5063233375549316, "22026": 0.058784693479537964, "22031": 0.034552380442619324, "22490": 0.15023678541183472, "22552": 0.38441169261932373, "22931": 0.472198486328125, "23021": 0.18492233753204346, "23041": 1.0742288827896118, "23260": 0.004870930220931768, "23900": 0.1332872211933136, "23924": 0.23633737862110138, "24163": 0.8861536383628845, "24335": 0.09317722171545029, "24552": 0.083342544734478, "24558": 0.04674193635582924, "24757": 0.0913962796330452, "24759": 0.21922965347766876, "24826": 0.08603433519601822, "25003": 1.0979610681533813, "25524": 0.1384023278951645, "25605": 0.10731173306703568, "25737": 0.11081436276435852, "25761": 0.03360854089260101, "26014": 0.7537717819213867, "26118": 0.38174858689308167, "26451": 0.5865923762321472, "26462": 0.014542185701429844, "26835": 0.1485546976327896, "27598": 0.44753631949424744, "27781": 0.176772341132164, "28466": 0.05139094591140747, "28767": 0.31132611632347107, "28788": 0.07884006202220917, "28828": 0.06977381557226181, "28873": 0.42096930742263794, "28896": 0.22001366317272186, "28964": 0.42926809191703796, "29172": 0.009718249551951885, "29206": 1.3305710554122925, "29320": 1.2797396183013916}
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26230669
|
The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low-grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here, we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.
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The role of epigenetics in aging and autoimmunity.
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26231129
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Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer. However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.
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A framework for understanding and targeting residual disease in oncogene-driven solid cancers
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26244918
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We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.
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Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer's prone mice.
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"16803": 0.659380316734314, "16882": 0.24248650670051575, "16991": 0.4337083101272583, "17367": 0.44691193103790283, "17578": 0.319873183965683, "17788": 0.2969166338443756, "17908": 0.2447827309370041, "17914": 0.21765978634357452, "17975": 0.2247048318386078, "18053": 0.2918238639831543, "18084": 0.3910386264324188, "18089": 0.07159364968538284, "18276": 0.12814582884311676, "18345": 0.23787821829319, "18600": 0.02412080205976963, "19003": 0.33115679025650024, "19101": 0.010684899985790253, "19137": 0.24171993136405945, "19160": 0.0354953333735466, "19202": 0.5882205963134766, "19476": 0.15860503911972046, "19481": 1.292691707611084, "19535": 0.20580662786960602, "19587": 0.04113444685935974, "19601": 0.4974553883075714, "19818": 0.46853771805763245, "19872": 0.4837033152580261, "19882": 0.2478361576795578, "19961": 0.2852376699447632, "20228": 0.12814582884311676, "20363": 0.0606246218085289, "20710": 0.05417001247406006, "20817": 0.861702561378479, "20886": 0.11517547070980072, "21486": 0.20739519596099854, "21619": 0.14518201351165771, "21755": 0.32129061222076416, "21890": 0.8567397594451904, "21903": 0.1677299439907074, "21972": 0.004870930220931768, "22022": 0.4196864068508148, "22248": 0.11778303235769272, "22264": 0.15943801403045654, "22394": 0.18167030811309814, "22476": 0.23402166366577148, "22644": 