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10555591
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Zn2+ is present at high concentrations in the synaptic vesicles of hippocampal mossy fibers. We have used Zn2+ chelators and the mocha mutant mouse to address the physiological role of Zn2+ in this pathway. Zn2+ is not involved in the unique presynaptic plasticities observed at mossy fiber synapses but is coreleased with glutamate from these synapses, both spontaneously and with electrical stimulation, where it exerts a strong modulatory effect on the NMDA receptors. Zn2+ tonically occupies the high-affinity binding site of NMDA receptors at mossy fiber synapses, whereas the lower affinity voltage-dependent Zn2+ binding site is occupied during action potential driven-release. We conclude that Zn2+ is a modulatory neurotransmitter released from mossy fiber synapses and plays an important role in shaping the NMDA receptor response at these synapses.
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The Actions of Synaptically Released Zinc at Hippocampal Mossy Fiber Synapses
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10557471
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The aim of the present investigation was to study the effect of a dietary intervention which combined nutrition information with increased availability of vegetables, fruits and wholegrain bread. The effect of the intervention was determined by changes in the intake of vegetables, fruits, wholegrain bread and estimated nutrients. Furthermore, the study investigated whether changes in relative contribution from different food sources of folate were related to changes in the concentration of plasma total homocysteine (p-tHcy). The 5-month intervention study included 376 male recruits from the Norwegian National Guard, Vaernes (intervention group) and 105 male recruits from the Norwegian National Guard, Heggelia (control group). The study resulted in an increase in the total consumption of vegetables, fruits, berries and juice (P < 0.001) and of wholegrain bread (P < 0.001). The participants in the intervention group showed a higher increase in the intake of dietary fibre (P < 0.001) and folate (P < 0.001) compared with the control group. The relative contribution of folate intake from fruits, vegetables and wholegrain bread was higher in the intervention group compared with the control group (P < 0.001 for all). The increased intake of folate from wholegrain bread was inversely associated with a reduced concentration of p-tHcy (P = 0.017). In summary, the dietary intervention resulted in an increased intake of vegetables, fruits and wholegrain bread and a subsequent increase in folate intake from these food components. Reduction in the concentration of p-tHcy was significantly related to an increased folate intake due to an increased consumption of wholegrain bread.
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Association between folate intake from different food sources in Norway and homocysteine status in a dietary intervention among young male adults.
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10559501
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Studies with mice lacking the common plasma membrane receptor for type I interferon (IFN-αβR(-)(/)(-)) have revealed that IFN signaling restricts tropism, dissemination, and lethality after infection with West Nile virus (WNV) or several other pathogenic viruses. However, the specific functions of individual IFN subtypes remain uncertain. Here, using IFN-β(-)(/)(-) mice, we defined the antiviral and immunomodulatory function of this IFN subtype in restricting viral infection. IFN-β(-)(/)(-) mice were more vulnerable to WNV infection than wild-type mice, succumbing more quickly and with greater overall mortality, although the phenotype was less severe than that of IFN-αβR(-)(/)(-) mice. The increased susceptibility of IFN-β(-)(/)(-) mice was accompanied by enhanced viral replication in different tissues. Consistent with a direct role for IFN-β in control of WNV replication, viral titers in ex vivo cultures of macrophages, dendritic cells, fibroblasts, and cerebellar granule cell neurons, but not cortical neurons, from IFN-β(-)(/)(-) mice were greater than in wild-type cells. Although detailed immunological analysis revealed no major deficits in the quality or quantity of WNV-specific antibodies or CD8(+) T cells, we observed an altered CD4(+) CD25(+) FoxP3(+) regulatory T cell response, with greater numbers after infection. Collectively, these results suggest that IFN-β controls WNV pathogenesis by restricting infection in key cell types and by modulating T cell regulatory networks.
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Beta interferon controls West Nile virus infection and pathogenesis in mice.
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0.6265231370925903, "25354": 1.117955207824707, "25473": 0.10818854719400406, "25605": 0.14686977863311768, "25761": 0.5209306478500366, "25952": 0.15359249711036682, "25971": 0.3519764244556427, "26058": 0.043007105588912964, "26211": 0.10467668622732162, "26243": 0.4879087805747986, "26402": 0.1905880719423294, "26601": 0.7665573358535767, "26892": 0.4537591338157654, "27011": 0.3262358605861664, "27295": 0.39696553349494934, "27404": 0.0019512200960889459, "27419": 0.07068414986133575, "27781": 0.7445381283760071, "27831": 0.009718249551951885, "27854": 0.306306391954422, "27995": 0.0913962796330452, "28156": 0.09584271162748337, "28432": 0.3777405619621277, "28577": 0.00875066313892603, "28788": 0.18167030811309814, "28815": 0.10906458646059036, "28873": 0.3409265875816345, "28938": 0.7258110046386719, "29003": 0.06337817758321762, "29248": 0.16607704758644104, "29290": 0.04207121208310127, "29295": 0.5016035437583923, "29304": 0.0038986403960734606, "29431": 1.1834511756896973, "29490": 0.10467668622732162, "29610": 0.175953671336174}
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10562341
|
The activation of T cells is the fundamental on switch for the adaptive immune system. Ca2+ signaling is essential for T cell activation and starts as initial, short-lived, localized Ca2+ signals. The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) forms rapidly upon T cell activation and stimulates early Ca2+ signaling. We developed a high-resolution imaging technique using multiple fluorescent Ca2+ indicator dyes to characterize these early signaling events and investigate the channels involved in NAADP-dependent Ca2+ signals. In the first seconds of activation of either primary murine T cells or human Jurkat cells with beads coated with an antibody against CD3, we detected Ca2+ signals with diameters close to the limit of detection and that were close to the activation site at the plasma membrane. In Jurkat cells in which the ryanodine receptor (RyR) was knocked down or in primary T cells from RyR1−/− mice, either these early Ca2+ signals were not detected or the number of signals was markedly reduced. Local Ca2+ signals observed within 20 ms upon microinjection of Jurkat cells with NAADP were also sensitive to RyR knockdown. In contrast, TRPM2 (transient receptor potential channel, subtype melastatin 2), a potential NAADP target channel, was not required for the formation of initial Ca2+ signals in primary T cells. Thus, through our high-resolution imaging method, we characterized early Ca2+ release events in T cells and obtained evidence for the involvement of RyR and NAADP in such signals.
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Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor
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"24278": 0.08692999184131622, "24355": 0.5127768516540527, "24471": 0.1710275560617447, "24532": 0.18004031479358673, "24972": 0.3743882179260254, "25125": 0.7845434546470642, "25172": 0.4093637466430664, "25714": 0.7258110046386719, "25746": 0.5404602885246277, "26279": 0.11168810725212097, "26305": 0.09406650811433792, "26601": 0.24325250089168549, "26723": 0.5080875158309937, "26741": 0.2830325961112976, "26858": 0.08244366943836212, "26963": 1.2421036958694458, "27179": 0.2394166737794876, "27480": 1.1689931154251099, "27633": 0.12470348179340363, "27703": 1.2677175998687744, "28156": 0.32129061222076416, "28227": 0.41647201776504517, "28290": 0.037378571927547455, "28685": 0.10291612148284912, "28788": 0.469759464263916, "28828": 0.6212902665138245, "28829": 0.14602625370025635, "28873": 0.05786345899105072, "29166": 0.43623676896095276, "29181": 0.9739698171615601, "29199": 0.45499902963638306, "29720": 0.35060185194015503}
|
10574949
|
Laminin β2 is a component of laminin-521, which is an important constituent of the glomerular basement membrane (GBM). Null mutations in laminin β2 (LAMB2) cause Pierson syndrome, a severe congenital nephrotic syndrome with ocular and neurologic defects. In contrast, patients with LAMB2 missense mutations, such as R246Q, can have less severe extrarenal defects but still exhibit congenital nephrotic syndrome. To investigate how such missense mutations in LAMB2 cause proteinuria, we generated three transgenic lines of mice in which R246Q-mutant rat laminin β2 replaced the wild-type mouse laminin β2 in the GBM. These transgenic mice developed much less severe proteinuria than their nontransgenic Lamb2-deficient littermates; the level of proteinuria correlated inversely with R246Q-LAMB2 expression. At the onset of proteinuria, expression and localization of proteins associated with the slit diaphragm and foot processes were normal, and there were no obvious ultrastructural abnormalities. Low transgene expressors developed heavy proteinuria, foot process effacement, GBM thickening, and renal failure by 3 months, but high expressors developed only mild proteinuria by 9 months. In vitro studies demonstrated that the R246Q mutation results in impaired secretion of laminin. Taken together, these results suggest that the R246Q mutation causes nephrotic syndrome by impairing secretion of laminin-521 from podocytes into the GBM; however, increased expression of the mutant protein is able to overcome this secretion defect and improve glomerular permselectivity.
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A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion.
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10576136
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BACKGROUND ST2 is an interleukin (IL)-1 receptor family member with membrane-bound (ST2L) and soluble (sST2) isoforms, and sST2 is a biomarker for poor outcome in patients with myocardial infarction (MI). IL-33, the recently discovered ligand for ST2, activates nuclear factor kappaB and thus may regulate apoptotic cell death. We tested the hypothesis that IL-33 is cardioprotective after MI through ST2 signaling. METHODS AND RESULTS IL-33 protected cultured cardiomyocytes from hypoxia-induced apoptosis, and this cardioprotection was partially inhibited by sST2. IL-33 induced expression of the antiapoptotic factors XIAP, cIAP1, and survivin. To define the cardioprotective role of IL-33 in vivo, we performed a blinded and randomized study of ischemia/reperfusion in rats. IL-33 reduced cardiomyocyte apoptosis, suppressed caspase-3 activity, and increased expression of IAP family member proteins. IL-33 decreased both infarct and fibrosis volumes at 15 days; furthermore, both echocardiographic and hemodynamic studies revealed that IL-33 improved ventricular function. To determine whether cardioprotection by IL-33 is mediated through ST2 signaling, a randomized and blinded study of ST2(-/-) versus wild-type littermate mice was performed in 98 mice subjected to MI. At 4 weeks after MI, IL-33 reduced ventricular dilation and improved contractile function in wild-type mice but not in ST2(-/-) mice. Finally, IL-33 improved survival after MI in wild-type but not in ST2(-/-) mice. CONCLUSIONS IL-33 prevents cardiomyocyte apoptosis and improves cardiac function and survival after MI through ST2 signaling.
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Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling.
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10577574
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BACKGROUND In the year 2000, the organizational structure of the ICU in the Zaandam Medical Centre (ZMC) changed from an open to a closed format ICU. The objective of this study was to evaluate the effect of this organizational change on outcome in high risk surgical patients. METHODS The medical records of all consecutive high risk surgical patients admitted to the ICU from 1996 to 1998 (open format) and from 2003 to 2005 (closed format), were reviewed. High-risk patients were defined according to the Identification of Risk in Surgical patients (IRIS) score. Parameters studied were: mortality, morbidity, ICU length of stay (LOS) and hospital LOS. RESULTS Mortality of ICU patients was 25.7% in the open format group and 15.8% in the closed format group (p = 0.01). Morbidity decreased from 48.6% to 46.1% (p = 0.6). The average length of hospital stay was 17 days in the open format group, and 21 days in the closed format group (p = 0.03). CONCLUSIONS High risk surgical patients in the ICU are patients that have undergone complex and often extensive surgery. These patients are in need of specialized treatment and careful monitoring for maximum safety and optimal care. Our results suggest that closed format is a more favourable setting than open format to minimize the effects of high risk surgery, and to warrant safe outcome in this patient group.
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The impact of open versus closed format ICU admission practices on the outcome of high risk surgical patients: a cohort analysis
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"29107": 0.2969166338443756, "29129": 0.0317181795835495, "29235": 0.05417001247406006, "29290": 0.31845372915267944, "29490": 0.5723689198493958, "29513": 0.09584271162748337}
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10582939
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CONTEXT Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. OBJECTIVE To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. DESIGN, SETTING, AND PATIENTS One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. INTERVENTION Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. MAIN OUTCOME MEASURES The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. RESULTS Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) CONCLUSION Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00658073.
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Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial.
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10605189
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The mammalian cerebral cortex is responsible for the highest levels of associative, cognitive and motor functions. In the central nervous system (CNS) the cortex stands as a prime example of extreme neuronal diversity, broadly classified into excitatory projection neurons (PNs) and inhibitory interneurons (INs). We review here recent progress made in understanding the strategies and mechanisms that shape PN diversity during embryogenesis, and discuss how PN classes may be maintained, postnatally, for the life of the organism. In addition, we consider the intriguing possibility that PNs may be amenable to directed reprogramming of their class-specific features to allow enhanced cortical plasticity in the adult.
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Cerebral cortex assembly: generating and reprogramming projection neuron diversity
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10607877
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Cell surface receptors have been extensively studied because they initiate and regulate signal transduction cascades leading to a variety of functional cellular outcomes. An important class of immune receptors (e.g., T-cell antigen receptors) whose ligands are anchored to the surfaces of other cells remain poorly understood. The mechanism by which ligand binding initiates receptor phosphorylation, a process termed "receptor triggering", remains controversial. Recently, direct measurements of the (two-dimensional) receptor-ligand complex lifetimes at cell-cell interface were found to be smaller than (three-dimensional) lifetimes in solution but the underlying mechanism is unknown. At the cell-cell interface, the receptor-ligand complex spans a short intermembrane distance (15 nm) compared to long surface molecules (LSMs) whose ectodomains span >40 nm and these LSMs include phosphatases (e.g., CD45) that dephosphorylate the receptor. It has been proposed that size-based segregation of LSMs from a receptor-ligand complex is a mechanism of receptor triggering but it is unclear whether the mechanochemistry supports such small-scale segregation. Here we present a nanometer-scale mathematical model that couples membrane elasticity with the compressional stiffness and lateral mobility of LSMs. We find robust supradiffusive segregation of LSMs from a single receptor-ligand complex. The model predicts that LSM redistribution will result in a time-dependent tension on the complex leading to a decreased two-dimensional lifetime. Interestingly, the model predicts a nonlinear relationship between the three- and two-dimensional lifetimes, which can enhance the ability of receptors to discriminate between similar ligands.
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Mechanical modulation of receptor-ligand interactions at cell-cell interfaces.
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"28503": 0.7683706283569336, "28507": 0.29328158497810364, "28516": 0.0019512200960889459, "28657": 0.26820653676986694, "28667": 0.02887592278420925, "29202": 0.823009729385376, "29525": 0.2763880789279938}
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10608397
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BACKGROUND Paralysis or amputation of an arm results in the loss of the ability to orient the hand and grasp, manipulate, and carry objects, functions that are essential for activities of daily living. Brain-machine interfaces could provide a solution to restoring many of these lost functions. We therefore tested whether an individual with tetraplegia could rapidly achieve neurological control of a high-performance prosthetic limb using this type of an interface. METHODS We implanted two 96-channel intracortical microelectrodes in the motor cortex of a 52-year-old individual with tetraplegia. Brain-machine-interface training was done for 13 weeks with the goal of controlling an anthropomorphic prosthetic limb with seven degrees of freedom (three-dimensional translation, three-dimensional orientation, one-dimensional grasping). The participant's ability to control the prosthetic limb was assessed with clinical measures of upper limb function. This study is registered with ClinicalTrials.gov, NCT01364480. FINDINGS The participant was able to move the prosthetic limb freely in the three-dimensional workspace on the second day of training. After 13 weeks, robust seven-dimensional movements were performed routinely. Mean success rate on target-based reaching tasks was 91·6% (SD 4·4) versus median chance level 6·2% (95% CI 2·0-15·3). Improvements were seen in completion time (decreased from a mean of 148 s [SD 60] to 112 s [6]) and path efficiency (increased from 0·30 [0·04] to 0·38 [0·02]). The participant was also able to use the prosthetic limb to do skilful and coordinated reach and grasp movements that resulted in clinically significant gains in tests of upper limb function. No adverse events were reported. INTERPRETATION With continued development of neuroprosthetic limbs, individuals with long-term paralysis could recover the natural and intuitive command signals for hand placement, orientation, and reaching, allowing them to perform activities of daily living. FUNDING Defense Advanced Research Projects Agency, National Institutes of Health, Department of Veterans Affairs, and UPMC Rehabilitation Institute.
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High-performance neuroprosthetic control by an individual with tetraplegia.
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10608822
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Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer.
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Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.
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0.11343330889940262, "29090": 0.36967599391937256, "29105": 0.7683706283569336, "29107": 0.09672962874174118, "29295": 0.07793712615966797, "29393": 0.2837681770324707, "29490": 0.3554046154022217, "29596": 0.2516399025917053}
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10617916
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Background. Artemisinin-based combination therapy (ACT) reduces microscopically confirmed gametocytemia and mosquito infection. However, molecular techniques have recently revealed high prevalences of submicroscopic gametocytemia. Our objective here was to determine the effect of sulfadoxine-pyrimethamine (SP) monotherapy and treatment with SP plus amodiaquine (AQ), SP plus artesunate (AS), and artemether-lumefantrine (AL; Coartem) on submicroscopic gametocytemia and infectiousness. Methods. Kenyan children (n=528) 6 months-10 years of age were randomized to 4 treatment arms. Gametocytemia was determined by both microscopy and Pfs25 RNA-based quantitative nucleic acid sequence-based amplification (Pfs25 QT-NASBA). Transmission was determined by membrane-feeding assays. Results. Gametocyte prevalence, as determined by Pfs25 QT-NASBA, was 89.4% (219/245) at enrollment and decreased after treatment with SP plus AS, SP plus AQ, and AL. Membrane-feeding assays for a group of randomly selected children revealed that the proportion of infectious children was as much as 4-fold higher than expected when based on microscopy. ACT did not significantly reduce the proportion of infectious children but did reduce the proportion of infected mosquitoes. Conclusions. Submicroscopic gametocytemia is common after treatment and contributes considerably to mosquito infection. Our findings should be interpreted in the context of transmission intensity, but the effect of ACT on malaria transmission appears to be moderate and restricted to the duration of gametocyte carriage and the proportion of mosquitoes that are infected by carriers.
