Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of ...activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.
The corrosion rate of Mg indicates a strong crystallographic dependence in chloride-containing, alkaline environments that correlates inversely with oxide film thickness. In contrast, a different ...crystallographic orientation dependency is observed initially during open circuit corrosion in non-chloride containing, near neutral pH buffered, chelating environments such as Tris(hydroxymethyl)aminomethane (TRIS) and Ethylenediaminetetraacetic (EDTA) which minimize air-formed MgO oxides. The origins of the differences in the rates of the coupled corrosion processes as a function of crystallographic orientation were investigated utilizing electrochemical impedance spectroscopy (EIS) and Raman vibrational spectroscopy. High frequency constant phase elements (CPEs) were exploited to determine oxide thicknesses as a function of crystal orientation. In unbuffered NaCl, open circuit corrosion was faster on basal planes while lower corrosion rates were observed on low index, prismatic and pyramidal planes. This variation in rate with crystallographic orientation in 0.6M NaCl was interpreted to depend on the MgO and Mg(OH)2 film thicknesses as a function of orientation. In particular, crystal planes with a lower MgO/Mg(OH)2 thickness corroded at higher rates as assessed in-situ by EIS and suggested by Raman spectroscopy. The crystallographic orientation dependence of corrosion seen initially upon exposure in the buffered neutral pH environments corresponded with crystal facet surface energy for bare Mg but this trend disappeared with exposure time and Mg(OH)2 films were then detected.
Tests on B−L symmetry breaking models are important probes to search for new physics. One proposed model with Δ(B−L)=2 involves the oscillations of a neutron to an antineutron. In this paper, a new ...limit on this process is derived for the data acquired from all three operational phases of the Sudbury Neutrino Observatory experiment. The search concentrated on oscillations occurring within the deuteron, and 23 events were observed against a background expectation of 30.5 events. These translated to a lower limit on the nuclear lifetime of 1.48×1031 yr at 90% C.L. when no restriction was placed on the signal likelihood space (unbounded). Alternatively, a lower limit on the nuclear lifetime was found to be 1.18×1031 yr at 90% C.L. when the signal was forced into a positive likelihood space (bounded). Values for the free oscillation time derived from various models are also provided in this article. This is the first search for neutron-antineutron oscillation with the deuteron as a target.
The long baseline between Earth and the Sun makes solar neutrinos an excellent test beam for exploring possible neutrino decay. The signature of such decay would be an energy-dependent distortion of ...the traditional survival probability which can be fit for using well-developed and high-precision analysis methods. Here a model including neutrino decay is fit to all three phases of B8 solar neutrino data taken by the Sudbury Neutrino Observatory (SNO). This fit constrains the lifetime of neutrino mass state ν2 to be >8.08×10−5 s/eV at 90% confidence. An analysis combining this SNO result with those from other solar neutrino experiments results in a combined limit for the lifetime of mass state ν2 of >1.92×10−3 s/eV at 90% confidence.
The use of left ventricular assist devices in treating patients with end-stage heart failure has increased significantly in recent years, both as a bridge to transplantation and as destination ...therapy in those who are ineligible for cardiac transplantation. This increase is based largely on the results of several recently completed clinical trials with the new second-generation continuous-flow devices that showed significant improvements in survival, functional capacity, and quality of life. Additional information on the use of the first- and second-generation left ventricular assist devices has come from a recently released report spanning the years 2006 to 2009, from the Interagency Registry for Mechanically Assisted Circulatory Support, a National Heart, Lung, and Blood Institute–sponsored collaboration between the U.S. Food and Drug Administration, the Centers for Medicare and Medicaid Services, and the scientific community. The authors review the latest clinical trials and data from the registry, with tight integration of the landmark molecular, cellular, and genomic research that accompanies the reverse remodeling of the human heart in response to a left ventricular assist device and functional recovery that has been reported in a subset of these patients.