0.8433839678764343, "22694": 0.14349138736724854, "22806": 0.1510767638683319, "22869": 0.9724938273429871, "22932": 0.1808556467294693, "23079": 1.2599912881851196, "23247": 0.7987030148506165, "23267": 0.1485546976327896, "23352": 0.1718502640724182, "23463": 0.10818854719400406, "23499": 0.3262358605861664, "23725": 0.016465263441205025, "23892": 0.00875066313892603, "23951": 0.20739519596099854, "24137": 0.7220231294631958, "24171": 0.3499138653278351, "24312": 0.10818854719400406, "24314": 0.22079704701900482, "24345": 0.03831886500120163, "24434": 0.2317005842924118, "24569": 0.14349138736724854, "24972": 1.2035820484161377, "25722": 0.16359257698059082, "25950": 0.034552380442619324, "26122": 0.4818955361843109, "26134": 0.03831886500120163, "26187": 0.1619328260421753, "26244": 0.18492233753204346, "26288": 0.009718249551951885, "26384": 0.17267228662967682, "26572": 0.09672962874174118, "26646": 0.03360854089260101, "27059": 0.22782009840011597, "27169": 0.2969166338443756, "27777": 0.2539152204990387, "27846": 0.09938567131757736, "27854": 0.13925230503082275, "27998": 0.7898768186569214, "28007": 0.029824240133166313, "28144": 0.176772341132164, "28433": 0.036437395960092545, "28570": 0.02412080205976963, "28691": 0.013579257763922215, "29060": 0.5069117546081543}
|
26283293
|
Eukaryotic cells are compartmentalized into membrane-bounded organelles whose functions rely on lipid trafficking to achieve membrane-specific compositions of lipids. Here we focused on the Ups1-Mdm35 system, which mediates phosphatidic acid (PA) transfer between the outer and inner mitochondrial membranes, and determined the X-ray structures of Mdm35 and Ups1-Mdm35 with and without PA. The Ups1-Mdm35 complex constitutes a single domain that has a deep pocket and flexible Ω-loop lid. Structure-based mutational analyses revealed that a basic residue at the pocket bottom and the Ω-loop lid are important for PA extraction from the membrane following Ups1 binding. Ups1 binding to the membrane is enhanced by the dissociation of Mdm35. We also show that basic residues around the pocket entrance are important for Ups1 binding to the membrane and PA extraction. These results provide a structural basis for understanding the mechanism of PA transfer between mitochondrial membranes.
|
Structural and mechanistic insights into phospholipid transfer by Ups1–Mdm35 in mitochondria
|
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0.09850110858678818, "2590": 0.5301685929298401, "2693": 0.6280876994132996, "2832": 0.02887592278420925, "2891": 0.006812678650021553, "2895": 0.4041621685028076, "2920": 0.28670501708984375, "2929": 0.10993985831737518, "3048": 0.46608972549438477, "3145": 0.47463157773017883, "3161": 0.176772341132164, "3248": 0.29619070887565613, "3302": 0.8748174905776978, "3366": 0.3106105625629425, "3372": 0.0029254043474793434, "3378": 0.040196798741817474, "3391": 0.04674193635582924, "3433": 0.3601844012737274, "3466": 0.3304552733898163, "3526": 0.9980146884918213, "3594": 0.16524957120418549, "3604": 0.28082266449928284, "3625": 0.21765978634357452, "3665": 0.43623676896095276, "3688": 0.02792670577764511, "3747": 0.49864232540130615, "3772": 0.3339579105377197, "3800": 0.2983669638633728, "3853": 0.4337083101272583, "3881": 0.1693800985813141, "3896": 0.1718502640724182, "3930": 0.7500885725021362, "3949": 0.07884006202220917, "4005": 0.4374985992908478, "4009": 0.7445381283760071, "4072": 0.03925827145576477, "4081": 0.34300774335861206, "4139": 0.21372433006763458, "4328": 0.1212492436170578, "4395": 