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Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum.
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10624000
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During continuous speech, lip movements provide visual temporal signals that facilitate speech processing. Here, using MEG we directly investigated how these visual signals interact with rhythmic brain activity in participants listening to and seeing the speaker. First, we investigated coherence between oscillatory brain activity and speaker's lip movements and demonstrated significant entrainment in visual cortex. We then used partial coherence to remove contributions of the coherent auditory speech signal from the lip-brain coherence. Comparing this synchronization between different attention conditions revealed that attending visual speech enhances the coherence between activity in visual cortex and the speaker's lips. Further, we identified a significant partial coherence between left motor cortex and lip movements and this partial coherence directly predicted comprehension accuracy. Our results emphasize the importance of visually entrained and attention-modulated rhythmic brain activity for the enhancement of audiovisual speech processing.
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Lip movements entrain the observers’ low-frequency brain oscillations to facilitate speech intelligibility
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10627801
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The DExD/H box RNA helicase retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene 5 (MDA5) are key intracellular receptors that recognize virus infection to produce type I IFN. A third helicase gene, Lgp2, is homologous to Rig-I and Mda5 but lacks a caspase activation and recruitment domain. We generated Lgp2-deficient mice and report that the loss of this gene greatly sensitizes cells to cytosolic polyinosinic/polycytidylic acid-mediated induction of type I IFN. However, negative feedback inhibition of IFN-beta transcription was found to be normal in the absence of LGP2, indicating that LGP2 is not the primary negative regulator of type I IFN production. Our data further indicate that Lgp2-/- mice exhibited resistance to lethal vesicular stomatitis virus infection, a virus whose replicative RNA intermediates are recognized specifically by RIG-I rather than by MDA5 to trigger the production of type I IFN. However, mice lacking LGP2 were observed to exhibit a defect in type I IFN production in response to infection by the encephalomyocarditis virus, the replication of which activates MDA5-dependent innate immune responses. Collectively, our data indicate a disparate regulatory role for LGP2 in the triggering of innate immune signaling pathways following RNA virus infection.
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Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses.
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1.439538836479187, "24840": 0.13925230503082275, "24895": 0.02792670577764511, "24961": 0.2990913391113281, "25059": 0.28670501708984375, "25086": 0.255429208278656, "25254": 0.3601844012737274, "25458": 0.5618454217910767, "25533": 1.1481462717056274, "25743": 1.17624831199646, "26127": 0.05139094591140747, "26166": 0.04394211992621422, "26221": 0.09850110858678818, "26228": 0.20977331697940826, "26315": 0.06886265426874161, "26383": 0.2749055027961731, "26396": 0.1718502640724182, "26572": 0.07612881064414978, "26691": 0.08961215615272522, "26819": 0.9987343549728394, "26884": 0.5021947622299194, "27011": 0.4196864068508148, "27097": 0.13499516248703003, "27216": 0.7629209756851196, "27404": 0.4926934838294983, "27679": 0.1930064558982849, "27725": 0.11691460013389587, "28026": 0.06337817758321762, "28144": 1.6432353258132935, "28433": 0.015504186972975731, "28741": 0.2018241584300995, "28815": 0.06429435312747955, "28991": 0.20977331697940826, "29105": 1.033379077911377, "29237": 0.13925230503082275, "29263": 0.3163207769393921, "29304": 0.05139094591140747, "29320": 0.3526630103588104}
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10628767
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We demonstrate single-molecule fluorescence imaging beyond the optical diffraction limit in 3 dimensions with a wide-field microscope that exhibits a double-helix point spread function (DH-PSF). The DH-PSF design features high and uniform Fisher information and has 2 dominant lobes in the image plane whose angular orientation rotates with the axial (z) position of the emitter. Single fluorescent molecules in a thick polymer sample are localized in single 500-ms acquisitions with 10- to 20-nm precision over a large depth of field (2 microm) by finding the center of the 2 DH-PSF lobes. By using a photoactivatable fluorophore, repeated imaging of sparse subsets with a DH-PSF microscope provides superresolution imaging of high concentrations of molecules in all 3 dimensions. The combination of optical PSF design and digital postprocessing with photoactivatable fluorophores opens up avenues for improving 3D imaging resolution beyond the Rayleigh diffraction limit.
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Three-dimensional, single-molecule fluorescence imaging beyond the diffraction limit by using a double-helix point spread function.
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"16706": 0.34300774335861206, "16762": 0.07431721687316895, "16896": 0.03831886500120163, "16961": 0.8941729068756104, "17086": 0.5957841277122498, "17112": 1.0250049829483032, "17287": 0.7610978484153748, "17341": 0.861702561378479, "17367": 0.08782484382390976, "17603": 0.9271688461303711, "17666": 0.06886265426874161, "17782": 0.791648268699646, "17785": 0.06886265426874161, "17820": 0.13925230503082275, "17864": 0.623910129070282, "18120": 0.09850110858678818, "18771": 0.8707374930381775, "18963": 0.7601850032806396, "19269": 0.12986256182193756, "19293": 0.020300358533859253, "19476": 0.10291612148284912, "19515": 0.00875066313892603, "19570": 1.0423725843429565, "19616": 0.5092619061470032, "19653": 0.619189441204071, "19716": 0.04113444685935974, "19825": 0.0752234235405922, "19852": 0.3241194784641266, "19872": 0.03266380727291107, "20159": 0.02887592278420925, "20307": 0.00875066313892603, "20444": 0.7647408246994019, "20487": 0.7105726003646851, "20582": 0.3034266233444214, "20640": 0.029824240133166313, "20806": 0.19541899859905243, "20868": 0.1889725625514984, "21040": 0.09495500475168228, "21053": 0.7028654217720032, "21114": 0.04767346754670143, "21162": 0.7907629609107971, "21396": 0.9302552938461304, "21557": 0.0797421783208847, "21575": 0.13670019805431366, "21618": 0.23864774405956268, "21647": 0.4512746334075928, "21663": 0.3012613356113434, "21685": 0.11168810725212097, "21697": 0.6207655072212219, "21716": 0.045809537172317505, "21754": 0.42225050926208496, "21781": 0.23324857652187347, "21821": 0.23864774405956268, "21890": 0.09406650811433792, "21957": 0.12814582884311676, "21996": 1.147526502609253, "22210": 0.969535231590271, "22311": 1.1350497007369995, "22330": 0.08961215615272522, "22422": 0.3283478021621704, "22869": 0.24325250089168549, "22922": 0.22704219818115234, "23068": 0.6212902665138245, "23079": 0.0913962796330452, "23092": 0.4132472574710846, "23150": 0.3318578004837036, "23192": 1.024303913116455, "23350": 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"27521": 0.3106105625629425, "27691": 0.16690383851528168, "28086": 0.2223619967699051, "28297": 0.28450319170951843, "28424": 0.17922431230545044, "28691": 0.1064341589808464, "29091": 0.12470348179340363, "29206": 0.5074998140335083, "29290": 0.2247048318386078, "29295": 0.0770333781838417, "29389": 0.39762192964553833, "29486": 0.4794800877571106}
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10641162
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In contrast to the cell division machineries of bacteria, euryarchaea, and eukaryotes, no division components have been identified in the second main archaeal phylum, Crenarchaeota. Here, we demonstrate that a three-gene operon, cdv, in the crenarchaeon Sulfolobus acidocaldarius, forms part of a unique cell division machinery. The operon is induced at the onset of genome segregation and division, and the Cdv proteins then polymerize between segregating nucleoids and persist throughout cell division, forming a successively smaller structure during constriction. The cdv operon is dramatically down-regulated after UV irradiation, indicating division inhibition in response to DNA damage, reminiscent of eukaryotic checkpoint systems. The cdv genes exhibit a complementary phylogenetic range relative to FtsZ-based archaeal division systems such that, in most archaeal lineages, either one or the other system is present. Two of the Cdv proteins, CdvB and CdvC, display homology to components of the eukaryotic ESCRT-III sorting complex involved in budding of luminal vesicles and HIV-1 virion release, suggesting mechanistic similarities and a common evolutionary origin.
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A unique cell division machinery in the Archaea.
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10641715
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Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contributes to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects.
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Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21
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0.5651806592941284, "21759": 0.21135559678077698, "21850": 0.1619328260421753, "21903": 0.3423145115375519, "21935": 0.24171993136405945, "21967": 0.030771657824516296, "22330": 0.5773153901100159, "22694": 0.13670019805431366, "22851": 1.1319060325622559, "22930": 0.4500300884246826, "22931": 0.40285754203796387, "23041": 0.9546096324920654, "23216": 0.07068414986133575, "23467": 0.0317181795835495, "23586": 0.6451379656791687, "23692": 0.15359249711036682, "23760": 0.6704301834106445, "23900": 0.3339579105377197, "23924": 0.09050461649894714, "24054": 0.6989894509315491, "24093": 0.5822374224662781, "24269": 0.1677299439907074, "24838": 0.0019512200960889459, "24840": 0.056018441915512085, "24848": 1.2533208131790161, "25117": 0.037378571927547455, "25194": 0.12986256182193756, "25219": 0.004870930220931768, "25456": 0.5506471395492554, "25714": 0.12986256182193756, "25761": 0.17020416259765625, "25969": 0.3499138653278351, "26013": 0.07250232994556427, "26282": 0.4158279001712799, "26288": 0.05694137513637543, "26402": 1.0755622386932373, "26419": 0.10906458646059036, "26451": 0.33325836062431335, "26591": 0.4041621685028076, "26721": 0.09317722171545029, "26773": 0.058784693479537964, "26786": 0.6548244953155518, "26835": 0.7389566898345947, "27099": 0.40546512603759766, "27321": 0.9287132620811462, "27781": 0.20660123229026794, "27854": 0.9761797785758972, "27989": 0.04207121208310127, "28024": 0.42225050926208496, "28389": 0.02316705882549286, "28466": 0.678390383720398, "28696": 0.3870677351951599, "28788": 0.4831010699272156, "28873": 0.5027855634689331, "29170": 0.27044451236724854, "29290": 0.23247487843036652, "29490": 0.11604541540145874}
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10648422
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Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.
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Programmed death-1–induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection
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1.1756457090377808, "17175": 0.03925827145576477, "17181": 0.083342544734478, "17424": 0.3409265875816345, "17441": 0.4400174915790558, "17541": 0.21687394380569458, "17614": 0.10026945173740387, "17629": 0.10906458646059036, "17820": 0.20501139760017395, "17890": 0.1808556467294693, "18231": 0.06886265426874161, "19009": 0.06795065850019455, "19335": 0.26820653676986694, "19413": 0.12470348179340363, "19601": 0.7683706283569336, "19653": 0.3269403576850891, "19780": 0.030771657824516296, "20226": 0.7898768186569214, "20544": 0.7863243818283081, "20828": 0.12384103983640671, "21114": 0.11517547070980072, "21312": 0.09317722171545029, "21557": 0.23787821829319, "21618": 0.27786844968795776, "21647": 0.09317722171545029, "21775": 0.06246116757392883, "21821": 0.3923587501049042, "21967": 0.1229778528213501, "22260": 0.1229778528213501, "22415": 1.0172666311264038, "23021": 0.2763880789279938, "23150": 0.06795065850019455, "23207": 0.1229778528213501, "23216": 0.35813871026039124, "23586": 0.24325250089168549, "23606": 0.06795065850019455, "23851": 0.2561853528022766, "24558": 0.1946154683828354, "24791": 0.09672962874174118, "25194": 0.3177432417869568, "25212": 0.0174254160374403, "25505": 0.5573811531066895, "25582": 0.0029254043474793434, "25761": 0.0606246218085289, "26356": 0.06886265426874161, "26402": 0.23247487843036652, "26408": 0.0029254043474793434, "26512": 0.19541899859905243, "26601": 0.2667117714881897, "26986": 0.26446542143821716, "27169": 1.1051015853881836, "27226": 0.2089812457561493, "27777": 0.8383291959762573, "28517": 0.13157635927200317, "28848": 0.012615402229130268, "29146": 0.9302552938461304, "29513": 0.996573805809021}
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10650521
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Exonic splicing enhancers (ESEs) facilitate exon definition by assisting in the recruitment of splicing factors to the adjacent intron. Here we demonstrate that suboptimal 5' and 3' splice sites are activated independently by ESEs when they are located on different exons. However, when they are situated within a single exon, the same weak 5' and 3' splice sites are activated simultaneously by a single ESE. These findings demonstrate that a single ESE promotes the recognition of both exon/intron junctions within the same step during exon definition. Our results suggest that ESEs recruit a multicomponent complex that minimally contains components of the splicing machinery required for 5' and 3' splice site selection.
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A general role for splicing enhancers in exon definition.
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10660080
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SecDFyajC of Escherichia coli is required for efficient export of proteins in vivo. However, the functional role of SecDFyajC in protein translocation is unclear. We evaluated the postulated function of SecDFyajC in the maintenance of the proton motive force. As previously reported, inner membrane vesicles (IMVs) lacking SecDFyajC are defective in the generation of a stable proton motive force when energized with succinate. This phenomenon is, however, not observed when NADH is used as an electron donor. Moreover, the proton motive force generated in SecDFyajC-depleted vesicles stimulated translocation to the same extent as seen with IMVs containing SecDFyajC. Further analysis demonstrates that the reduced proton motive force with succinate in IMVs lacking SecDFyajC is due to a lower amount of the enzyme succinate dehydrogenase. The expression of this enzyme complex is repressed by growth on glucose media, the condition used to deplete SecDFyajC. These results demonstrate that SecDFyajC is not required for proton motive force-driven protein translocation.
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SecDFyajC is not required for the maintenance of the proton motive force.
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10666475
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Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbred lines of rats, which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain.
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The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase
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0.2447827309370041, "25394": 0.18816383183002472, "25643": 0.09672962874174118, "25708": 0.011650617234408855, "25714": 0.979118824005127, "26244": 0.9021284580230713, "26402": 0.23479416966438293, "26435": 0.2652147710323334, "26651": 0.09228714555501938, "26721": 0.09050461649894714, "27598": 0.5551415085792542, "27777": 0.10203468054533005, "27854": 0.16359257698059082, "28414": 0.021256839856505394, "28424": 0.4512746334075928, "28522": 0.026025565341114998, "28691": 0.04860413447022438, "28835": 0.43434104323387146, "29107": 0.18573370575904846, "29269": 0.27934664487838745, "29403": 0.03266380727291107, "29489": 0.3388410806655884}
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10669582
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The protein cross-linking enzyme tissue transglutaminase binds in vitro with high affinity to fibronectin via its 42-kD gelatin-binding domain. Here we report that cell surface transglutaminase mediates adhesion and spreading of cells on the 42-kD fibronectin fragment, which lacks integrin-binding motifs. Overexpression of tissue transglutaminase increases its amount on the cell surface, enhances adhesion and spreading on fibronectin and its 42-kD fragment, enlarges focal adhesions, and amplifies adhesion-dependent phosphorylation of focal adhesion kinase. These effects are specific for tissue transglutaminase and are not shared by its functional homologue, a catalytic subunit of factor XIII. Adhesive function of tissue transglutaminase does not require its cross-linking activity but depends on its stable noncovalent association with integrins. Transglutaminase interacts directly with multiple integrins of β1 and β3 subfamilies, but not with β2 integrins. Complexes of transglutaminase with integrins are formed inside the cell during biosynthesis and accumulate on the surface and in focal adhesions. Together our results demonstrate that tissue transglutaminase mediates the interaction of integrins with fibronectin, thereby acting as an integrin-associated coreceptor to promote cell adhesion and spreading.
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Tissue Transglutaminase Is an Integrin-Binding Adhesion Coreceptor for Fibronectin
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0.2607102394104004, "25409": 0.29473719000816345, "25714": 0.9333322048187256, "25957": 1.0868242979049683, "26013": 0.21293537318706512, "26236": 1.0179725885391235, "26419": 0.08782484382390976, "26520": 0.26820653676986694, "26524": 0.16690383851528168, "26535": 0.7755908370018005, "26835": 0.2667117714881897, "27011": 0.7881022095680237, "27144": 0.012615402229130268, "27312": 0.10555581003427505, "27404": 0.26446542143821716, "27598": 0.7028654217720032, "27601": 0.043007105588912964, "27942": 0.9363996982574463, "28041": 0.2561853528022766, "28086": 0.28963330388069153, "28277": 0.9747070074081421, "28522": 0.011650617234408855, "28667": 0.5707147121429443, "28848": 0.7436100244522095, "28873": 0.19381128251552582, "28901": 0.9546096324920654, "29371": 0.004870930220931768, "29480": 0.3519764244556427, "29510": 0.20580662786960602}
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10669939
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Imaging the expression of successful gene transduction has been demonstrated in vivo for the first time by using an appropriate combination of "marker gene" and "marker substrate" in an experimental animal model. The herpes simplex virus 1 thymidine kinase (HSV1-tk) gene was selected as an example of a marker gene, and the recombinant STK retrovirus containing HSV1-tk was used to transduce RG2 glioma cells in vitro and in vivo. RG2TK+ cell lines expressing the HSV1-tk gene and three potential marker substrates for the HSV1-TK enzyme were evaluated. Radiolabeled 5-iodo-2'-fluoro-2'deoxy-1-beta-D-arabinofuranosyluracil (FIAU) was shown to be a substantially better marker substrate for the HSV1-TK enzyme than 5-iodo-2'-deoxyuridine or ganciclovir. The magnitude of FIAU accumulation in different RG2TK+ clones corresponded to their sensitivity to ganciclovir and to the level of HSV1-tk mRNA expression. Imaging the expression of HSV1-tk in transduced RG2 tumor cells was demonstrated in animals using quantitative autoradiography; 2-[14C]FIAU accumulation was shown to be high in RG2TK+ brain tumors growing in one hemisphere and very low in nontransduced RG2 tumors in the contralateral hemisphere. Transduction of RG2 tumor cells with the HSV-tk gene in vivo resulted in tumors which accumulated FIAU to high levels and produced clearly defined images. Given the level of FIAU accumulation in the transduced tumors, it is likely that a clinically applicable method for imaging HSV1-tk gene expression can be implemented using existing clinical imaging techniques.