Phosphoinositides, diacylglycerolpyrophosphate, ceramide-1-phosphate, and phosphatidic acid belong to a unique class of membrane signaling lipids that contain phosphomonoesters in their headgroups ...having pKa values in the physiological range. The phosphomonoester headgroup of phosphatidic acid enables this lipid to act as a pH biosensor as changes in its protonation state with intracellular pH regulate binding to effector proteins. Here, we demonstrate that binding of pleckstrin homology (PH) domains to phosphatidylinositol 4-phosphate (PI4P) in the yeast trans-Golgi network (TGN) is dependent on intracellular pH, indicating PI4P is a pH biosensor. pH biosensing by TGN PI4P in response to nutrient availability governs protein sorting at the TGN, likely by regulating sterol transfer to the TGN by Osh1, a member of the conserved oxysterol-binding protein (OSBP) family of lipid transfer proteins. Thus, pH biosensing by TGN PI4P allows for direct metabolic regulation of protein trafficking and cell growth.
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•PI4P in the TGN senses changes in intracellular pH via protonation of its headgroup•pH via protonation of PI4P regulates recruitment of effector proteins to the TGN•pH-dependent recruitment of Osh1 to TGN PI4P regulates cargo sorting at the TGN•Glucose regulates pH and Osh1 TGN localization coupling nutrients to trafficking
PI4P is an important signaling lipid in the TGN regulating adapter recruitment and cargo trafficking. Shin et al. show that a change in intracellular pH in response to glucose governs the protonation state of TGN PI4P, which controls recruitment of Osh1 and cargo sorting at the TGN.
Tardigrades are renowned for their ability to survive a wide array of environmental stressors. In particular, tardigrades can curl in on themselves while losing a significant proportion of their ...internal water content to form a structure referred to as a tun. In surviving varying conditions, tardigrades undergo distinct morphological transformations that could indicate different mechanisms of stress sensing and tolerance specific to the stress condition. Methods to effectively distinguish between morphological transformations, including between tuns induced by different stress conditions, are lacking. Herein, an approach for discriminating between tardigrade morphological states is developed and utilized to compare sucrose- and CaCl2-induced tuns, using the model species Hypsibius exemplaris. A novel approach of shadow imaging with confocal laser scanning microscopy enabled production of three-dimensional renderings of Hys. exemplaris in various physiological states resulting in volume measurements. Combining these measurements with qualitative morphological analysis using scanning electron microscopy revealed that sucrose- and CaCl2-induced tuns have distinct morphologies, including differences in the amount of water expelled during tun formation. Further, varying the concentration of the applied stressor did not affect the amount of water lost, pointing towards water expulsion by Hys. exemplaris being a controlled process that is adapted to the specific stressors.
Medication-related visits to the emergency department are an important but poorly understood phenomenon. We sought to evaluate the frequency, severity and preventability of drug-related visits to the ...emergency department.
We performed a prospective observational study of randomly selected adults presenting to the emergency department over a 12-week period. Emergency department visits were identified as drug-related on the basis of assessment by a pharmacist research assistant and an emergency physician; discrepancies were adjudicated by 2 independent reviewers.
Among the 1017 patients included in the study, the emergency department visit was identified as drug-related for 122 patients (12.0%, 95% confidence interval CI 10.1%-14.2%); of these, 83 visits (68.0%, 95% CI 59.0%-76.2%) were deemed preventable. Severity was classified as mild in 15.6% of the 122 cases, moderate in 74.6% and severe in 9.8%. The most common reasons for drug-related visits were adverse drug reactions (39.3%), nonadherence (27.9%) and use of the wrong or suboptimal drug (11.5%). The probability of admission was significantly higher among patients who had a drug-related visit than among those whose visit was not drug-related (OR 2.18, 95% CI 1.46-3.27, p < 0.001), and among those admitted, the median length of stay was longer (8.0 interquartile range 23.5 v. 5.5 interquartile range 10.0 days, p = 0.06).
More than 1 in 9 emergency department visits are due to drug-related adverse events, a potentially preventable problem in our health care system.
Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N ...termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
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