0.6244332790374756, "4442": 1.0471819639205933, "4456": 0.46853771805763245, "4490": 0.4855078160762787, "4506": 0.20660123229026794, "4539": 0.004870930220931768, "4567": 0.058784693479537964, "4621": 0.11343330889940262, "4651": 0.2223619967699051, "4712": 0.0019512200960889459, "4742": 0.5186077356338501, "4748": 0.5506471395492554, "4757": 0.29400965571403503, "4758": 0.004870930220931768, "4801": 0.11604541540145874, "4815": 0.35813871026039124, "4972": 0.29255300760269165, "5059": 0.7881022095680237, "5072": 0.28670501708984375, "5105": 0.06337817758321762, "5197": 0.2983669638633728, "5248": 0.48610860109329224, "5250": 0.6989894509315491, "5302": 0.12384103983640671, "5320": 0.013579257763922215, "5326": 0.5255602598190308, "5387": 0.4537591338157654, "5449": 0.16442140936851501, "5668": 0.0009760859538801014, "5794": 0.5506471395492554, "5829": 0.06429435312747955, "5850": 0.07250232994556427, "5876": 0.6011518239974976, "6051": 0.02792670577764511, "6074": 0.4938860833644867, "6083": 0.2763880789279938, "6194": 0.18573370575904846, "6296": 0.2954642176628113, "6309": 0.10906458646059036, "6357": 0.7683706283569336, "6370": 0.2659635543823242, "6487": 0.010684899985790253, "6592": 0.22079704701900482, "6653": 0.20818853378295898, "6666": 0.08244366943836212, "6897": 0.16524957120418549, "6902": 0.11778303235769272, "7013": 0.49864232540130615, "7118": 0.16110190749168396, "7126": 0.037378571927547455, "7137": 0.012615402229130268, "7242": 0.14349138736724854, "7337": 0.39367714524269104, "7366": 0.3409265875816345, "7461": 0.2711893916130066, "7490": 0.17267228662967682, "7521": 0.30558720231056213, "7666": 0.1889725625514984, "7691": 0.06429435312747955, "7694": 0.23556606471538544, "7711": 0.4158279001712799, "7722": 1.4151703119277954, "7755": 0.6598852276802063, "7816": 0.4855078160762787, "8005": 0.23092569410800934, "8092": 0.34577593207359314, "8153": 0.33115679025650024, "8171": 0.8255793452262878, "8249": 0.1384023278951645, "8524": 0.32199856638908386, "8583": 0.15526613593101501, "8710": 0.8195732831954956, "8846": 0.9256220459938049, "8878": 0.2247048318386078, "9005": 0.13670019805431366, "9007": 0.45870962738990784, "9099": 0.306306391954422, "9164": 0.1212492436170578, "9230": 1.276475191116333, "9597": 0.043007105588912964, "9687": 0.08513788133859634, "9699": 0.5162794589996338, "9732": 1.202995777130127, "9891": 0.6950984001159668, "9958": 0.36426326632499695, "9972": 0.57457035779953, "10163": 0.15693697333335876, "10210": 0.1685553640127182, "10327": 0.025073638185858727, "10509": 0.4228905141353607, "10536": 0.083342544734478, "10572": 0.07884006202220917, "10595": 0.13499516248703003, "10737": 0.26446542143821716, "10738": 0.23556606471538544, "10744": 0.11430477350950241, "10769": 0.7276995778083801, "10956": 0.11778303235769272, "11311": 0.8074519634246826, "11636": 0.3339579105377197, "11717": 0.14602625370025635, "11767": 0.3784096837043762, "11835": 0.02316705882549286, "11852": 0.28155985474586487, "12053": 0.11604541540145874, "12141": 0.3910386264324188, "12222": 0.5773153901100159, "12247": 0.12814582884311676, "12540": 0.1011524572968483, "12562": 0.5573811531066895, "12732": 0.09317722171545029, "13103": 0.11430477350950241, "13330": 0.0842406153678894, "13447": 0.630689799785614, "13531": 0.07612881064414978, "13791": 0.2478361576795578, "13833": 0.9710156321525574, "13907": 0.013579257763922215, "13922": 0.28082266449928284, "13978": 0.0354953333735466, "14067": 0.30917787551879883, "14095": 0.1221139207482338, "14449": 0.17020416259765625, "14828": 0.7389566898345947, "15176": 