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Imaging the expression of transfected genes in vivo.
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10670430
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The clearance of apoptotic cells by phagocytes is an integral component of normal life, and defects in this process can have significant implications for self tolerance and autoimmunity. Recent studies have provided new insights into the engulfment process, including how phagocytes seek apoptotic cells, how they recognize and ingest these targets and how they maintain cellular homeostasis after the 'meal'. Several new factors that regulate engulfment have been identified, whereas the roles of some of the older players require revision. This Review focuses on these recent developments and attempts to highlight some of the important questions in this field.
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Engulfment of apoptotic cells: signals for a good meal
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10675756
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BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory bowel disease in which the colonic mucosa is infiltrated with plasma cells producing IgG autoantibodies. It is not known whether this represents a local mucosal response which has switched to IgG or a peripheral response which may have been initiated by peripheral antigen which homed to the colonic mucosa. The clonal distribution of IgG secreting cells and isotype switched variants in UC is not known. AIMS To investigate the clonal distribution of mucosal IgG in UC and to search for related IgG and IgA secreting cells in normal and diseased mucosa and blood in UC. To investigate characteristics which may discriminate between the mucosal and peripheral repertoire in the normal mucosa and in UC. PATIENTS Blood and normal and diseased mucosa from two patients with UC were studied. METHODS Immunoglobulin gene analysis and clone specific polymerase chain reaction were used to study the clonal distribution and characteristics of IgG and related IgA in the mucosa and blood of patients with UC. RESULTS The IgG response in the mucosa of UC patients included widespread clones of cells that were present in both the diseased mucosa and blood but that were scarce in normal mucosa. Clonally related IgA class switch variants, all IgA1, were detected but also only in the diseased mucosa and blood. This suggests that these clones home preferentially to the diseased mucosa. We showed that J(H)1 usage was characteristic of the peripheral repertoire, and that examples of J(H)1 usage were observed in mucosal IgG in UC. CONCLUSIONS Overall, these data are consistent with a model of UC in which a peripheral response is expressed and expanded in the colonic mucosa.
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Related IgA1 and IgG producing cells in blood and diseased mucosa in ulcerative colitis.
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10692412
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BACKGROUND Kulldorff's spatial scan statistic and its software implementation - SaTScan - are widely used for detecting and evaluating geographic clusters. However, two issues make using the method and interpreting its results non-trivial: (1) the method lacks cartographic support for understanding the clusters in geographic context and (2) results from the method are sensitive to parameter choices related to cluster scaling (abbreviated as scaling parameters), but the system provides no direct support for making these choices. We employ both established and novel geovisual analytics methods to address these issues and to enhance the interpretation of SaTScan results. We demonstrate our geovisual analytics approach in a case study analysis of cervical cancer mortality in the U.S. RESULTS We address the first issue by providing an interactive visual interface to support the interpretation of SaTScan results. Our research to address the second issue prompted a broader discussion about the sensitivity of SaTScan results to parameter choices. Sensitivity has two components: (1) the method can identify clusters that, while being statistically significant, have heterogeneous contents comprised of both high-risk and low-risk locations and (2) the method can identify clusters that are unstable in location and size as the spatial scan scaling parameter is varied. To investigate cluster result stability, we conducted multiple SaTScan runs with systematically selected parameters. The results, when scanning a large spatial dataset (e.g., U.S. data aggregated by county), demonstrate that no single spatial scan scaling value is known to be optimal to identify clusters that exist at different scales; instead, multiple scans that vary the parameters are necessary. We introduce a novel method of measuring and visualizing reliability that facilitates identification of homogeneous clusters that are stable across analysis scales. Finally, we propose a logical approach to proceed through the analysis of SaTScan results. CONCLUSION The geovisual analytics approach described in this manuscript facilitates the interpretation of spatial cluster detection methods by providing cartographic representation of SaTScan results and by providing visualization methods and tools that support selection of SaTScan parameters. Our methods distinguish between heterogeneous and homogeneous clusters and assess the stability of clusters across analytic scales. METHOD We analyzed the cervical cancer mortality data for the United States aggregated by county between 2000 and 2004. We ran SaTScan on the dataset fifty times with different parameter choices. Our geovisual analytics approach couples SaTScan with our visual analytic platform, allowing users to interactively explore and compare SaTScan results produced by different parameter choices. The Standardized Mortality Ratio and reliability scores are visualized for all the counties to identify stable, homogeneous clusters. We evaluated our analysis result by comparing it to that produced by other independent techniques including the Empirical Bayes Smoothing and Kafadar spatial smoother methods. The geovisual analytics approach introduced here is developed and implemented in our Java-based Visual Inquiry Toolkit.
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Geovisual analytics to enhance spatial scan statistic interpretation: an analysis of U.S. cervical cancer mortality
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10692948
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CONTEXT Early childhood introduction of nutritional habits aimed at atherosclerosis prevention is compatible with normal growth, but its effect on neurological development is unknown. OBJECTIVE To analyze how parental counseling aimed at keeping children's diets low in saturated fat and cholesterol influences neurodevelopment during the first 5 years of life. DESIGN Randomized controlled trial conducted between February 1990 and November 1996. SETTING Outpatient clinic of a university department in Turku, Finland. PARTICIPANTS A total of 1062 seven-month-old infants and their parents, recruited at well-baby clinics between 1990 and 1992. At age 5 years, 496 children still living in the city of Turku were available to participate in neurodevelopmental testing. INTERVENTION Participants were randomly assigned to receive individualized counseling aimed at limiting the child's fat intake to 30% to 35% of daily energy, with a saturated:monounsaturated:polyunsaturated fatty acid ratio of 1:1:1 and a cholesterol intake of less than 200 mg/d (n = 540) or usual health education (control group, n = 522). MAIN OUTCOME MEASURES Nutrient intake, serum lipid concentrations, and neurological development at 5 years, among children in the intervention vs control groups. RESULTS Absolute and relative intakes of fat, saturated fatty acids, and cholesterol among children in the intervention group were markedly less than the respective values of control children. Mean (SD) percentages of daily energy at age 5 years for the intervention vs control groups were as follows: for total fat, 30.6% (4.5%) vs 33.4% (4.4%) (P<. 001); and for saturated fat, 11.7% (2.3%) vs 14.5% (2.4%) (P<.001). Mean intakes of cholesterol were 164.2 mg (60.1 mg) and 192.5 mg (71. 9 mg) (P<.001) for the intervention and control groups, respectively. Serum cholesterol concentrations were continuously 3% to 5% lower in children in the intervention group than in children in the control group. At age 5 years, mean (SD) serum cholesterol concentration of the intervention group was 4.27 (0.63) mmol/L (165 [24] mg/dL) and of the control group, 4.41 (0.74) mmol/L (170 [29] mg/dL) (P =.04). Neurological development of children in the intervention group was at least as good as that of children in the control group. Relative risks for children in the intervention group to fail tests of speech and language skills, gross motor functioning plus perception, and visual motor skills were 0.95 (90% confidence interval [CI], 0.60-1.49), 0.95 (90% CI, 0.58-1.55), and 0.65 (90% CI, 0.39-1.08), respectively (P =.85,.86, and.16, respectively, vs control children). CONCLUSION Our data indicate that repeated child-targeted dietary counseling of parents during the first 5 years of a child's life lessens age-associated increases in children's serum cholesterol and is compatible with normal neurological development. JAMA. 2000;284:993-1000
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Neurological development of 5-year-old children receiving a low-saturated fat, low-cholesterol diet since infancy: A randomized controlled trial.
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1.0023250579833984, "29454": 0.5718178153038025, "29514": 0.16607704758644104, "29598": 0.5551415085792542, "29607": 0.03831886500120163}
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10697096
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BACKGROUND The purpose of this study was to test the hypothesis that vasodilator responses of porcine coronary resistance arteries are increased by exercise training. METHODS AND RESULTS Yucatan miniature swine were randomly divided into groups of exercise-trained (ET) and sedentary (SED) control pigs. ET pigs were placed on a progressive treadmill training program lasting 16 to 20 weeks, and SED pigs remained inactive during the same time period. Coronary resistance arteries 64 to 157 microns in diameter were isolated for in vitro evaluation of relaxation responses to the endothelium-independent dilators sodium nitroprusside (1 x 10(-10) to 1 x 10(-4) mol/L) and adenosine (1 x 10(-10) to 1 x 10(-5) mol/L) and to bradykinin (1 x 10(-13) to 3 x 10(-7) mol/L), an endothelium-dependent agent. Relaxation responses to adenosine and sodium nitroprusside were not altered by exercise training. Endothelium-dependent relaxation to bradykinin was enhanced in coronary resistance arteries from ET pigs (IC50: ET, 0.07 +/- 0.02 nmol/L; SED, 1.59 +/- 0.09 nmol/L). To determine whether prostanoids and/or the nitric oxide synthase pathway were involved in the ET-induced changes in bradykinin-induced vasodilation, responses to bradykinin were examined in coronary resistance arteries from both ET and SED pigs in the presence of indomethacin and in the presence of nitro-monomethyl L-arginine (L-NMMA). Both indomethacin and L-NMMA produced significant inhibition of the bradykinin-induced relaxation in vessels from both groups. Despite decreased bradykinin-induced relaxation after indomethacin, bradykinin-induced vasodilation was still enhanced in vessels from the ET group. L-NMMA caused greater inhibition of the bradykinin-induced relaxation in coronary resistance arteries from ET pigs relative to arteries from SED pigs and eliminated the training-induced enhancement of the bradykinin responses. CONCLUSIONS These results suggest that exercise training enhances bradykinin-induced vasodilation through increased endothelium-derived relaxing factor/nitric oxide production by the L-arginine/nitric oxide synthase pathway.
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Vasodilator responses of coronary resistance arteries of exercise-trained pigs.
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10698739
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Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has been linked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine protease released as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Under physiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but the cytological and molecular mechanisms are not clear. Omi/HtrA2 deficiency caused an accumulation of reactive oxygen species and reduced mitochondrial membrane potential. In Omi/HtrA2 knockout mouse embryonic fibroblasts, as well as in Omi/HtrA2 silenced human HeLa cells and Drosophila S2R+ cells, we found elongated mitochondria by live cell imaging. Electron microscopy confirmed the mitochondrial morphology alterations and showed abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, we found a selective up-regulation of more soluble OPA1 protein. Complementation of knockout cells with wild-type Omi/HtrA2 but not with the protease mutant [S306A]Omi/HtrA2 reversed the mitochondrial elongation phenotype and OPA1 alterations. Finally, co-immunoprecipitation showed direct interaction of Omi/HtrA2 with endogenous OPA1. Thus, we show for the first time a direct effect of loss of Omi/HtrA2 on mitochondrial morphology and demonstrate a novel role of this mitochondrial serine protease in the modulation of OPA1. Our results underscore a critical role of impaired mitochondrial dynamics in neurodegenerative disorders.
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Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1.
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0.3601844012737274, "28436": 0.06977381557226181, "28788": 0.12642613053321838, "29134": 0.10291612148284912, "29458": 0.9302552938461304}
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10699587
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PURPOSE Gleason score (GS), T stage, and pathologic lymph node status have been described as major independent predictors of death due to prostate cancer in men treated with external beam radiotherapy (XRT). In this analysis we combine these three factors to define prognostic subgroups that correlate with disease-specific survival (DSS) death from prostate cancer. METHODS AND MATERIALS Men entered on one of four Radiation Therapy Oncology Group (RTOG) Phase III randomized trials between 1975 and 1992, for clinically localized prostate cancer (CAP) (n = 1557), were selected for this analysis. Patients were included if: 1) they were evaluable, and eligible for the trial; 2) they received no hormonal therapy with their initial treatment; and 3) follow-up was available. For this study a DSS event was declared if: 1) death was certified as due to CAP; 2) death was due to complications of treatment; or 3) death was from unknown causes with active malignancy. The median follow-up for patients treated on early and late RTOG studies exceeded 11 and 6 years respectively. Subgroups were identified based on their pretreatment GS, T-stage, and lymph node such that patients with similar risk of dying from prostate cancer were combined. RESULTS By combining patients with similar DSS, four subgroups were identified. Risk Group 1 patients had a GS = 2-6, and T1-2Nx; Group 2: GS = 2-6, T3Nx; or GS = 2-6, N+, or GS = 7, T1-2Nx; Group 3: T3Nx, GS = 7; or N+, GS = 7, or T1-2Nx, GS = 8-10; and Group 4 patients were T3Nx, GS = 8-10, or N+, GS = 8-10. The 5-, 10-, and 15-year DSS was 96%, 86%, and 72%; 94%, 75%, and 61%; 83%, 62%, and 39%; and 64%, 34%, and 27% for Groups 1 through 4, respectively. CONCLUSIONS Recognition of these four risk groups provides a basis for estimating the long-term DSS for men treated with XRT alone and should facilitate the design of future prospective randomized trials.
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Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials.
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"24798": 0.10379679501056671, "24826": 0.8756314516067505, "24887": 0.00875066313892603, "24972": 0.6773988008499146, "25243": 0.18004031479358673, "25543": 0.3084607720375061, "25714": 0.06795065850019455, "25780": 0.19622190296649933, "25817": 0.255429208278656, "25969": 0.007782140281051397, "26180": 0.18004031479358673, "26296": 0.3464667797088623, "26591": 0.5562619566917419, "26646": 0.007782140281051397, "26655": 0.10026945173740387, "26785": 0.8357921838760376, "27011": 0.129004567861557, "27152": 0.05046287178993225, "27165": 0.016465263441205025, "28105": 0.757441520690918, "28156": 0.6415454745292664, "28522": 0.5838727951049805, "28583": 0.045809537172317505, "28674": 1.1561684608459473, "28741": 0.23402166366577148, "28788": 0.6482070088386536, "28817": 0.9333322048187256, "28915": 0.7978238463401794, "28965": 0.18492233753204346, "29166": 0.8957691192626953, "29290": 0.5092619061470032, "29325": 0.052318159490823746, "29543": 0.5301685929298401}
|
10703001
|
Administration of 0.5 mg bleomycin to mice twice weekly for 4 weeks induced pulmonary fibrosis. The initial site of injury was the intima of pulmonary arteries and veins where endothelial cells became edematous and were separated from the underlying basement membrane by large blebs. These lesions occurred after 2 weeks and were associated with infiltration of perivascular spaces by lymphocytes and plasma cells. Capillary endothelial blebbing and interstitial edema were observed after 4 weeks, when multifocal necrosis of type 1 alveolar epithelial cells was accompanied by fibrinous exudation into the alveoli. The process of repair was characterized by proliferation and metaplasia of type 2 epithelial cells, fibroblastic organization of alveolar fibrin and fibrosis of the interstitium within 8 to 12 weeks. The consistent induction of changes similar to those of diffuse pulmonary fibrosis or fibrosing alveolitis in man suggests that bleomycin-induced injury may provide a suitable model for the investigation of this ill-defined group of diseases.
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The pathogenesis of bleomycin-induced pulmonary fibrosis in mice.
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|
10704438
|
Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various downstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively, the DDR can mediate clearance of affected cells that are beyond repair through apoptosis or senescence. The DDR can be activated in response to DNA damage throughout the cell cycle, although the extent of DDR signaling is different in each cell cycle phase. Especially in response to DNA double strand breaks, only a very marginal response was observed during mitosis. Early on it was recognized that cells which are irradiated during mitosis continued division without repairing broken chromosomes. Although these initial observations indicated diminished DNA repair and lack of an acute DNA damage-induced cell cycle arrest, insight into the mechanistic re-wiring of DDR signaling during mitosis was only recently provided. Different mechanisms appear to be at play to inactivate specific signaling axes of the DDR network in mitosis. Importantly, mitotic cells not simply inactivate the entire DDR, but appear to mark their DNA damage for repair after mitotic exit. Since the treatment of cancer frequently involves agents that induce DNA damage as well as agents that block mitotic progression, it is clinically relevant to obtain a better understanding of how cancer cells deal with DNA damage during interphase versus mitosis. In this review, the molecular details concerning DDR signaling during mitosis as well as the consequences of encountering DNA damage during mitosis for cellular fate are discussed.
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The DNA damage response during mitosis.
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10743131
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Geostatistics is concerned with estimation and prediction problems for spatially continuous phenomena, using data obtained at a limited number of spatial locations. Model-based geostatistics refers to the application of general statistical principles of modelling and inference to geostatisatical problems. This volume is the first book-length treatment of model-based geostatistics.
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Model-based Geostatistics
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10749308
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Placebo-controlled trials are used extensively in the development of new pharmaceuticals. They are sometimes challenged as unethical in settings in which patients could be treated with an existing therapy (1-7). The issues of when placebo controls are ethically acceptable and when they are scientifically necessary are important and worthy of discussion. The Ethics of Placebo Controls The Declaration of Helsinki The Declaration of Helsinki (8) is an international document that describes ethical principles for clinical investigation. Those who contend that placebo controls are unethical whenever known effective therapy exists for a condition usually cite the following sentence in the Declaration as support for that position: In any medical study, every patientincluding those of a control group, if anyshould be assured of the best proven diagnostic and therapeutic method. We believe that an interpretation of this sentence as barring placebo controls whenever an effective treatment exists is untenable. First, the requirement that all patients receive the best proven diagnostic and therapeutic method would bar not only placebo-controlled trials but also active-control and historically controlled trials. When effective treatment exists, the patient receiving the investigational treatment instead of the established therapy is clearly not getting the best proven treatment. Second, it does not seem reasonable to consider as equivalent all failures to use known effective therapy. Historically, concerns about placebo use have usually arisen in the context of serious illness. There is universal agreement that use of placebo or otherwise untreated controls is almost always unethical when therapy shown to improve survival or decrease serious morbidity is available. But in cases in which the treatment does not affect the patient's long-term health, an ethical imperative to use existing therapy is not plausible. Can it be, for example, that because topical minoxidil or oral finasteride can grow hair, a placebo-controlled trial of a new remedy for baldness is unethical? Is it really unethical to use placebos in short-term studies of drugs for allergic rhinitis, insomnia, anxiety, dermatoses, heartburn, or headaches in fully informed patients? We do not believe that there is a reasonable basis for arguing that such studies and many other placebo-controlled studies of symptom relief are unethical and that an informed patient cannot properly be asked to participate in them. Third, there is good reason to doubt that the cited phrase was intended to discourage placebo-controlled trials. The phrase under discussion was not part of the original 1964 Declaration but was added in 1975 to reinforce the idea that the physicianpatient relationship must be respected just as it would be in a purely therapeutic situation not involving research objectives (8). In the explanation accompanying the 1975 change, the issue of placebo-controlled trials was not even mentioned (9). The American Medical Association (10), the World Health Organization (11), and the Council for International Organizations of Medical Sciences (12) have rejected the position that the Declaration uniformly bars placebo-controlled trials when proven therapy is available. Informed Consent in Placebo-Controlled Trials Patients asked to participate in a placebo-controlled trial must be informed of the existence of any effective therapy, must be able to explore the consequences of deferring such therapy with the investigator, and must provide fully informed consent. Concern about whether consent to participate in trials is as informed as we would like to believe is valid, but these concerns apply as much to the patient's decision to forgo known effective treatment and risk exposure to a potentially ineffective or even harmful new agent in an active-control trial as to a decision to accept possible persistence of symptoms in a placebo-controlled trial. Thus, this problem is not unique to placebo-controlled trials. For the above reasons, we conclude that placebo-controlled trials may be ethically conducted even when effective therapy exists, as long as patients will not be harmed by participation and are fully informed about their alternatives. Although in many cases application of this standard will be fairly straightforward, in others it will not, and there may be debate about the consequences of deferring treatment (13). Assessment of Effectiveness with Active-Control Trials Clinical trials that, because of deficiencies in study design or conduct, are unlikely to provide scientifically valid and clinically meaningful results raise their own ethical concerns (12, 14). The remainder of this paper will address the inability of commonly proposed alternatives to placebo-controlled trials to evaluate the effectiveness of new treatments in many medical settings. Active-Control Equivalence Trials (Noninferiority Trials) The ability to conduct a placebo-controlled trial ethically in a given situation does not necessarily mean that placebo-controlled trials should be carried out when effective therapy exists. Patients and physicians might still prefer a trial in which every participant is given an active treatment. What remains to be examined is why placebo-controlled trials (or, more generally, trials intended to show an advantage of one treatment over another) are frequently needed to demonstrate the effectiveness of new treatments and often cannot be replaced by active-control trials showing that a new drug is equivalent or noninferior to a known effective agent. The limitations of active-control equivalence trials (ACETs) that are intended to show the effectiveness of a new drug have long been recognized and are well described (15-33) but are perhaps not as widely appreciated as they should be. A recent proposed international guideline on choice of control group addresses this issue in detail (33). The Fundamental Problem: Need for Assay Sensitivity There are two distinct ways to show that a new therapy is effective. One can show that the new therapy is superior to a control treatment, or one can show that the new therapy is equivalent to or not worse by some defined amount than a known effective treatment. Each method can be valid, but each requires entirely different inferential approaches. A well-designed study that shows superiority of a treatment to a control (placebo or active therapy) provides strong evidence of the effectiveness of the new treatment, limited only by the statistical uncertainty of the result. No information external to the trial is needed to support the conclusion of effectiveness. In contrast, a study that successfully shows equivalencethat is, little difference between a new drug and known active treatmentdoes not by itself demonstrate that the new treatment is effective. Equivalence could mean that the treatments were both effective in the study, but it could also mean that both treatments were ineffective in the study. To conclude from an ACET that a new treatment is effective on the basis of its similarity to the active control, one must make the critical (and untestable within the study) assumption that the active control had an effect in that particular study. In other words, one must assume that if a placebo group had been included, the placebo would have been inferior to the active control (15-33). Support for this assumption must come from sources external to the trial. Although it might appear reasonable to expect a known active agent to be superior to placebo in any given appropriately designed trial, experience has shown that this is not the case for many types of drugs. The ability of a study to distinguish between active and inactive treatments is termed assay sensitivity. If assay sensitivity cannot be assumed, then even if the new and standard treatments appear virtually identical and the confidence interval for their comparison is exquisitely narrow, the study cannot demonstrate effectiveness of the new drug. (Note that in practice, ACETs are not designed simply to show lack of a statistically significant difference between treatments. Rather, such trials are designed to show noninferioritythat the new treatment is not inferior to the control by more than a specified margin. This approach is described in the Appendix.) The best evidence that an active drug would have an effect superior to that of placebo in a given study would be a series of trials of similar design in which the active drug has reliably outperformed placebo. The ACET thus requires information external to the trial (the information about past placebo-controlled studies of the active control) to interpret the results. In this respect, an ACET is similar to a historically controlled trial. In some settings, such as highly responsive cancers, most infectious diseases, and some cardiovascular conditions, such external information is available and ACETs can and do provide a valid and reliable basis for evaluating new treatments. In many cases, however, the historically based assumption of assay sensitivity cannot be made; for many types of effective drugs, studies of apparently adequate size and design do not regularly distinguish drugs from placebo (16-18, 25, 34). More than 20 years ago, Lasagna (19) described this difficulty particularly well (reflecting long recognition of the problem among analgesiologists): a comparison between new drug and standard is convincing only when the new remedy is superior to standard treatment. If it is inferior, or even indistinguishable from a standard remedy, the results are not readily interpretable. In the absence of placebo controls, one does not know if the inferior new medicine has any efficacy at all, and equivalent performance may reflect simply a patient population that cannot distinguish between two active treatments that differ considerably from each other, or between active drug and placebo. Certain clinical conditions, such as seri
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Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 1: Ethical and Scientific Issues
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|
10761515
|
In 30 patients with cancer of the large bowel, 24 (80%) had detectable levels of methane in their breath, compared with 25 (39%) of 64 patients with non-malignant large-bowel disease and 83 (40%) of 208 subjects without large-bowel disease. These findings suggest that there may be a difference in anaerobic intestinal flora between patients with cancer of the large bowel and those without the disease. This difference may antedate the development of the tumour or, alternatively, result from the tumour.
|
Breath-methane in patients with cancer of the large bowel.
|
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|
10765888
|
Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.
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Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood
|
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10766688
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Population diversity data have recently provided profound, albeit inferential, insights into meiotic recombination across the human genome, revealing a landscape dominated by thousands of cross-over hotspots. However, very few of these putative hotspots have been directly analyzed for cross-over activity. We now describe a search for very active hotspots, by using extreme breakdown of marker association as a guide for high-resolution sperm cross-over analysis. This strategy has led to the isolation of the most active cross-over hotspots yet described. Their morphology, sequence attributes, and cross-over processes are very similar to those seen at less active hotspots, but their activity in sperm is poorly predicted from population diversity information. Several of these hotspots showed evidence for biased gene conversion accompanying cross-over, in some cases associated with variation between men in cross-over activity and with two hotspots showing complete presence/absence polymorphism in different men. Hotspot polymorphism is very common at less active hotspots but curiously was not seen at any of the most active hotspots. This contrasts with the prediction that extreme hotspots should be the most vulnerable to attenuation by meiotic drive in favor of mutations that suppress recombination and should therefore show rapid rate evolution and thus variation in activity between men. Finally, these very intense hotspots provide a valuable resource for dissecting meiotic recombination processes and pathways in humans.
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Sperm cross-over activity in regions of the human genome showing extreme breakdown of marker association.
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10786948
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The generation of induced pluripotent stem cells (iPSCs) provides the opportunity to use patient-specific somatic cells, which are a valuable source for disease modeling and drug discovery. To promote research involving these cells, it is important to make iPSCs from easily accessible and less invasive tissues, like blood. We have recently reported the efficient generation of human iPSCs from adult fibroblasts using a combination of plasmids encoding OCT3/4, SOX2, KLF4, L-MYC, LIN28, and shRNA for TP53. We herein report a modified protocol enabling efficient iPSC induction from CD34+ cord blood cells and from peripheral blood isolated from healthy donors using these plasmid vectors. The original plasmid mixture could induce iPSCs; however, the efficiency was low. The addition of EBNA1, an essential factor for episomal amplification of the vectors, by an extra plasmid greatly increased the efficiency of iPSC induction, especially when the induction was performed from αβT cells. This improvement enabled the establishment of blood-derived iPSCs from seven healthy donors ranging in age from their 20s to their 60s. This induction method will be useful for the derivation of patient-specific integration-free iPSCs and would also be applicable to the generation of clinical-grade iPSCs in the future.
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An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells.
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10790846
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Many forms of long-lasting behavioral and synaptic plasticity require the synthesis of new proteins. For example, long-term potentiation (LTP) that endures for more than an hour requires both transcription and translation. The signal-transduction mechanisms that couple synaptic events to protein translational machinery during long-lasting synaptic plasticity, however, are not well understood. One signaling pathway that is stimulated by growth factors and results in the translation of specific mRNAs includes the rapamycin-sensitive kinase mammalian target of rapamycin (mTOR, also known as FRAP and RAFT-1). Several components of this translational signaling pathway, including mTOR, eukaryotic initiation factor-4E-binding proteins 1 and 2, and eukaryotic initiation factor-4E, are present in the rat hippocampus as shown by Western blot analysis, and these proteins are detected in the cell bodies and dendrites in the hippocampal slices by immunostaining studies. In cultured hippocampal neurons, these proteins are present in dendrites and are often found near the presynaptic protein, synapsin I. At synaptic sites, their distribution completely overlaps with a postsynaptic protein, PSD-95. These observations suggest the postsynaptic localization of these proteins. Disruption of mTOR signaling by rapamycin results in a reduction of late-phase LTP expression induced by high-frequency stimulation; the early phase of LTP is unaffected. Rapamycin also blocks the synaptic potentiation induced by brain-derived neurotrophic factor in hippocampal slices. These results demonstrate an essential role for rapamycin-sensitive signaling in the expression of two forms of synaptic plasticity that require new protein synthesis. The localization of this translational signaling pathway at postsynaptic sites may provide a mechanism that controls local protein synthesis at potentiated synapses.
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A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus.
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0.5220900774002075, "29720": 0.8212929964065552}
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10795063
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SPECIFIC AIMSOur previous studies implied the relation between lipid metabolism and amyloid beta protein (Aβ) as ‘a missing link in Alzheimer’s puzzle’ [FASEB J., vol. 12, p. 1097 (1998)]. In the present study, we evaluated the role of cholesterol in synaptic plasticity and neuronal degeneration by a combination of adult rat hippocampal slice technology, a well-established procedure for limited cholesterol efflux, lipid metabolic labeling, extracellular recording of CA1 field excitatory postsynaptic potentials (fEPSPs), and immunofluorescence. PRINCIPAL FINDINGS1. Increased cholesterol efflux impairs short- and long-term synaptic plasticitySynaptic plasticity is a fundamental feature of the central nervous system (CNS) that allows synapses to ‘remember’ previous activity and express plastic changes to fine-tune current synaptic action. In this study, we asked whether an increased cholesterol efflux induced ex vivo by normal human CSF-HDL3 and methyl-β-cyclodextrin (MβCD) (a natural and model cholesterol ac...
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The FASEB Journal express article 10.1096/fj.00-0815fje. Published online June 27, 2001. Essential role for cholesterol in synaptic plasticity and neuronal degeneration
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10795340
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Pancytopenia is a major cause of morbidity in acute myeloid leukemia (AML), yet its cause is unclear. Normal osteoblastic cells have been shown to support hematopoiesis. To define the effects of leukemia on osteoblastic cells, we used an immunocompetent murine model of AML. Leukemic mice had inhibition of osteoblastic cells, with decreased serum levels of the bone formation marker osteocalcin. Osteoprogenitor cells and endosteal-lining osteopontin(+) cells were reduced, and osteocalcin mRNA in CD45(-) marrow cells was diminished. This resulted in severe loss of mineralized bone. Osteoclasts were only transiently increased without significant increases in bone resorption, and their inhibition only partially rescued leukemia-induced bone loss. In vitro data suggested that a leukemia-derived secreted factor inhibited osteoblastic cells. Because the chemokine CCL-3 was recently reported to inhibit osteoblastic function in myeloma, we tested its expression in our model and in AML patients. Consistent with its potential novel role in leukemic-dependent bone loss, CCL-3 mRNA was significantly increased in malignant marrow cells from leukemic mice and from samples from AML patients. Based on these results, we propose that therapeutic mitigation of leukemia-induced uncoupling of osteoblastic and osteoclastic cells may represent a novel approach to promote normal hematopoiesis in patients with myeloid neoplasms.
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Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia.
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10812605
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Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.
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Fibroblast heterogeneity in the cancer wound
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"27615": 0.1693800985813141, "27794": 0.4556184411048889, "27805": 0.32129061222076416, "27922": 0.6892333030700684, "28321": 0.6011518239974976, "28329": 0.045809537172317505, "28689": 0.5540198087692261, "28767": 0.0038986403960734606, "28794": 0.03266380727291107, "29382": 0.07250232994556427, "29392": 0.04113444685935974}
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10827901
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The China Health and Retirement Longitudinal Study (CHARLS) is a nationally representative longitudinal survey of persons in China 45 years of age or older and their spouses, including assessments of social, economic, and health circumstances of community-residents. CHARLS examines health and economic adjustments to rapid ageing of the population in China. The national baseline survey for the study was conducted between June 2011 and March 2012 and involved 17 708 respondents. CHARLS respondents are followed every 2 years, using a face-to-face computer-assisted personal interview (CAPI). Physical measurements are made at every 2-year follow-up, and blood sample collection is done once in every two follow-up periods. A pilot survey for CHARLS was conducted in two provinces of China in 2008, on 2685 individuals, who were resurveyed in 2012. To ensure the adoption of best practices and international comparability of results, CHARLS was harmonized with leading international research studies in the Health and Retirement Study (HRS) model. Requests for collaborations should be directed to Dr Yaohui Zhao ([email protected]). All data in CHARLS are maintained at the National School of Development of Peking University and will be accessible to researchers around the world at the study website. The 2008 pilot data for CHARLS are available at: http://charls.ccer.edu.cn/charls/. National baseline data for the study are expected to be released in January 2013.
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Cohort profile: the China Health and Retirement Longitudinal Study (CHARLS).
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0.8433839678764343, "27166": 0.7370892763137817, "27321": 0.5849615335464478, "27781": 0.7105726003646851, "28025": 0.6358738541603088, "28674": 1.0193830728530884, "28788": 0.3084607720375061, "28873": 0.1332872211933136, "29215": 0.4794800877571106, "29532": 0.1221139207482338, "29543": 0.7028654217720032}
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10831818
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OBJECTIVE Multiple sclerosis (MS) is a disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Based on infiltrating immune cells, deposition of humoral factors and loss of oligodendrocytes and/or myelin proteins, four lesion patterns have been described. Pattern II is characterized by antibody and complement deposition in addition to T-cell infiltration. MS is considered a T-cell-mediated disease, but until now the study of pathogenic T cells has encountered major challenges, most importantly the limited access of brain-infiltrating T cells. Our objective was to identify, isolate, and characterize brain-infiltrating clonally expanded T cells in pattern II MS lesions. METHODS We used next-generation sequencing to identify clonally expanded T cells in demyelinating pattern II brain autopsy lesions, subsequently isolated these as T-cell clones from autologous cerebrospinal fluid and functionally characterized them. RESULTS We identified clonally expanded CD8(+) but also CD4(+) T cells in demyelinating pattern II lesions and for the first time were able to isolate these as live T-cell clones. The functional characterization shows that T cells releasing Th2 cytokines and able to provide B cell help dominate the T-cell infiltrate in pattern II brain lesions. INTERPRETATION Our data provide the first functional evidence for a putative role of Th2/Tc2 cells in pattern II MS supporting the existence of this pathogenic phenotype and questioning the protective role that is generally ascribed to Th2 cells. Our observations are important to consider for future treatments of pattern II MS patients.
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Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions
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10846815
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The actin cortex both facilitates and hinders the exocytosis of secretory granules. How cells consolidate these two opposing roles was not well understood. Here we show that antigen activation of mast cells induces oscillations in Ca(2+) and PtdIns(4,5)P(2) lipid levels that in turn drive cyclic recruitment of N-WASP and cortical actin level oscillations. Experimental and computational analysis argues that vesicle fusion correlates with the observed actin and Ca(2+) level oscillations. A vesicle secretion cycle starts with the capture of vesicles by actin when cortical F-actin levels are high, followed by vesicle passage through the cortex when F-actin levels are low, and vesicle fusion with the plasma membrane when Ca(2+) levels subsequently increase. Thus, cells employ oscillating levels of Ca(2+), PtdIns(4,5)P(2) and cortical F-actin to increase secretion efficiency, explaining how the actin cortex can function as a carrier as well as barrier for vesicle secretion.
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Coordinated oscillations in cortical actin and Ca2+ correlate with cycles of vesicle secretion
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10852047
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We recently developed a class of novel antitumor agents that elicit a potent growth-inhibitory response in many tumor cells cultured in vitro. WK175, a member of this class, was chosen as a model compound that showed strong in vitro efficacy. WK175 interferes with the intracellular steady-state level of NAD(+), resulting in a decreased cellular NAD(+) concentration. We found that WK175 induces apoptotic cell death without any DNA-damaging effect. The apoptotic death signaling pathway initiated by WK175 was examined in detail: mitochondrial membrane potential, cytochrome c release, caspase 3 activation, caspase 3 and poly(ADP-ribose) polymerase cleavage, and the appearance of a sub-G(1) cell cycle population were determined in time course studies in THP-1 (a human monocytic leukemia cell line) cells. We found activation of this cascade after 24 h of treatment with 10 nM WK175. Induction of apoptosis was prevented by bongkrekic acid, Z-Asp-Glu-Val-Asp-fluoromethylketone, and Z-Leu-Glu-His-Asp-fluoromethylketone, inhibitors of the mitochondrial permeability transition and of caspase 3 and 9, respectively, but not by Ac-Tyr-Val-Ala-Asp-CHO, a specific caspase 1 inhibitor, suggesting the involvement of the permeability transition pore, caspase 3, and caspase 9 in the WK175-induced apoptotic cascade. These results imply that decreased NAD(+) concentration initiates the apoptotic cascade, resulting in the antitumor effect of WK175.