0.7105726003646851, "15403": 0.48008447885513306, "15592": 0.1602703034877777, "15612": 0.026025565341114998, "15680": 0.043007105588912964, "15772": 0.35334911942481995, "15865": 0.10026945173740387, "15923": 0.3339579105377197, "15924": 0.14349138736724854, "16012": 0.04487626627087593, "16285": 0.3353555500507355, "16360": 0.0009760859538801014, "16731": 0.17759032547473907, "16771": 0.2493593990802765, "16836": 0.39762192964553833, "16910": 0.1221139207482338, "16937": 0.04674193635582924, "17201": 0.040196798741817474, "17379": 0.13499516248703003, "17441": 0.03925827145576477, "17771": 0.34577593207359314, "18178": 1.25777268409729, "18344": 0.3084607720375061, "18479": 0.16359257698059082, "18714": 0.12986256182193756, "18938": 0.3923587501049042, "18941": 0.06154331564903259, "19003": 0.04113444685935974, "19220": 0.36426326632499695, "19241": 0.32058215141296387, "19321": 1.0423725843429565, "19421": 0.6118015646934509, "19491": 0.11691460013389587, "19577": 0.10467668622732162, "19601": 0.10993985831737518, "19653": 0.058784693479537964, "19818": 0.025073638185858727, "20350": 0.20818853378295898, "20387": 0.2576959431171417, "20538": 0.0009760859538801014, "20544": 0.1808556467294693, "20731": 0.5584990978240967, "20752": 0.18167030811309814, "20817": 0.09050461649894714, "20858": 0.7845434546470642, "20996": 1.531476378440857, "21471": 1.3346925973892212, "21575": 0.40806588530540466, "21579": 0.7105726003646851, "21618": 0.37907835841178894, "21919": 0.40871503949165344, "22239": 0.20580662786960602, "22262": 0.7583568692207336, "22643": 1.483910083770752, "22648": 0.841701865196228, "22658": 0.20501139760017395, "22780": 0.9702757596969604, "22806": 1.0868242979049683, "23041": 0.1994270235300064, "23060": 0.6348392367362976, "23216": 0.603290855884552, "23586": 0.0058422754518687725, "24054": 0.3019835948944092, "24269": 0.07159364968538284, "24587": 0.08064348995685577, "25194": 0.6212902665138245, "25238": 0.23633737862110138, "25276": 0.14686977863311768, "25354": 0.011650617234408855, "25456": 0.2516399025917053, "25644": 0.2231435477733612, "25870": 0.0913962796330452, "26089": 0.2247048318386078, "26288": 0.040196798741817474, "26402": 0.055094651877880096, "26443": 0.18248429894447327, "26651": 0.12728634476661682, "26773": 0.7701805830001831, "26835": 0.14433705806732178, "27099": 0.013579257763922215, "27144": 0.9842413663864136, "27285": 0.08064348995685577, "27295": 0.32270604372024536, "27444": 0.13243216276168823, "27777": 0.1229778528213501, "28105": 0.18004031479358673, "28166": 0.13414156436920166, "28183": 1.0229004621505737, "28479": 1.6582280397415161, "28636": 0.9170717000961304, "28938": 0.0029254043474793434, "29235": 0.016465263441205025, "29397": 0.6989894509315491}
|
26297042
|
Reactive oxygen species (ROS), particularly hydrogen peroxide, and the proteins that regulate them play important roles in the migration and adhesion of cells. Stimulation of cell surface receptors with growth factors and chemoattractants generates ROS, which relay signals from the cell surface to key signaling proteins inside the cell. ROS act within cells to promote migration and also in nonmigrating cells to influence the behavior of migrating cells. Hydrogen peroxide has also been suggested to act as a chemoattractant in its own right, drawing immune cells to wounds. We discuss recent progress made towards understanding how organisms use ROS, and to what degree they depend on them, during the related processes of cell migration and adhesion.
|
Redox regulation of cell migration and adhesion.