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WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells.
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10854174
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BACKGROUND A primary cause of high maternal mortality in Bangladesh is lack of access to professional delivery care. Examining the role of the family, particularly the husband, during pregnancy and childbirth is important to understanding women's access to and utilization of professional maternal health services that can prevent maternal mortality. This qualitative study examines husbands' involvement during childbirth and professional delivery care utilization in a rural sub-district of Netrokona district, Bangladesh. METHODS Using purposive sampling, ten households utilizing a skilled attendant during the birth of the youngest child were selected and matched with ten households utilizing an untrained traditional birth attendant, or dhatri. Households were selected based on a set of inclusion criteria, such as approximate household income, ethnicity, and distance to the nearest hospital. Twenty semi-structured interviews were conducted in Bangla with husbands in these households in June 2010. Interviews were transcribed, translated into English, and analyzed using NVivo 9.0. RESULTS By purposefully selecting households that differed on the type of provider utilized during delivery, common themes--high costs, poor transportation, and long distances to health facilities--were eliminated as sufficient barriers to the utilization of professional delivery care. Divergent themes, namely husbands' social support and perceived social norms, were identified as underlying factors associated with delivery care utilization. We found that husbands whose wives utilized professional delivery care provided emotional, instrumental and informational support to their wives during delivery and believed that medical intervention was necessary. By contrast, husbands whose wives utilized an untrained dhatri at home were uninvolved during delivery and believed childbirth should take place at home according to local traditions. CONCLUSIONS This study provides novel evidence about male involvement during childbirth in rural Bangladesh. These findings have important implications for program planners, who should pursue culturally sensitive ways to involve husbands in maternal health interventions and assess the effectiveness of education strategies targeted at husbands.
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Husbands' involvement in delivery care utilization in rural Bangladesh: A qualitative study
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10874408
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DNA double-strand breaks (DSBs), which are formed by the Spo11 protein, initiate meiotic recombination. Previous DSB-mapping studies have used rad50S or sae2Δ mutants, which are defective in break processing, to accumulate Spo11-linked DSBs, and report large (≥ 50 kb) “DSB-hot” regions that are separated by “DSB-cold” domains of similar size. Substantial recombination occurs in some DSB-cold regions, suggesting that DSB patterns are not normal in rad50S or sae2Δ mutants. We therefore developed a novel method to map genome-wide, single-strand DNA (ssDNA)–associated DSBs that accumulate in processing-capable, repair-defective dmc1Δ and dmc1Δ rad51Δ mutants. DSBs were observed at known hot spots, but also in most previously identified “DSB-cold” regions, including near centromeres and telomeres. Although approximately 40% of the genome is DSB-cold in rad50S mutants, analysis of meiotic ssDNA from dmc1Δ shows that most of these regions have substantial DSB activity. Southern blot assays of DSBs in selected regions in dmc1Δ, rad50S, and wild-type cells confirm these findings. Thus, DSBs are distributed much more uniformly than was previously believed. Comparisons of DSB signals in dmc1, dmc1 rad51, and dmc1 spo11 mutant strains identify Dmc1 as a critical strand-exchange activity genome-wide, and confirm previous conclusions that Spo11-induced lesions initiate all meiotic recombination.
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Mapping Meiotic Single-Strand DNA Reveals a New Landscape of DNA Double-Strand Breaks in Saccharomyces cerevisiae
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"29237": 0.30989447236061096, "29295": 0.17922431230545044, "29299": 0.500420093536377, "29458": 0.6931471824645996, "29592": 0.06429435312747955}
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10883736
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CONTEXT The mechanisms that drive progression from fatty liver to steatohepatitis and cirrhosis are unknown. In animal models, obese mice with fatty livers are vulnerable to liver adenosine triphosphate (ATP) depletion and necrosis, suggesting that altered hepatic energy homeostasis may be involved. OBJECTIVE To determine if patients with fatty liver disease exhibit impaired recovery from hepatic ATP depletion. DESIGN Laboratory analysis of liver ATP stores monitored by nuclear magnetic resonance spectroscopy before and after transient hepatic ATP depletion was induced by fructose injection. The study was conducted between July 15 and August 30, 1998. SETTING University hospital. PATIENTS Eight consecutive adults with biopsy-proven nonalcoholic steatohepatitis and 7 healthy age- and sex-matched controls. MAIN OUTCOME MEASURE Level of ATP 1 hour after fructose infusion in patients vs controls. RESULTS In patients, serum aminotransferase levels were increased (P = .02 vs controls); albumin and bilirubin values were normal and clinical evidence of portal hypertension was absent in both groups. However, 2 patients had moderate fibrosis and 1 had cirrhosis on liver biopsy. Mean serum glucose, cholesterol, and triglyceride levels were similar between groups but patients weighed significantly more than controls (P = .02). Liver ATP levels were similar in the 2 groups before fructose infusion and decreased similarly in both after fructose infusion (P = .01 vs initial ATP levels). However, controls replenished their hepatic ATP stores during the 1-hour follow-up period (P<.02 vs minimum ATP) but patients did not. Hence, patients' hepatic ATP levels were lower than those of controls at the end of the study (P = .04). Body mass index (BMI) correlated inversely with ATP recovery, even in controls (R = -0.768; P = .07). Although BMI was greater in patients than controls (P = .02) and correlated strongly with fatty liver and serum aminotransferase elevations, neither of the latter 2 parameters nor the histologic severity of fibrosis strongly predicted hepatic ATP recovery. CONCLUSIONS These data suggest that recovery from hepatic ATP depletion becomes progressively less efficient as body mass increases in healthy controls and is severely impaired in patients with obesity-related nonalcoholic steatohepatitis.
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Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study.
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10889845
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Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.
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Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance.
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0.08064348995685577, "24873": 0.5410289764404297, "25172": 1.2721059322357178, "25737": 1.3238370418548584, "26046": 0.15275461971759796, "26163": 0.2247048318386078, "26186": 0.05417001247406006, "26206": 0.0913962796330452, "26290": 0.5495203733444214, "26452": 0.20022670924663544, "26480": 0.34508460760116577, "26497": 0.6714286804199219, "26677": 0.4093637466430664, "26745": 0.02792670577764511, "27196": 0.15023678541183472, "27241": 0.5957841277122498, "27274": 0.24631060659885406, "27354": 0.04394211992621422, "27484": 0.14095009863376617, "27520": 0.8917738795280457, "27615": 0.13157635927200317, "27800": 0.15023678541183472, "28042": 0.176772341132164, "28266": 0.010684899985790253, "28268": 0.495672345161438, "28466": 0.1510767638683319, "28767": 0.5952457785606384, "28776": 0.13670019805431366, "28965": 0.0038986403960734606, "29025": 0.12384103983640671, "29080": 0.1905880719423294, "29277": 0.2689530849456787, "29353": 0.025073638185858727, "29392": 0.1602703034877777, "29394": 0.2539152204990387, "29417": 0.29473719000816345, "29458": 0.39893341064453125, "29533": 0.11778303235769272}
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10893238
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BACKGROUND Frail and dependent older people in resource-poor settings are poorly served by health systems that lack outreach capacity. The COPE (Caring for Older PEople) multidimensional assessment tool is designed to help community health workers (CHWs) identify clinically significant impairments and deliver evidence-based interventions METHODS Older people (n = 150) identified by CHWs as frail or dependent, were assessed at home by the CHW using the structured COPE assessment tool, generating information on impairments in nutrition, mobility, vision, hearing, continence, cognition, mood and behaviour. The older people were reassessed by local physicians who reached a clinical judgment regarding the presence or absence of the same impairments based upon clinical examination guided by the EASY-Care assessment tool. RESULTS The COPE tool was considered easy to administer, and gave CHWs a sense of empowerment to understand and act upon the needs of older people. Agreement between COPE assessment by CHW and clinician assessors was modest (ranged from 45.8 to 91.3 %) for most impairments. However, the prevalence of impairments was generally higher according to clinicians, particularly for visual impairment (98.7 vs 45.8 %), cognitive impairment (78.4 vs. 38.2 %) and depression (82.0 vs. 59.9 %). Most cases identified by WHO-COPE were clinician confirmed (positive predictive values - 72.2 to 98.5 %), and levels of disability and needs for care among those identified by COPE were higher than those additionally identified by the clinician alone. CONCLUSIONS The COPE is a feasible tool for the identification of specific impairments in frail dependent older people in the community. Those identified are likely to be confirmed as having clinically relevant problems by clinicians working in the same service, and the COPE may be particularly effective at targeting attention upon those with the most substantial unmet needs.
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Identifying common impairments in frail and dependent older people: validation of the COPE assessment for non-specialised health workers in low resource primary health care settings
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10906636
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US28 is one of four 7 transmembrane (7TM) chemokine receptors encoded by human cytomegalovirus and has been shown to both signal and endocytose in a ligand-independent, constitutively active manner. Here we show that the constitutive activity and constitutive endocytosis properties of US28 are separable entities in this viral chemokine receptor. We generated chimeric and mutant US28 proteins that were altered in either their constitutive endocytic (US28 Delta 300, US28 Delta 317, US28-NK1-ctail, and US28-ORF74-ctail) or signaling properties (US28R129A). By using this series of mutants, we show that the cytoplasmic tail domain of US28 per se regulates receptor endocytosis, independent of the signaling ability of the core domain of US28. The constitutive endocytic property of the US28 c-tail was transposable to other 7TM receptors, the herpes virus 8-encoded ORF74 and the tachykinin NK1 receptor (ORF74-US28-ctail and NK1-US28-ctail). Deletion of the US28 C terminus resulted in reduced constitutive endocytosis and consequently enhanced signaling capacity of all receptors tested as assessed by inositol phosphate turnover, NF-kappa B, and cAMP-responsive element-binding protein transcription assays. We further show that the constitutive endocytic property of US28 affects the action of its chemokine ligand fractalkine/CX3CL1 and show that in the absence of the US28 C terminus, fractalkine/CX3CL1 acts as an agonist on US28. This demonstrates for the first time that the endocytic properties of a 7TM receptor can camouflage the agonist properties of a ligand.
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The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis.
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10931595
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Developmental signaling networks are composed of dozens of components whose interactions are very difficult to quantify in an embryo. Geometric reasoning enumerates a discrete hierarchy of phenotypic models with a few composite variables whose parameters may be defined by in vivo data. Vulval development in the nematode Caenorhabditis elegans is a classic model for the integration of two signaling pathways; induction by EGF and lateral signaling through Notch. Existing data for the relative probabilities of the three possible terminal cell types in diverse genetic backgrounds as well as timed ablation of the inductive signal favor one geometric model and suffice to fit most of its parameters. The model is fully dynamic and encompasses both signaling and commitment. It then predicts the correlated cell fate probabilities for a cross between any two backgrounds/conditions. The two signaling pathways are combined additively, without interactions, and epistasis only arises from the nonlinear dynamical flow in the landscape defined by the geometric model. In this way, the model quantitatively fits genetic experiments purporting to show mutual pathway repression. The model quantifies the contributions of extrinsic vs. intrinsic sources of noise in the penetrance of mutant phenotypes in signaling hypomorphs and explains available experiments with no additional parameters. Data for anchor cell ablation fix the parameters needed to define Notch autocrine signaling.
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Geometry, epistasis, and developmental patterning.
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10937190
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The morphogenesis of the C. elegans embryo is largely controlled by the development of the epidermis, also known as the hypodermis, a single epithelial layer that surrounds the animal. Morphogenesis of the epidermis involves cell-cell interactions with internal tissues, such as the developing nervous system and musculature. Genetic analysis of mutants with aberrant epidermal morphology has defined multiple steps in epidermal morphogenesis. In the wild type, epidermal cells are generated on the dorsal side of the embryo among the progeny of four early embryonic blastomeres. Specification of epidermal fate is regulated by a hierarchy of transcription factors. After specification, dorsal epidermal cells rearrange, a process known as dorsal intercalation. Most epidermal cells fuse to generate multinucleate syncytia. The dorsally located epidermal sheet undergoes epiboly to enclose the rest of the embryo in a process known as ventral enclosure; this movement requires both an intact epidermal layer and substrate neuroblasts. At least three distinct types of cellular behavior underlie the enclosure of different regions of the epidermis. Following enclosure, the epidermis elongates, a process driven by coordinated cell shape changes. Epidermal actin microfilaments, microtubules, and intermediate filaments all play roles in elongation, as do body wall muscles. The final shape of the epidermis is maintained by the collagenous exoskeleton, secreted by the apical surface of the epidermis.
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Table of Contents
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10944947
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Using high-throughput sequencing, we devised a technique to determine the insertion sites of virtually all members of the human-specific L1 retrotransposon family in any human genome. Using diagnostic nucleotides, we were able to locate the approximately 800 L1Hs copies corresponding specifically to the pre-Ta, Ta-0, and Ta-1 L1Hs subfamilies, with over 90% of sequenced reads corresponding to human-specific elements. We find that any two individual genomes differ at an average of 285 sites with respect to L1 insertion presence or absence. In total, we assayed 25 individuals, 15 of which are unrelated, at 1139 sites, including 772 shared with the reference genome and 367 nonreference L1 insertions. We show that L1Hs profiles recapitulate genetic ancestry, and determine the chromosomal distribution of these elements. Using these data, we estimate that the rate of L1 retrotransposition in humans is between 1/95 and 1/270 births, and the number of dimorphic L1 elements in the human population with gene frequencies greater than 0.05 is between 3000 and 10,000.
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High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes.
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"23699": 0.27564704418182373, "23900": 0.1734936386346817, "24501": 0.672426164150238, "24759": 0.3141832649707794, "24952": 0.3141832649707794, "25050": 0.02792670577764511, "25086": 0.4425300657749176, "25229": 0.10379679501056671, "25409": 0.8764448165893555, "25468": 0.07068414986133575, "25549": 0.5871354341506958, "25604": 0.6853039860725403, "25778": 0.16442140936851501, "26033": 0.24018502235412598, "26179": 0.3883931338787079, "26226": 0.00875066313892603, "26351": 1.227902889251709, "26462": 0.35334911942481995, "26745": 0.7047978043556213, "26906": 0.13071982562541962, "27144": 0.5612884759902954, "27441": 0.0317181795835495, "27881": 0.06337817758321762, "28207": 0.18573370575904846, "28314": 0.255429208278656, "28389": 0.10379679501056671, "28472": 0.009718249551951885, "28667": 0.3077431619167328, "29109": 0.0354953333735466, "29110": 0.01934296265244484}
|
10958594
|
The aim of this study was to determine trends in incidence, treatment and survival of colorectal cancer (CRC) patients with synchronous metastases (Stage IV) in the Netherlands. This nationwide population-based study included 160,278 patients diagnosed with CRC between 1996 and 2011. We evaluated changes in stage distribution, location of synchronous metastases and treatment in four consecutive periods, using Chi square tests for trend. Median survival in months was determined, using Kaplan–Meier analysis. The proportion of Stage IV CRC patients (n = 33,421) increased from 19 % (1996–1999) to 23 % (2008–2011, p < 0.001). This was predominantly due to a major increase in the incidence of lung metastases (1.7–5.0 % of all CRC patients). During the study period, the primary tumor was resected less often in Stage IV patients (65–46 %) and the use of systemic treatment has increased (29–60 %). Also an increase in metastasectomy was found in patients with one metastatic site, especially in patients with liver-only disease (5–18 %, p < 0.001). Median survival of all Stage IV CRC patients increased from 7 to 12 months. Especially in patients with metastases confined to the liver or lungs this improvement in survival was apparent (9–16 and 12–24 months respectively, both p < 0.001). In the last two decades, more lung metastases were detected and an increasing proportion of Stage IV CRC patients was treated with systemic therapy and/or metastasectomy. Survival of patients has significantly improved. However, the prognosis of Stage IV patients becomes increasingly diverse.
|
Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases
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{"1005": 0.10379679501056671, "1038": 1.225611925125122, "1041": 0.8893690705299377, "1048": 0.46117570996284485, "1055": 0.5092619061470032, "1999": 0.07884006202220917, "2001": 0.3910386264324188, "2007": 0.3897167444229126, "2010": 0.05970508232712746, "2026": 0.8829278349876404, "2029": 0.26296505331993103, "2034": 0.817850649356842, "2038": 0.12470348179340363, "2042": 0.08871890604496002, "2043": 0.17759032547473907, "2076": 0.12470348179340363, "2106": 0.40220460295677185, "2140": 1.0423725843429565, "2144": 0.23864774405956268, "2158": 0.0354953333735466, "2171": 0.08244366943836212, "2179": 0.48670899868011475, "2211": 0.007782140281051397, "2234": 0.0797421783208847, "2278": 0.2954642176628113, "2315": 0.02887592278420925, "2318": 0.1602703034877777, "2381": 0.2786078155040741, "2434": 0.020300358533859253, "2458": 0.6286086440086365, "2497": 0.755608320236206, "2522": 0.25995752215385437, "2529": 0.7445381283760071, "2535": 0.6764062643051147, "2580": 0.19541899859905243, 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0.1946154683828354, "21198": 0.14433705806732178, "21434": 0.7951818704605103, "21557": 0.09406650811433792, "21754": 0.24171993136405945, "21890": 0.030771657824516296, "21935": 0.17267228662967682, "22186": 0.23633737862110138, "22520": 0.1401015669107437, "22529": 0.20660123229026794, "22931": 0.23092569410800934, "23041": 0.08871890604496002, "23150": 0.175953671336174, "23340": 0.012615402229130268, "23350": 0.6980181336402893, "23572": 0.0038986403960734606, "23737": 0.21765978634357452, "23824": 0.2105647772550583, "23900": 0.036437395960092545, "24093": 0.17840765416622162, "24129": 0.2317005842924118, "24290": 0.11865071207284927, "24335": 1.179255723953247, "24759": 0.09317722171545029, "24817": 0.8649974465370178, "25320": 0.14602625370025635, "25409": 0.5827828645706177, "25468": 0.9232974052429199, "26013": 0.5472630262374878, "26305": 0.12038381397724152, "26475": 0.3325583338737488, "26646": 1.4874467849731445, "26757": 1.061472773551941, "26835": 0.9209672808647156, "26994": 0.8500841856002808, "27881": 0.18329764902591705, "28086": 0.151916041970253, "28723": 0.04394211992621422, "28788": 0.20421554148197174, "28873": 0.4487839937210083}
|
10976596
|
Burkitt's lymphoma (BL) was first described 50 years ago, and the first human tumour virus Epstein–Barr virus (EBV) was discovered in BL tumours soon after. Since then, the role of EBV in the development of BL has become more and more enigmatic. Only recently have we finally begun to understand, at the cellular and molecular levels, the complex and interesting interaction of EBV with B cells that creates a predisposition for the development of BL. Here, we discuss the intertwined histories of EBV and BL and their relationship to the cofactors in BL pathogenesis: malaria and the MYC translocation.
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The curious case of the tumour virus: 50 years of Burkitt's lymphoma
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10982689
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Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.
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Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles
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10984005
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CONTEXT More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention-deficit/hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure, raising concerns about their cardiovascular safety. OBJECTIVE To examine whether current use of medications prescribed primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults. DESIGN, SETTING, AND PARTICIPANTS Retrospective, population-based cohort study using electronic health care records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at 1 site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data. Participants were adults aged 25 through 64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n = 150,359) was matched to 2 nonusers on study site, birth year, sex, and calendar year (443,198 total users and nonusers). MAIN OUTCOME MEASURES Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke, with comparison between current or new users and remote users to account for potential healthy-user bias. RESULTS During 806,182 person-years of follow-up (median, 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person-years of current use (median, 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14-1.57) for MI, 0.30 (95% CI, 0.20-0.42) for SCD, and 0.56 (95% CI, 0.43-0.72) for stroke. The multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current use vs nonuse of ADHD medications was 0.83 (95% CI, 0.72-0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI, 0.63-0.94). The adjusted RR for current use vs remote use was 1.03 (95% CI, 0.86-1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI, 0.82-1.28); the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years at ages 25-44 years and 0.77 events per 1000 person-years at ages 45-64 years. CONCLUSIONS Among young and middle-aged adults, current or new use of ADHD medications, compared with nonuse or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy-user bias.
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ADHD medications and risk of serious cardiovascular events in young and middle-aged adults.
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10991183
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How individual cells respond to mechanical forces is of considerable interest to biologists as force affects many aspects of cell behaviour. The application of force on integrins triggers cytoskeletal rearrangements and growth of the associated adhesion complex, resulting in increased cellular stiffness, also known as reinforcement. Although RhoA has been shown to play a role during reinforcement, the molecular mechanisms that regulate its activity are unknown. By combining biochemical and biophysical approaches, we identified two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signalling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signalling cascade that includes FAK and Ras.
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The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins
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10993232
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Recent observations have suggested that classic antibiotics kill bacteria by stimulating the formation of reactive oxygen species (ROS). If true, this notion might guide new strategies to improve antibiotic efficacy. In this study, the model was directly tested. Contrary to the hypothesis, antibiotic treatment did not accelerate the formation of hydrogen peroxide in Escherichia coli and did not elevate intracellular free iron, an essential reactant for the production of lethal damage. Lethality persisted in the absence of oxygen, and DNA repair mutants were not hypersensitive, undermining the idea that toxicity arose from oxidative DNA lesions. We conclude that these antibiotic exposures did not produce ROS and that lethality more likely resulted from the direct inhibition of cell-wall assembly, protein synthesis, and DNA replication.
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Cell death from antibiotics without the involvement of reactive oxygen species.
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11011905
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Pioneer transcription factors (TFs) access silent chromatin and initiate cell-fate changes, using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer TF, has a winged helix DBD that resembles linker histone and thereby binds its target sites on nucleosomes and in compacted chromatin. Herein, we compare the nucleosome and chromatin targeting activities of Oct4 (POU DBD), Sox2 (HMG box DBD), Klf4 (zinc finger DBD), and c-Myc (bHLH DBD), which together reprogram somatic cells to pluripotency. Purified Oct4, Sox2, and Klf4 proteins can bind nucleosomes in vitro, and in vivo they preferentially target silent sites enriched for nucleosomes. Pioneer activity relates simply to the ability of a given DBD to target partial motifs displayed on the nucleosome surface. Such partial motif recognition can occur by coordinate binding between factors. Our findings provide insight into how pioneer factors can target naive chromatin sites.
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Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
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0.21135559678077698, "29458": 0.022212404757738113}
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11016410
|
Within hosts, RNA viruses form populations that are genetically and phenotypically complex. Heterogeneity in RNA virus genomes arises due to error-prone replication and is reduced by stochastic and selective mechanisms that are incompletely understood. Defining how natural selection shapes RNA virus populations is critical because it can inform treatment paradigms and enhance control efforts. We allowed West Nile virus (WNV) to replicate in wild-caught American crows, house sparrows and American robins to assess how natural selection shapes RNA virus populations in ecologically relevant hosts that differ in susceptibility to virus-induced mortality. After five sequential passages in each bird species, we examined the phenotype and population diversity of WNV through fitness competition assays and next generation sequencing. We demonstrate that fitness gains occur in a species-specific manner, with the greatest replicative fitness gains in robin-passaged WNV and the least in WNV passaged in crows. Sequencing data revealed that intrahost WNV populations were strongly influenced by purifying selection and the overall complexity of the viral populations was similar among passaged hosts. However, the selective pressures that control WNV populations seem to be bird species-dependent. Specifically, crow-passaged WNV populations contained the most unique mutations (~1.7× more than sparrows, ~3.4× more than robins) and defective genomes (~1.4× greater than sparrows, ~2.7× greater than robins), but the lowest average mutation frequency (about equal to sparrows, ~2.6× lower than robins). Therefore, our data suggest that WNV replication in the most disease-susceptible bird species is positively associated with virus mutational tolerance, likely via complementation, and negatively associated with the strength of selection. These differences in genetic composition most likely have distinct phenotypic consequences for the virus populations. Taken together, these results reveal important insights into how different hosts may contribute to the emergence of RNA viruses.
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Experimental Evolution of an RNA Virus in Wild Birds: Evidence for Host-Dependent Impacts on Population Structure and Competitive Fitness
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"23977": 0.1685553640127182, "24628": 0.21293537318706512, "24755": 0.129004567861557, "24829": 0.21214580535888672, "24977": 0.0752234235405922, "25022": 1.3838499784469604, "25095": 0.04207121208310127, "25458": 0.3824150264263153, "25505": 0.10993985831737518, "25510": 0.05786345899105072, "25533": 0.49982786178588867, "25572": 0.22859740257263184, "25620": 0.020300358533859253, "25778": 0.006812678650021553, "26228": 0.520350456237793, "26384": 0.12470348179340363, "27425": 0.5995445251464844, "27777": 0.3683255612850189, "28041": 0.08692999184131622, "28170": 0.16690383851528168, "28353": 0.18411032855510712, "28648": 0.00875066313892603, "28775": 0.07341018319129944, "29137": 0.01934296265244484, "29296": 0.2105647772550583, "29347": 0.026025565341114998}
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11016788
|
Data acquisition packages developed at different small angle scattering facilities use different formats both for raw and processed data storage. To facilitate the data exchange between laboratories, a consensus in the small angle scattering community has been reached on an ASCII format for one-dimensional data which includes a self-describing header containing relevant information about the sample and instrumental conditions followed by raw or reduced data in a tabular form. This format called sasCIF was implemented as an extension of core CIF (Crystallographic Information File) dictionary.
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sasCIF: an extension of core Crystallographic Information File for SAS
|
{"1009": 0.5562619566917419, "1011": 0.06337817758321762, "1022": 0.0797421783208847, "1039": 0.29400965571403503, "1040": 0.30558720231056213, "1041": 0.10906458646059036, "1045": 0.4132472574710846, "1048": 0.5197699069976807, "1049": 0.6853039860725403, "1056": 0.9621002674102783, "1999": 0.11430477350950241, "2004": 0.06612417846918106, "2005": 0.16442140936851501, "2007": 0.10731173306703568, "2008": 0.04767346754670143, "2011": 0.3615458607673645, "2014": 0.9546096324920654, "2015": 1.0158531665802002, "2024": 0.09406650811433792, "2029": 0.28082266449928284, "2044": 0.40806588530540466, "2076": 0.16359257698059082, "2079": 0.3388410806655884, "2109": 0.22157983481884003, "2124": 0.007782140281051397, "2140": 0.8861536383628845, "2147": 0.10379679501056671, "2182": 0.0842406153678894, "2193": 0.056018441915512085, "2206": 0.25995752215385437, "2227": 0.3554046154022217, "2235": 0.016465263441205025, "2245": 0.4248080551624298, "2334": 0.9470623731613159, "2339": 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11020556
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Skin dendritic cells (DCs) are thought to act as key initiators of local T cell immunity. Here we show that after skin infection with herpes simplex virus (HSV), cytotoxic T lymphocyte (CTL) activation required MHC class I-restricted presentation by nonmigratory CD8(+) DCs rather than skin-derived DCs. Despite a lack of direct presentation by migratory DCs, blocking their egress from infected skin substantially inhibited class I-restricted presentation and HSV-specific CTL responses. These results support the argument for initial transport of antigen by migrating DCs, followed by its transfer to the lymphoid-resident DCs for presentation and CTL priming. Given that relatively robust CTL responses were seen with small numbers of skin-emigrant DCs, we propose that this inter-DC antigen transfer functions to amplify presentation across a larger network of lymphoid-resident DCs for efficient T cell activation.
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Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.
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11020675
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Megakaryocytes undergo a unique differentiation program, becoming polyploid through repeated cycles of DNA synthesis without concomitant cell division. However, the mechanism underlying this polyploidization remains totally unknown. It has been postulated that polyploidization is due to a skipping of mitosis after each round of DNA replication. We carried out immunohistochemical studies on mouse bone marrow megakaryocytes during thrombopoietin- induced polyploidization and found that during this process megakaryocytes indeed enter mitosis and progress through normal prophase, prometaphase, metaphase, and up to anaphase A, but not to anaphase B, telophase, or cytokinesis. It was clearly observed that multiple spindle poles were formed as the polyploid megakaryocytes entered mitosis; the nuclear membrane broke down during prophase; the sister chromatids were aligned on a multifaced plate, and the centrosomes were symmetrically located on either side of each face of the plate at metaphase; and a set of sister chromatids moved into the multiple centrosomes during anaphase A. We further noted that the pair of spindle poles in anaphase were located in close proximity to each other, probably because of the lack of outward movement of spindle poles during anaphase B. Thus, the reassembling nuclear envelope may enclose all the sister chromatids in a single nucleus at anaphase and then skip telophase and cytokinesis. These observations clearly indicate that polyploidization of megakaryocytes is not simply due to a skipping of mitosis, and that the megakaryocytes must have a unique regulatory mechanism in anaphase, e.g., factors regulating anaphase such as microtubule motor proteins might be involved in this polyploidization process.
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Thrombopoietin-induced Polyploidization of Bone Marrow Megakaryocytes Is Due to a Unique Regulatory Mechanism in Late Mitosis
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0.2317005842924118, "19241": 0.40611594915390015, "19293": 0.2493593990802765, "19476": 0.03360854089260101, "19518": 0.4437839686870575, "19852": 0.3723714053630829, "19857": 1.310231328010559, "19939": 0.8195732831954956, "20062": 0.7028654217720032, "20155": 0.440646231174469, "20248": 0.5220900774002075, "20253": 0.2247048318386078, "20272": 0.09050461649894714, "20302": 0.13499516248703003, "20607": 0.12556517124176025, "20731": 0.35950297117233276, "20792": 0.11430477350950241, "20861": 0.5629584193229675, "20932": 0.9994535446166992, "20969": 0.7086513638496399, "21425": 0.1212492436170578, "21641": 0.18816383183002472, "21663": 0.08782484382390976, "21685": 0.0797421783208847, "21796": 0.23556606471538544, "22248": 0.28597161173820496, "22262": 0.5483922958374023, "22380": 0.07250232994556427, "22574": 0.2184450328350067, "22806": 0.6420594453811646, "22835": 0.07793712615966797, "22924": 0.3248254358768463, "22963": 0.08064348995685577, "23041": 0.18978065252304077, "23191": 0.011650617234408855, "23192": 0.5433003902435303, "23247": 0.08871890604496002, "23283": 0.32270604372024536, "23350": 0.2763880789279938, "23884": 0.9621002674102783, "23900": 0.28597161173820496, "23943": 0.018384648486971855, "23983": 0.12814582884311676, "24110": 0.6482070088386536, "24155": 0.10026945173740387, "24370": 0.5696102976799011, "24442": 1.4633277654647827, "24558": 0.28890204429626465, "24710": 0.41065993905067444, "24836": 0.1212492436170578, "24899": 0.030771657824516296, "25095": 0.2018241584300995, "25169": 0.35128939151763916, "25524": 0.2501201331615448, "25969": 0.08603433519601822, "26013": 0.11691460013389587, "26236": 0.23092569410800934, "26237": 0.01934296265244484, "26305": 0.1685553640127182, "26319": 0.21687394380569458, "26640": 0.05139094591140747, "26786": 0.16690383851528168, "26835": 1.1115491390228271, "26972": 0.010684899985790253, "27166": 0.04674193635582924, "27351": 0.6512666940689087, "27602": 0.9084475636482239, "27839": 0.12384103983640671, "27974": 0.0058422754518687725, "28170": 0.32129061222076416, "28424": 0.1332872211933136, "28636": 0.33675122261047363, "28736": 0.3883931338787079, "29458": 0.9084475636482239}
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11026600
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Information on global human movement patterns is central to spatial epidemiological models used to predict the behavior of influenza and other infectious diseases. Yet it remains difficult to test which modes of dispersal drive pathogen spread at various geographic scales using standard epidemiological data alone. Evolutionary analyses of pathogen genome sequences increasingly provide insights into the spatial dynamics of influenza viruses, but to date they have largely neglected the wealth of information on human mobility, mainly because no statistical framework exists within which viral gene sequences and empirical data on host movement can be combined. Here, we address this problem by applying a phylogeographic approach to elucidate the global spread of human influenza subtype H3N2 and assess its ability to predict the spatial spread of human influenza A viruses worldwide. Using a framework that estimates the migration history of human influenza while simultaneously testing and quantifying a range of potential predictive variables of spatial spread, we show that the global dynamics of influenza H3N2 are driven by air passenger flows, whereas at more local scales spread is also determined by processes that correlate with geographic distance. Our analyses further confirm a central role for mainland China and Southeast Asia in maintaining a source population for global influenza diversity. By comparing model output with the known pandemic expansion of H1N1 during 2009, we demonstrate that predictions of influenza spatial spread are most accurate when data on human mobility and viral evolution are integrated. In conclusion, the global dynamics of influenza viruses are best explained by combining human mobility data with the spatial information inherent in sampled viral genomes. The integrated approach introduced here offers great potential for epidemiological surveillance through phylogeographic reconstructions and for improving predictive models of disease control.
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Unifying Viral Genetics and Human Transportation Data to Predict the Global Transmission Dynamics of Human Influenza H3N2
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"23586": 0.6317287683486938, "23892": 0.8013357520103455, "23931": 0.29619070887565613, "24054": 0.5651806592941284, "24137": 0.19541899859905243, "24269": 0.8109301924705505, "24312": 0.0317181795835495, "24532": 0.012615402229130268, "25022": 0.40285754203796387, "25456": 0.45623743534088135, "25505": 0.17431432008743286, "25644": 0.27342069149017334, "25714": 0.3897167444229126, "26356": 1.049919843673706, "26396": 0.045809537172317505, "26402": 1.0066169500350952, "26734": 0.37371641397476196, "26773": 0.347847044467926, "27005": 0.021256839856505394, "27356": 0.21135559678077698, "27448": 0.7009293437004089, "27697": 0.23402166366577148, "27777": 0.7163142561912537, "27790": 0.5127768516540527, "27822": 1.1300151348114014, "27854": 0.11517547070980072, "27965": 0.28082266449928284, "28046": 0.14433705806732178, "28079": 0.026976587250828743, "28251": 1.2421036958694458, "28689": 0.8022117614746094, "28715": 0.20660123229026794, "29398": 0.9005423784255981, "29532": 0.36426326632499695, "29535": 0.13925230503082275}
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11041152
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Molecular motors play critical roles in the formation of mitotic spindles, either through controlling the stability of individual microtubules, or by crosslinking and sliding microtubule arrays. Kinesin-8 motors are best known for their regulatory roles in controlling microtubule dynamics. They contain microtubule-destabilizing activities, and restrict spindle length in a wide variety of cell types and organisms. Here, we report an antiparallel microtubule-sliding activity of the budding yeast kinesin-8, Kip3. The in vivo importance of this sliding activity was established through the identification of complementary Kip3 mutants that separate the sliding activity and microtubule-destabilizing activity. In conjunction with Cin8, a kinesin-5 family member, the sliding activity of Kip3 promotes bipolar spindle assembly and the maintenance of genome stability. We propose a slide-disassemble model where the sliding and destabilizing activity of Kip3 balance during pre-anaphase. This facilitates normal spindle assembly. However, the destabilizing activity of Kip3 dominates in late anaphase, inhibiting spindle elongation and ultimately promoting spindle disassembly.
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Microtubule sliding activity of a kinesin-8 promotes spindle assembly and spindle length control
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11043831
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Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
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A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling
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11048759
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The EBNA1 protein of Epstein-Barr virus (EBV) binds to and activates DNA replication from the EBV latent origin of replication, oriP, via a direct interaction with the two noncontiguous subelements of oriP. The EBNA1 molecules bound to the oriP subelements interact efficiently with each other by a DNA looping mechanism. We have previously mapped a region of EBNA1 (termed the looping region) that is required to mediate the interaction of the EBNA1 molecules bound to the oriP subelements. We now demonstrate that two fragments of this region of EBNA1, which consist largely of an eight amino acid repeat, can mediate homotypic interactions when transferred to another DNA-binding protein. Protein interactions mediated by the EBNA1 looping region appear to be dependent on DNA binding since these interactions were detected between DNA-bound forms of the proteins only.