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{"1014": 0.28963330388069153, "1016": 0.0770333781838417, "1017": 0.46424978971481323, "1018": 0.10291612148284912, "1053": 0.9944084882736206, "1513": 0.11168810725212097, "1609": 0.4196864068508148, "2001": 0.13071982562541962, "2004": 0.17840765416622162, "2007": 0.06612417846918106, "2015": 0.7746911644935608, "2020": 0.025073638185858727, "2061": 0.06886265426874161, "2062": 0.12728634476661682, "2080": 0.42353010177612305, "2086": 0.23092569410800934, "2090": 0.26146242022514343, "2093": 0.07159364968538284, "2104": 0.06703783571720123, "2106": 0.03360854089260101, "2109": 0.08692999184131622, "2146": 0.08961215615272522, "2152": 0.10467668622732162, "2168": 0.25467249751091003, "2181": 0.2231435477733612, "2193": 0.6233867406845093, "2291": 0.6096806526184082, "2302": 0.3241194784641266, "2331": 0.40546512603759766, "2340": 0.11691460013389587, "2353": 0.22392450273036957, "2443": 0.02412080205976963, "2478": 0.21214580535888672, "2483": 0.04487626627087593, "2504": 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26314743
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BACKGROUND: A proposed revision of sepsis definitions has abandoned the systemic inflammatory response syndrome (SIRS), defined organ dysfunction as an increase in total Sequential Organ Function Assessment (SOFA) score of ≥ 2, and conceived “qSOFA” (quick SOFA) as a bedside indicator of organ dysfunction. We aimed to (1) determine the prognostic impact of SIRS, (2) compare the diagnostic accuracy of SIRS and qSOFA for organ dysfunction, and (3) compare standard (Sepsis‐2) and revised (Sepsis‐3) definitions for organ dysfunction in ED patients with infection. METHODS: Consecutive ED patients admitted with presumed infection were prospectively enrolled over 3 years. Sufficient observational data were collected to calculate SIRS, qSOFA, SOFA, comorbidity, and mortality. RESULTS: We enrolled 8,871 patients, with SIRS present in 4,176 (47.1%). SIRS was associated with increased risk of organ dysfunction (relative risk [RR] 3.5) and mortality in patients without organ dysfunction (OR 3.2). SIRS and qSOFA showed similar discrimination for organ dysfunction (area under the receiver operating characteristic curve, 0.72 vs 0.73). qSOFA was specific but poorly sensitive for organ dysfunction (96.1% and 29.7%, respectively). Mortality for patients with organ dysfunction was similar for Sepsis‐2 and Sepsis‐3 (12.5% and 11.4%, respectively), although 29% of patients with Sepsis‐3 organ dysfunction did not meet Sepsis‐2 criteria. Increasing numbers of Sepsis‐2 organ system dysfunctions were associated with greater mortality. CONCLUSIONS: SIRS was associated with organ dysfunction and mortality, and abandoning the concept appears premature. A qSOFA score ≥ 2 showed high specificity, but poor sensitivity may limit utility as a bedside screening method. Although mortality for organ dysfunction was comparable between Sepsis‐2 and Sepsis‐3, more prognostic and clinical information is conveyed using Sepsis‐2 regarding number and type of organ dysfunctions. The SOFA score may require recalibration.
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Systemic Inflammatory Response Syndrome, Quick Sequential Organ Function Assessment, and Organ Dysfunction: Insights From a Prospective Database of ED Patients With Infection
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26330861
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Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.
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Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae.
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26336593
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Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.
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Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.
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"19037": 0.009718249551951885, "19064": 0.38041436672210693, "19235": 1.1325355768203735, "19265": 0.33953672647476196, "19319": 0.0354953333735466, "19362": 0.02412080205976963, "19536": 0.48430517315864563, "19629": 0.040196798741817474, "19716": 0.3005385100841522, "19883": 0.41840189695358276, "20098": 0.08154398202896118, "20162": 0.10026945173740387, "20166": 0.15359249711036682, "20350": 0.06429435312747955, "20382": 0.29473719000816345, "20569": 0.12814582884311676, "20576": 0.04860413447022438, "20588": 0.4537591338157654, "20842": 0.14349138736724854, "20871": 0.08513788133859634, "20892": 0.030771657824516296, "21011": 0.37907835841178894, "21150": 0.5069117546081543, "21262": 0.04674193635582924, "21391": 0.05694137513637543, "21572": 0.10906458646059036, "21879": 0.791648268699646, "21887": 0.3304552733898163, "21908": 0.18816383183002472, "21961": 0.09050461649894714, "22010": 0.5139457583427429, "22022": 0.08603433519601822, "22423": 0.23556606471538544, "22663": 0.3615458607673645, "22932": 0.018384648486971855, "22935": 0.6027565002441406, "22963": 0.3923587501049042, "23238": 0.07068414986133575, "23260": 0.3464667797088623, "23278": 0.029824240133166313, "23726": 0.535327672958374, "23900": 0.011650617234408855, "23926": 1.387270450592041, "23969": 0.04207121208310127, "24108": 0.2516399025917053, "24117": 0.02792670577764511, "24335": 0.8459017872810364, "24714": 0.5528968572616577, "24755": 0.5021947622299194, "24840": 0.1905880719423294, "25006": 0.791648268699646, "25022": 0.47402387857437134, "25032": 0.12384103983640671, "25060": 0.03925827145576477, "25070": 0.1718502640724182, "25172": 0.1221139207482338, "25353": 0.5033760666847229, "25455": 0.35950297117233276, "25604": 0.5805994272232056, "26163": 0.33115679025650024, "26187": 0.2317005842924118, "26204": 0.1384023278951645, "26226": 0.0029254043474793434, "26261": 0.2478361576795578, "26462": 0.757441520690918, "26478": 0.037378571927547455, "26557": 0.12384103983640671, "26745": 0.03831886500120163, "26837": 0.4286321699619293, "26906": 0.3963087201118469, "26907": 0.12642613053321838, "26927": 0.19622190296649933, "27009": 0.1229778528213501, "27144": 0.1510767638683319, "27354": 0.055094651877880096, "27377": 0.08782484382390976, "27480": 0.0606246218085289, "27531": 0.12728634476661682, "27697": 0.1401015669107437, "27718": 0.401551216840744, "27989": 0.42735910415649414, "28093": 0.2089812457561493, "28196": 0.23787821829319, "28297": 0.16524957120418549, "28436": 0.004870930220931768, "28466": 1.0828639268875122, "28697": 0.2247048318386078, "28879": 0.030771657824516296, "28927": 0.004870930220931768, "29048": 0.10993985831737518, "29251": 0.040196798741817474, "29361": 0.15442965924739838, "29458": 0.0019512200960889459, "29486": 0.10731173306703568}
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26341063
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BACKGROUND In the studies of left ventricular dysfunction (SOLVD), enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolic dysfunction during the trial. We did a 12-year follow-up of SOLVD to establish if the mortality reduction with enalapril among patients with heart failure was sustained, and whether a subsequent reduction in mortality would emerge among those with asymptomatic ventricular dysfunction. METHODS Of the 6797 patients previously enrolled in the SOLVD prevention and treatment trials, we ascertained the subsequent vital status of 5165 individuals who were alive when the trials had been completed. Follow-up was done through direct contacts in Belgium and linkages with national death registries and federal beneficiary or historic tax summary files in the USA and Canada. FINDINGS Follow-up was 99.8% (6784/6797) complete. In the prevention trial, 50.9% (1074/2111) of the enalapril group had died compared with 56.4% (1195/2117) of the placebo group (generalised Wilcoxon p=0.001). In the treatment trial, 79.8% (1025/1285) of the enalapril group had died compared with 80.8% (1038/1284) of the placebo group (generalised Wilcoxon p=0.01). The reductions in cardiac deaths were significant and similar in both trials. When data for the prevention and treatment trials were combined, the hazard ratio for death was 0.90 for the enalapril group compared with the placebo group (95% CI 0.84-0.95, generalised Wilcoxon p=0.0003). Enalapril extended median survival by 9.4 months in the combined trials (95% CI 2.8-16.5, p=0.004). INTERPRETATION Treatment with enalapril for 3-4 years led to a sustained improvement in survival beyond the original trial period in patients with left ventricular systolic dysfunction, with an important increase in life expectancy.
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Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.