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Identification of Epstein-Barr virus nuclear antigen 1 protein domains that direct interactions at a distance between DNA-bound proteins.
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11071351
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The National High Blood Pressure Education Program Coordinating Committee published its first statement on the primary prevention of hypertension in 1993. This article updates the 1993 report, using new and further evidence from the scientific literature. Current recommendations for primary prevention of hypertension involve a population-based approach and an intensive targeted strategy focused on individuals at high risk for hypertension. These 2 strategies are complementary and emphasize 6 approaches with proven efficacy for prevention of hypertension: engage in moderate physical activity; maintain normal body weight; limit alcohol consumption; reduce sodium intake; maintain adequate intake of potassium; and consume a diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Applying these approaches to the general population as a component of public health and clinical practice can help prevent blood pressure from increasing and can help decrease elevated blood pressure levels for those with high normal blood pressure or hypertension.
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Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program.
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11083121
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The control of cell growth and polarity depends on a dynamic actin cytoskeleton that has the ability to reorganize in response to developmental and environmental stimuli. In animals and fungi, formins are just one of the four major classes of poly-L-proline-containing (PLP) proteins that form part of the signal-transduction cascade that leads to rearrangement of the actin cytoskeleton. Analysis of the Arabidopsis genome sequence indicates that, unlike animals and fungi, formins are the only class of conserved profilin-binding PLP proteins in plants. Moreover, plant formins show significant structural differences compared with their animal and fungal counterparts, raising the possibility that plant formins are subject to novel mechanisms of control or perform unique roles in plants.
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Formins: intermediates in signal-transduction cascades that affect cytoskeletal reorganization.
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11090688
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The weight lowering potential of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) is inter-individually different and clinically unpredictable. The potential role of genetic variability of GLP-1R on body weight response to GLP-1 RAs in obese women with polycystic ovary syndrome (PCOS) has not yet been evaluated. Fifty-seven obese women with PCOS (aged 30.7 ± 7.0, BMI 38.6 ± 5.3 kg/m2) were assigned to liraglutide 1.2 mg QD s.c. for 12 weeks and classified as strong responders regarding weight loss if they lost 5 % or more of their initial body weight. They were genotyped for common GLP-1R single nucleotide polymorphisms (SNPs) rs6923761 and rs10305420. Changes of measures of obesity were measured before and at the end of the treatment. Twenty out of 57 subjects were strong responders and lost 7.38 ± 1.74 compared to 2.11 ± 2.17 kg lost in poor responders. Carriers of at least one polymorphic rs10305420 allele had poor treatment response compared to carriers of two wild type alleles (OR = 0.27, 95 % CI = 0.09–0.85, P = 0.025). Carriers of at least one polymorphic rs6923761 allele tended to have stronger treatment response compared to carriers of two wild type alleles (OR = 3.06, 95 % CI = 0.96–9.74, P = 0.058). Fasting glucose and glucose after oral glucose tolerance test (OGTT) comparably decreased in both groups when compared to baseline, whereas no within treatment differences were found in androgen profile. Gastrointestinal adverse events were transit and balanced between strong and poor responders. GLP-1R rs10305420 polymorphism explained some of the inter-individual differences in response to liraglutide regarding weight loss in obese PCOS women.
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Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight lowering potential of liraglutide in obese women with PCOS: a pilot study
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0.1229778528213501, "24759": 0.46853771805763245, "24841": 0.009718249551951885, "24848": 0.12384103983640671, "24921": 0.22392450273036957, "24936": 0.6960725784301758, "25025": 0.26446542143821716, "25128": 0.5805994272232056, "25194": 0.4568560719490051, "25389": 0.004870930220931768, "25456": 0.8349450826644897, "25504": 0.7500885725021362, "25714": 0.4196864068508148, "25937": 0.4500300884246826, "26089": 0.10555581003427505, "26163": 0.058784693479537964, "26402": 0.45499902963638306, "26721": 0.6960725784301758, "26802": 0.011650617234408855, "26877": 0.05786345899105072, "26989": 0.1011524572968483, "27144": 0.02412080205976963, "27159": 0.1384023278951645, "27295": 0.5773153901100159, "28086": 0.026976587250828743, "28196": 0.006812678650021553, "28207": 0.056018441915512085, "28370": 0.18492233753204346, "28687": 0.29255300760269165, "29129": 0.18004031479358673, "29242": 0.21135559678077698, "29295": 0.05139094591140747}
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11109043
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BACKGROUND To compare the clinical results and the cost-effectiveness of using the aromatase inhibitor, letrozole, in conjunction with FSH and FSH alone for controlled ovarian stimulation (COS) in patients undergoing intrauterine insemination (IUI) for a variety of indications. METHODS Four hundred and thirty-two consecutive patients who underwent 872 IUI cycles were included. The study population was composed of two groups. Group I included 308 patients who underwent 589 IUI cycles with letrozole and FSH for the following indications: anovulation (143 cycles), male factor infertility (147 cycles), unexplained infertility (250 cycles), endometriosis (18 cycles) and combined indications (31 cycles). Group II included 124 patients who underwent 283 IUI cycles who received FSH only for the following indications: ovarian factor infertility (82 cycles), male factor infertility (66 cycles), unexplained infertility (114 cycles), endometriosis (13 cycles) and other indications (8 cycles). Main outcome measures included number of mature follicles >16 mm in diameter, dose of FSH used per cycle, clinical pregnancy rate and cost-effectiveness ratio per pregnancy. RESULTS FSH dose required for ovarian stimulation was significantly lower when letrozole was used (P < 0.0001). Although a significantly higher number of follicles >16 mm and endometrial thickness at the day of hCG administration (P < 0.0001) were observed in Group II, pregnancy rate per started (14.4 versus 15.9%) and per completed cycles (15.77 versus 18.07%) was the same in Group I and Group II, respectively. IUI cancellation rate was significantly lower with letrozole treatment (P = 0.05%). The cost per cycle was significantly lower in Group I versus Group II (468.93 Can dollars +/- 418.18 versus 1067.28 +/- 921.43; P < 0.0001). The cost-effectiveness ratio was 3249.42 dollars in the letrozole group and 6712.00 dollars in the FSH-only group. CONCLUSION A letrozole-FSH combination could be an effective ovarian stimulation protocol in IUI cycles. Such a protocol may be more cost-effective than FSH alone because of the difference of FSH dose and cost. A randomized controlled trial is needed to further substantiate this finding.
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Cost-effectiveness of aromatase inhibitor co-treatment for controlled ovarian stimulation.
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11117498
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Solitary metastatic brain tumors are the most common intracranial neoplasms encountered by neurosurgeons. Surgical resection of brain metastasis with whole brain radiotherapy (WBR) significantly increases survival in comparison with WBR alone. Stereotactic radiosurgery (SR) seems to provide results that are similar to those of surgical resection. To analyze the economic efficiency of these different treatments, we compared the results of surgical resection and SR as reported in the medical literature between 1974 and 1994. We included studies in which: 1) at least 75% of patients received WBR; 2) study dates were in the computed tomography era (after 1975); 3) operative morbidity, mortality, and median survival were reported; 4) study dates were not included in a more recent update or review; 5) tumor histologies were reported; and 6) the cobalt-60 gamma unit was used for SR. Three surgical resection studies and one SR study met all entry requirements. The WBR baseline was developed from two prospective, randomized trials and used for incremental cost effectiveness analysis. We developed a model of typical resource usage for uncomplicated procedures, reported complications, and subsequent craniotomies (for recurrent tumor or radiation necrosis) for both treatment options. Costs were estimated from the societal viewpoint using the 1992 Medicare Provider Analysis and Review database with average cost:charge ratios for surgery and WBR. A survey of capital and operating costs from five sites was used for radiosurgery. Our analysis revealed that radiosurgery had a lower uncomplicated procedure cost ($20,209 versus $27,587), a lower average complication cost per case ($2,534 versus $2,874), and a lower total cost per procedure ($22,743 versus $30,461), was more cost effective ($24,811 versus $32,149 per life year), and had a better incremental cost effectiveness ($40,648 versus $52,384 per life year) than surgical resection. A sensitivity analysis revealed that large changes in key assumptions would be required to change the analysis outcome. Equalization of the incremental cost effectiveness of the two treatments would require one of the following: 1) a 38.7% reduction in SR annual case volume, 2) a 34.7% increase in SR procedure cost, 3) a 18.8% reduction in surgical resection procedure cost, 4) a 240.5% increase in SR morbidity cost, 5) a 12.7% reduction in SR median survival, 6) a 16.8% increase in surgical resection median survival. Elimination of all surgical resection morbidity cost would still result in superior incremental cost effectiveness for SR.(ABSTRACT TRUNCATED AT 400 WORDS)
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The cost effectiveness of stereotactic radiosurgery versus surgical resection in the treatment of solitary metastatic brain tumors.
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11117679
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Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.
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Trans-ancestry mutational landscape of hepatocellular carcinoma genomes
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11141995
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Mitotic chromosomes are among the most recognizable structures in the cell, yet for over a century their internal organization remains largely unsolved. We applied chromosome conformation capture methods, 5C and Hi-C, across the cell cycle and revealed two distinct three-dimensional folding states of the human genome. We show that the highly compartmentalized and cell type-specific organization described previously for nonsynchronous cells is restricted to interphase. In metaphase, we identified a homogenous folding state that is locus-independent, common to all chromosomes, and consistent among cell types, suggesting a general principle of metaphase chromosome organization. Using polymer simulations, we found that metaphase Hi-C data are inconsistent with classic hierarchical models and are instead best described by a linearly organized longitudinally compressed array of consecutive chromatin loops.
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Organization of the mitotic chromosome.
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0.03831886500120163, "25714": 0.053244512528181076, "25761": 0.025073638185858727, "25969": 0.1946154683828354, "26014": 0.25694093108177185, "26358": 0.18492233753204346, "26616": 0.16690383851528168, "26651": 0.3191637098789215, "26659": 0.004870930220931768, "26721": 0.17759032547473907, "26773": 0.12814582884311676, "26835": 0.5162794589996338, "26986": 0.0354953333735466, "27321": 0.02792670577764511, "27354": 0.04207121208310127, "27641": 0.05139094591140747, "27781": 0.11343330889940262, "27998": 0.638455867767334, "28252": 0.0058422754518687725, "28389": 0.1064341589808464, "28788": 0.817850649356842, "28873": 0.4177590310573578, "29226": 0.32270604372024536, "29258": 0.19862671196460724}
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11156883
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The concept of 'Compensatory anti-inflammatory response syndrome' (CARS) was proposed in 1997 by Roger Bone (1941-1997) to qualify the consequences of the counter-regulatory mechanisms initiated to limit the overzealous inflammatory process in patients with infectious (sepsis) or non-infectious systemic inflammatory response syndrome (SIRS). One major consequence of CARS is the modification of the immune status that could favour the enhanced susceptibility of intensive care patients to nosocomial infections. Indeed, most animal 'two-hit' models illustrate an enhanced sensitivity to infection after a first insult. However, this observation is highly dependent on the experimental procedure. Numerous functions of circulating leukocytes are altered in sepsis and SIRS patients, as well as in animal models of sepsis or SIRS. However, this is rather a reprogramming of circulating leukocytes, since there is not a global defect of the immune cells functions. Furthermore, within tissues, leukocytes are rather primed or activated than immunosuppressed. Thus, CARS may be considered as an adapted compartmentalized response with the aim to silence some acute proinflammatory genes, and to maintain the possible expression of certain genes involved in the anti-infectious process.
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Compensatory anti-inflammatory response syndrome.
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11172205
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A solid tumor is an organ composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels. A prerequisite to understanding tumor pathophysiology is the ability to distinguish and monitor each component in dynamic studies. Standard fluorophores hamper simultaneous intravital imaging of these components. Here, we used multiphoton microscopy techniques and transgenic mice that expressed green fluorescent protein, and combined them with the use of quantum dot preparations. We show that these fluorescent semiconductor nanocrystals can be customized to concurrently image and differentiate tumor vessels from both the perivascular cells and the matrix. Moreover, we used them to measure the ability of particles of different sizes to access the tumor. Finally, we successfully monitored the recruitment of quantum dot–labeled bone marrow–derived precursor cells to the tumor vasculature. These examples show the versatility of quantum dots for studying tumor pathophysiology and creating avenues for treatment.
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Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo
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11181416
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Because arginase hydrolyzes arginine to produce ornithine and urea, it has the potential to regulate nitric oxide (NO) and polyamine synthesis. We tested whether expression of the cytosolic isoform of arginase (arginase I) was limiting for NO or polyamine production by activated RAW 264.7 macrophage cells. RAW 264.7 cells, stably transfected to overexpress arginase I or beta-galactosidase, were treated with interferon-gamma to induce type 2 NO synthase or with lipopolysaccharide or 8-bromo-cAMP (8-BrcAMP) to induce ornithine decarboxylase. Overexpression of arginase I had no effect on NO synthesis. In contrast, cells overexpressing arginase I produced twice as much putrescine after activation than did cells expressing beta-galactosidase. Cells overexpressing arginase I also produced more spermidine after treatment with 8-BrcAMP than did cells expressing beta-galactosidase. Thus endogenous levels of arginase I are limiting for polyamine synthesis, but not for NO synthesis, by activated macrophage cells. This study also demonstrates that it is possible to alter arginase I levels sufficiently to affect polyamine synthesis without affecting induced NO synthesis.
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Arginase I: a limiting factor for nitric oxide and polyamine synthesis by activated macrophages?
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11195653
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The immunological synapse (IS) is a junction between the T cell and antigen-presenting cell and is composed of supramolecular activation clusters (SMACs). No studies have been published on naive T cell IS dynamics. Here, we find that IS formation during antigen recognition comprises cycles of stable IS formation and autonomous naive T cell migration. The migration phase is driven by PKCtheta, which is localized to the F-actin-dependent peripheral (p)SMAC. PKCtheta(-/-) T cells formed hyperstable IS in vitro and in vivo and, like WT cells, displayed fast oscillations in the distal SMAC, but they showed reduced slow oscillations in pSMAC integrity. IS reformation is driven by the Wiscott Aldrich Syndrome protein (WASp). WASp(-/-) T cells displayed normal IS formation but were unable to reform IS after migration unless PKCtheta was inhibited. Thus, opposing effects of PKCtheta and WASp control IS stability through pSMAC symmetry breaking and reformation.
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Opposing Effects of PKCθ and WASp on Symmetry Breaking and Relocation of the Immunological Synapse
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11200685
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Microtubule nucleation is an essential step in the formation of the microtubule cytoskeleton. We recently showed that androgen and Src promote microtubule nucleation and γ-tubulin accumulation at the centrosome. Here, we explore the mechanisms by which androgen and Src regulate these processes and ask whether integrins play a role. We perturb integrin function by a tyrosine-to-alanine substitution in membrane-proximal NPIY motif in the integrin β1 tail and show that this mutant substantially decreases microtubule nucleation and γ-tubulin accumulation at the centrosome. Because androgen stimulation promotes the interaction of the androgen receptor with Src, resulting in PI3K/AKT and MEK/ERK signaling, we asked whether these pathways are inhibited by the mutant integrin and whether they regulate microtubule nucleation. Our results indicate that the formation of the androgen receptor-Src complex and the activation of downstream pathways are significantly suppressed when cells are adhered by the mutant integrin. Inhibitor studies indicate that microtubule nucleation requires MEK/ERK but not PI3K/AKT signaling. Importantly, the expression of activated RAF-1 is sufficient to rescue microtubule nucleation inhibited by the mutant integrin by promoting the centrosomal accumulation of γ-tubulin. Our data define a novel paradigm of integrin signaling, where integrins regulate microtubule nucleation by promoting the formation of androgen receptor-Src signaling complexes to activate the MEK/ERK signaling pathway.
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Integrins regulate microtubule nucleating activity of centrosome through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling.
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11201004
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Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associations were observed with consumption of added sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity.
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Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasis and insulin resistance among youth at risk of obesity.
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11230569
|
Substantial changes are needed to achieve a more targeted and strategic approach to investment in the response to the HIV/AIDS epidemic that will yield long-term dividends. Until now, advocacy for resources has been done on the basis of a commodity approach that encouraged scaling up of numerous strategies in parallel, irrespective of their relative effects. We propose a strategic investment framework that is intended to support better management of national and international HIV/AIDS responses than exists with the present system. Our framework incorporates major efficiency gains through community mobilisation, synergies between programme elements, and benefits of the extension of antiretroviral therapy for prevention of HIV transmission. It proposes three categories of investment, consisting of six basic programmatic activities, interventions that create an enabling environment to achieve maximum effectiveness, and programmatic efforts in other health and development sectors related to HIV/AIDS. The yearly cost of achievement of universal access to HIV prevention, treatment, care, and support by 2015 is estimated at no less than US$22 billion. Implementation of the new investment framework would avert 12·2 million new HIV infections and 7·4 million deaths from AIDS between 2011 and 2020 compared with continuation of present approaches, and result in 29·4 million life-years gained. The framework is cost effective at $1060 per life-year gained, and the additional investment proposed would be largely offset from savings in treatment costs alone.
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Towards an improved investment approach for an effective response to HIV/AIDS.