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26374799
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Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of all three primary germ layers, yet little is known about the signaling cascades that govern their pluripotent character. Because it plays a prominent role in the early cell fate decisions of embryonic development, we have examined the role of TGFbeta superfamily signaling in hESCs. We found that, in undifferentiated cells, the TGFbeta/activin/nodal branch is activated (through the signal transducer SMAD2/3) while the BMP/GDF branch (SMAD1/5) is only active in isolated mitotic cells. Upon early differentiation, SMAD2/3 signaling is decreased while SMAD1/5 signaling is activated. We next tested the functional role of TGFbeta/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers of the undifferentiated state. We extend these findings to show that SMAD2/3 activation is required downstream of WNT signaling, which we have previously shown to be sufficient to maintain the undifferentiated state of hESCs. Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3 signaling is also required to maintain the inner cell mass (from which stem cells are derived). These data reveal a crucial role for TGFbeta signaling in the earliest stages of cell fate determination and demonstrate an interconnection between TGFbeta and WNT signaling in these contexts.
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TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells.
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26378103
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We report the cloning and sequence determination of the mouse H19 gene. This gene is under the genetic control of two trans-acting loci in the mouse, termed raf and Rif. These loci determine the adult basal and inducible levels, respectively, of H19 mRNA, as well as the mRNA for alpha-fetoprotein. By elucidating the sequence and structure of the H19 gene we show that it is unrelated to the alpha-fetoprotein gene, and therefore must have acquired its regulation by raf and Rif independently. The sequence also indicates that the H19 gene has a very unusual structure. It is composed of five exons, 1307, 135, 119, 127 and 560 bp in size, along with four very small introns whose combined lengths are 270 bases. The largest open reading frame of the gene, sufficient to encode a protein of approximately 14 kd, is contained entirely within the first large exon, 680 bases downstream of the cap site of the mRNA. Preceding the translation initiation codon are four ATG codons, each of which is followed shortly thereafter by translation terminator codons. The rest of the gene, which encompasses all five exons, is presumed to be untranslated. That the long 5' untranslated region may be used to regulate the translation of the mRNA is suggested from in vitro translation studies. Experiments which utilized tissue culture cell lines of the mesodermal lineage suggest that the gene is activated very early during muscle cell differentiation.
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The structure and expression of a novel gene activated in early mouse embryogenesis.
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26409363
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Daily calcitriol therapy has been reported to improve linear growth in children with renal bone disease, and 1,25-dihydroxyvitamin D is a key regultor of chondrocyte proliferation and differentiation. Whereas large intermittent doses of calcitriol can lower serum parathyroid hormone (PTH) levels and reverse the skeletal changes of secondary hyperparathyroidism, the impact of intermittent calcitriol therapy on linear growth in children is not known. Thus, we studied 16 pre-pubertal patients with bone biopsy-proven secondary hyperparathyroidism who completed a 12-month prospective clinical trial of intermittent calcitriol therapy. Biochemical results and growth data obtained during intermittent calcitriol therapy were compared to values determined during the preceding 12 months of daily calcitriol therapy in each study subject; changes in bone histology were assessed after one year of intermittent calcitriol therapy. Z-scores for height did not change during 12 months of daily calcitriol therapy. Although the skeletal lesions of secondary hyperparathyroidism improved in most patients, Z-scores for height decreased from -1.8 +/- 0.32 to -2.0 +/- 0.33, P < 0.01, during intermittent calcitriol therapy. The largest reductions were seen in patients who developed adynamic bone lesions after 12 months of treatment. Delta Z-scores for height correlated with serum PTH, r = 0.71, P < 0.01, and alkaline phosphatase levels, r = 0.67, P < 0.01, during intermittent calcitriol therapy but not during daily calcitriol therapy. The data suggest that high dose intermittent calcitriol therapy adversely affects linear growth, particularly in patients with the adynamic lesion. The higher doses of calcitriol or the intermittent schedule of calcitriol administration may directly inhibit chondrocyte activity within growth plate cartilage of children with end-stage renal disease.
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Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD.
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