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"24054": 0.08692999184131622, "24203": 0.055094651877880096, "24529": 0.24171993136405945, "25117": 0.14939609169960022, "25194": 0.4818955361843109, "25219": 0.1384023278951645, "25360": 0.10203468054533005, "25714": 0.02792670577764511, "26419": 0.10906458646059036, "26773": 0.10291612148284912, "26835": 0.27564704418182373, "27295": 0.3526630103588104, "27321": 0.3019835948944092, "27441": 0.8161250352859497, "27641": 0.981317400932312, "27781": 0.2659635543823242, "27854": 0.39433568716049194, "28156": 0.3601844012737274, "28286": 0.8306987881660461, "28389": 0.9287132620811462, "28621": 0.755608320236206, "28774": 0.3547199070453644, "28788": 0.46117570996284485, "28873": 0.3141832649707794, "29490": 0.04953393340110779, "29610": 0.42735910415649414}
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11233339
|
T-helper 17 (Th17) cells are characterized by producing interleukin-17 (IL-17, also called IL-17A), IL-17F, IL-21, and IL-22 and potentially TNF- α and IL-6 upon certain stimulation. IL-23, which promotes Th17 cell development, as well as IL-17 and IL-22 produced by the Th17 cells plays essential roles in various inflammatory diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, colitis, and Concanavalin A-induced hepatitis. In this review, we summarize the characteristics of the functional role of Th17 cells, with particular focus on the Th17 cell-related cytokines such as IL-17, IL-22, and IL-23, in mouse models and human inflammatory diseases.
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Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases
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11238784
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Liver X receptors (LXRs) and farnesoid X receptor (FXR) are nuclear receptors that function as intracellular sensors for sterols and bile acids, respectively. In response to their ligands, these receptors induce transcriptional responses that maintain a balanced, finely tuned regulation of cholesterol and bile acid metabolism. LXRs also permit the efficient storage of carbohydrate- and fat-derived energy, whereas FXR activation results in an overall decrease in triglyceride levels and modulation of glucose metabolism. The elegant, dual interplay between these two receptor systems suggests that they coevolved to constitute a highly sensitive and efficient system for the maintenance of total body fat and cholesterol homeostasis. Emerging evidence suggests that the tissue-specific action of these receptors is also crucial for the proper function of the cardiovascular, immune, reproductive, endocrine pancreas, renal, and central nervous systems. Together, LXRs and FXR represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases.
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LXRS and FXR: the yin and yang of cholesterol and fat metabolism.
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1.0193830728530884, "24473": 0.21372433006763458, "24826": 0.823009729385376, "24888": 0.3519764244556427, "25206": 0.040196798741817474, "25409": 0.006812678650021553, "25468": 0.4337083101272583, "26013": 0.6348392367362976, "26236": 0.42799583077430725, "26305": 0.22392450273036957, "26633": 0.2976420819759369, "26646": 1.3454316854476929, "26778": 0.7934166193008423, "26792": 0.8666408061981201, "26835": 0.5162794589996338, "27216": 0.35060185194015503, "27391": 0.006812678650021553, "27781": 0.0174254160374403, "28024": 0.4879087805747986, "28105": 0.9302552938461304, "28227": 0.030771657824516296, "28389": 0.32553088665008545, "28788": 0.012615402229130268, "28873": 0.45994341373443604, "29125": 0.7889899015426636, "29535": 1.2152372598648071}
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11238951
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Kaposi's sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus type 8, is consistently identified in Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Here we report four cases of KSHV-bearing solid lymphomas that occurred in AIDS patients (cases 1 to 3) and in a human immunodeficiency virus (HIV)-seronegative person (case 4). The patients presented extranodal masses in the abdomen (cases 1, 3, and 4) or skin (case 2), and nodal involvement, together with Kaposi's sarcoma (case 3). The gastrointestinal tract was involved in two patients (cases 1 and 3). The patients did not develop a lymphomatous effusion. KSHV was detected in the tumor cells of all cases by immunohistochemistry and by polymerase chain reaction. Epstein-Barr virus was detected in two of the HIV-related cases. All KSHV-positive solid lymphomas exhibited PEL-like cell morphology. To investigate the relationship of these disorders to PEL and to other AIDS-associated diffuse large cell lymphomas, KSHV-positive solid lymphomas were tested for the expression of a set of genes that were previously shown by gene profiling analysis to define PEL tumor cells. The results showed that expression of this set of genes in KSHV-positive lymphomas is similar to that of PEL but distinct from KSHV-negative AIDS-associated diffuse large cell lymphomas. Because pathobiological features of KSHV-positive solid lymphomas closely mimic those of PEL, our results suggest that KSHV-positive solid lymphomas should be considered as a tissue-based variant of classical PEL, irrespective of HIV status.
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Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: a tissue-based variant of primary effusion lymphoma.
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11244195
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MOTIVATION Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. RESULTS To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. AVAILABILITY AND IMPLEMENTATION STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
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STAR: ultrafast universal RNA-seq aligner.
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11246427
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CONTEXT Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures. OBJECTIVE To test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures. DESIGN Randomized, blinded, placebo-controlled trial. SETTING Eleven community-based clinical research centers. SUBJECTS Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later). INTERVENTION All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial. MAIN OUTCOME MEASURES Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry. RESULTS Alendronate increased BMD at all sites studied (P<.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (>2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects. CONCLUSIONS In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.
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Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.
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11250124
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Synaptic vesicle recycling involves AP-2/clathrin-mediated endocytosis, but it is not known whether the endosomal pathway is also required. Mice deficient in the tissue-specific AP-1-sigma1B complex have impaired synaptic vesicle recycling in hippocampal synapses. The ubiquitously expressed AP-1-sigma1A complex mediates protein sorting between the trans-Golgi network and early endosomes. Vertebrates express three sigma1 subunit isoforms: A, B and C. The expressions of sigma1A and sigma1B are highest in the brain. Synaptic vesicle reformation in cultured neurons from sigma1B-deficient mice is reduced upon stimulation, and large endosomal intermediates accumulate. The sigma1B-deficient mice have reduced motor coordination and severely impaired long-term spatial memory. These data reveal a molecular mechanism for a severe human X-chromosome-linked mental retardation.
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AP-1/sigma1B-adaptin mediates endosomal synaptic vesicle recycling, learning and memory.
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0.1358480453491211, "29296": 0.2741633653640747, "29438": 0.46608972549438477}
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11253758
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Upon the first publication of the fifth iteration of the Functional Annotation of Mammalian Genomes collaborative project, FANTOM5, we gathered a series of primary data and database systems into the FANTOM web resource (http://fantom.gsc.riken.jp) to facilitate researchers to explore transcriptional regulation and cellular states. In the course of the collaboration, primary data and analysis results have been expanded, and functionalities of the database systems enhanced. We believe that our data and web systems are invaluable resources, and we think the scientific community will benefit for this recent update to deepen their understanding of mammalian cellular organization. We introduce the contents of FANTOM5 here, report recent updates in the web resource and provide future perspectives.
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Update of the FANTOM web resource: high resolution transcriptome of diverse cell types in mammals
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0.10467668622732162, "27178": 0.40351006388664246, "28227": 0.12470348179340363, "29125": 0.966567873954773, "29361": 0.0019512200960889459, "29461": 0.04674193635582924}
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11254040
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Multidrug-resistant tuberculosis (MDR-TB) is a growing public health problem. Due to long duration of therapy and concurrent use of multiple second-line drugs, adverse drug events (ADEs) are regarded as the most important clinical consideration in patients undergoing anti-MDR-TB treatment. To evaluate the frequency and type of treatment-related ADEs owing to MDR-TB therapy. The Cochrane Library, MEDLINE, and EMBASE were searched from inception through October 1, 2012, with additional manual search of International Journal of Tuberculosis and Lung Disease. Studies with available ADEs were selected if MDR-TB patients were treated with regimen including second-line drugs. Pooled estimations of incidence for each specific type of ADEs were calculated with 95% confidence intervals using random-effects model. Of the 5346 patients included, 2602 (57.3%) experienced at least 1 kind of ADE. The 3 most common side effects were gastrointestinal disorders (32.1%), ototoxicity (14.6%), and psychiatric disorders (13.2%). Subgroup analyses based on each characteristic (study population, previous tuberculosis treated, human immunodeficiency virus prevalence, and length of treatment) did not show any significant difference between groups. Additionally, among 1519 patients who developed ADEs with available data of impact on MDR-TB therapy, 70.4% required change of MDR-TB treatment. Adverse events were common among MDR-TB cases, occurring in more than half of the cases, with over two-thirds requiring change of anti-MDR-TB treatment. MDR-TB patients should be monitored closely and managed aggressively for side effects during therapy, especially for ototoxicity and psychiatric disorders.
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Adverse Events Associated With the Treatment of Multidrug-Resistant Tuberculosis: A Systematic Review and Meta-analysis.
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0.47463157773017883}
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11254556
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Synaptic long-term potentiation (LTP) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. Previous studies have functionally implicated the NMDA receptor-NO pathway and the downstream second messenger, cGMP, in these processes. Because cGMP can broadly influence diverse ion-channels, kinases, and phosphodiesterases, pre- as well as post-synaptically, the precise identity of cGMP targets mediating spinal LTP, their mechanisms of action, and their locus in the spinal circuitry are still unclear. Here, we found that Protein Kinase G1 (PKG-I) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal LTP. Using the Cre-lox P system, we generated nociceptor-specific knockout mice lacking PKG-I specifically in presynaptic terminals of nociceptors in the spinal cord, but not in post-synaptic neurons or elsewhere (SNS-PKG-I(-/-) mice). Patch clamp recordings showed that activity-induced LTP at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) was completely abolished in SNS-PKG-I(-/-) mice, although basal synaptic transmission was not affected. Analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic PKG-I in regulating the probability of neurotransmitter release. Inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic PKG-I in nociceptive neurons. Finally, behavioural analyses in vivo showed marked defects in SNS-PKG-I(-/-) mice in several models of activity-induced nociceptive hypersensitivity, and pharmacological studies identified a clear contribution of PKG-I expressed in spinal terminals of nociceptors. Our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic LTP on spinal-PAG projection neurons and that PKG-I localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity.
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Presynaptically Localized Cyclic GMP-Dependent Protein Kinase 1 Is a Key Determinant of Spinal Synaptic Potentiation and Pain Hypersensitivity
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11255504
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The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy.
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A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer.
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11256632
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Protein-protein interactions (PPIs) represent an enormous source of opportunity for therapeutic intervention. We and others have recently pinpointed key rules that will help in identifying the next generation of innovative drugs to tackle this challenging class of targets within the next decade. We used these rules to design an oriented chemical library corresponding to a set of diverse "PPI-like" modulators with cores identified as privileged structures in therapeutics. In this work, we purchased the resulting 1664 structurally diverse compounds and evaluated them on a series of representative protein-protein interfaces with distinct "druggability" potential using homogeneous time-resolved fluorescence (HTRF) technology. For certain PPI classes, analysis of the hit rates revealed up to 100 enrichment factors compared with nonoriented chemical libraries. This observation correlates with the predicted "druggability" of the targets. A specific focus on selectivity profiles, the three-dimensional (3D) molecular modes of action resolved by X-ray crystallography, and the biological activities of identified hits targeting the well-defined "druggable" bromodomains of the bromo and extraterminal (BET) family are presented as a proof-of-concept. Overall, our present study illustrates the potency of machine learning-based oriented chemical libraries to accelerate the identification of hits targeting PPIs. A generalization of this method to a larger set of compounds will accelerate the discovery of original and potent probes for this challenging class of targets.
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Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.
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11271123
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Endometrial cancer is associated with numeric and structural chromosomal abnormalities, microsatellite instability (MSI), and alterations that activate oncogenes and inactivate tumor suppressor genes. The aim of this study was to characterize a set of endometrial cancers using multiple molecular genetic and immunohistochemical techniques. Ninety-six cases were examined for genomic alterations by MSI, MLH1 promoter hypermethylation, p53 and mismatch repair protein expression (MLH1, MSH2, MSH6, PMS2), and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. At least 1 alteration was identified in 48 of 87 (55%) specimens tested for PTEN, making it the most common abnormality in this study. A PIK3CA alteration was observed in 16 (17%) specimens. Twenty-nine of 94 (31%) MSI tested tumors exhibited an MSI-H phenotype. Of the 29 MSI-H cases, 24 (83%) were positive for methylation of the MLH1 promoter region. Twenty-three (82%) of the 28 MSI-H cases with immunohistochemistry results showed loss of expression of MLH1/PMS2 (n=19), MSH2/MSH6 (n=2), or MSH6 only (n=2). Of the 19 MSI-H cases with loss of MLH1/PMS2 on immunohistochemistry, 18 were positive, and 1 was equivocal for MLH1 promoter hypermethylation. Twelve of 94 cases (13%) analyzed for KRAS mutations were found to have a mutation. No BRAF V600E mutations were indentified. This study provides a comprehensive molecular genetic analysis of commonly analyzed targets in a large cohort of endometrial cancers.
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Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAF mutation analysis.
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"29564": 0.0317181795835495}
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11280569
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Plant resistance against the necrotrophic pathogen Plectosphaerella cucumerina is mediated by a combination of several hormonal-controlled signalling pathways. The priming agent β-aminobutyric acid (BABA) is able to induce effective resistance against this pathogen by stimulating callose-rich cell wall depositions. In the present research it is demonstrated that BABA-Induced Resistance (BABA-IR) against P. cucumerina in Arabidopsis has additional components such as the induction of defences mediated by indolic derivatives. Chromatographic approach for the detection and characterization of metabolites enhanced by BABA compared with water-treated plants only when the challenge is present has been developed. The metabolites matching this criteria are considered to be primed by BABA. The analytic procedure is based on the combination of liquid chromatography (LC) with a triple quadrupole (TQD) detector in a precursor ion scanning mode. Using this analytical system a signal in negative electro-spray mode of 160 m/z is primed by BABA in infected plants. A subsequent exact mass analysis in a quadrupole time-of-flight mass spectrometer demonstrated that this ion was the indole-derivative metabolite indole-3-carboxylic acid (I3CA). The identity of indole-3-carboxilic acid was definitively confirmed by comparing its retention time and fragmentation spectra with a commercial standard. Quantification of I3CA in primed plants showed that this indolic metabolite is specifically primed by BABA upon P. cucumerina infection, while other indolic compounds such as IAA and camalexin are not. Taking together these observations with the known role of callose in priming against this pathogen, suggests that priming is not a single mechanism but rather a multicomponent defence.
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Identification of indole-3-carboxylic acid as mediator of priming against Plectosphaerella cucumerina.
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"18154": 0.5990082025527954, "18224": 0.011650617234408855, "18288": 0.3170322775840759, "18539": 0.7229714393615723, "18700": 0.022212404757738113, "18804": 1.304418921470642, "19107": 0.03266380727291107, "19555": 0.5045560002326965, "19587": 0.417115718126297, "19940": 0.04953393340110779, "20155": 0.15023678541183472, "20253": 0.4093637466430664, "20302": 0.5191890001296997, "20567": 0.07250232994556427, "20767": 0.24554696679115295, "20792": 0.4709797203540802, "21104": 0.03925827145576477, "21470": 0.10818854719400406, "21672": 0.5197699069976807, "21991": 0.1994270235300064, "22318": 0.010684899985790253, "22778": 0.16110190749168396, "22963": 0.27934664487838745, "23087": 0.7546905279159546, "23208": 0.3499138653278351, "23323": 0.07250232994556427, "23476": 0.1677299439907074, "23521": 0.5618454217910767, "24039": 0.08064348995685577, "24327": 0.8780695199966431, "24335": 1.0250049829483032, "24555": 0.1510767638683319, "25095": 0.5267143249511719, "25284": 0.0058422754518687725, "25323": 0.4794800877571106, "25455": 0.8091925978660583, "25778": 0.04953393340110779, "27354": 0.052318159490823746, "27694": 0.2105647772550583, "27870": 1.1524739265441895, "28436": 0.12728634476661682, "29458": 0.05417001247406006}
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11288846
|
Randomized trials may be designed and interpreted as single experiments or they may be seen in the context of other similar or relevant evidence. The amount and complexity of available randomized evidence vary for different topics. Systematic reviews may be useful in identifying gaps in the existing randomized evidence, pointing to discrepancies between trials, and planning future trials. A new, promising, but also very much debated extension of systematic reviews, mixed treatment comparison (MTC) meta-analysis, has become increasingly popular recently. MTC meta-analysis may have value in interpreting the available randomized evidence from networks of trials and can rank many different treatments, going beyond focusing on simple pairwise-comparisons. Nevertheless, the evaluation of networks also presents special challenges and caveats. In this article, we review the statistical methodology for MTC meta-analysis. We discuss the concept of inconsistency and methods that have been proposed to evaluate it as well as the methodological gaps that remain. We introduce the concepts of network geometry and asymmetry, and propose metrics for the evaluation of the asymmetry. Finally, we discuss the implications of inconsistency, network geometry and asymmetry in informing the planning of future trials.
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Evaluation of networks of randomized trials.
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0.11691460013389587, "26773": 0.6921701431274414, "26986": 0.11865071207284927, "27152": 0.11168810725212097, "27287": 0.7601850032806396, "27427": 0.6430866718292236, "27788": 0.5651806592941284, "27989": 0.02792670577764511, "28032": 0.9232974052429199, "28046": 0.0009760859538801014, "28086": 0.09495500475168228, "28156": 0.42225050926208496, "28227": 0.684319257736206, "28635": 0.030771657824516296, "28696": 0.11691460013389587, "28723": 0.015504186972975731, "28828": 0.23556606471538544, "28829": 0.25088030099868774, "28835": 0.4041621685028076, "29125": 0.02792670577764511, "29290": 0.14939609169960022, "29516": 0.22937409579753876}
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11289247
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The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell (HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, a PTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resulted in hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs. Surprisingly, the HSC pool was increased by ∼40-fold in PTPMT1 knockout mice. Reintroduction of wild-type PTPMT1, but not catalytically deficient PTPMT1 or truncated PTPMT1 lacking mitochondrial localization, restored differentiation capabilities of PTPMT1 knockout HSCs. Further analyses demonstrated that PTPMT1 deficiency altered mitochondrial metabolism and that phosphatidylinositol phosphate substrates of PTPMT1 directly enhanced fatty-acid-induced activation of mitochondrial uncoupling protein 2. Intriguingly, depletion of PTPMT1 from myeloid, T lymphoid, or B lymphoid progenitors did not cause any defects in lineage-specific knockout mice. This study establishes a crucial role of PTPMT1 in the metabolic regulation of HSC function.
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Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation.
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