Twin studies indicate that obsessive-compulsive disorder (OCD) is strongly influenced by additive genetic factors. Yet, molecular genetic association studies have yielded inconsistent results, ...possibly because of differences across studies in statistical power. Meta-analysis can yield greater power. This study reports the first comprehensive meta-analysis of the relationship between OCD and all previously examined polymorphisms for which there was sufficient information in the source studies to compute odds ratios (ORs). A total of 230 polymorphisms from 113 genetic association studies were identified. A full meta-analysis was conducted for 20 polymorphisms that were examined in 5 or more data sets, and a secondary meta-analysis (limited to the computation of mean effect sizes) was conducted for 210 polymorphisms that were examined in fewer than 5 data sets. In the main meta-analysis, OCD was associated with serotonin-related polymorphisms (5-HTTLPR and HTR2A) and, in males only, with polymorphisms involved in catecholamine modulation (COMT and MAOA). Nonsignificant trends were identified for two dopamine-related polymorphisms (DAT1 and DRD3) and a glutamate-related polymorphism (rs3087879). The secondary meta-analysis identified another 18 polymorphisms with significant ORs that merit further investigation. This study demonstrates that OCD is associated with multiple genes, with most having a modest association with OCD. This suggests a polygenic model of OCD, consistent with twin studies, in which multiple genes make small, incremental contributions to the risk of developing the disorder. Future studies, with sufficient power to detect small effects, are needed to investigate the genetic basis of OCD subtypes, such as early vs late onset OCD.
Reconstructing Rawls has one overarching goal: to reclaim Rawls for the Enlightenment—more specifically, the Prussian Enlightenment. Rawls’s so-called political turn in the 1980s, motivated by a ...newfound interest in pluralism and the accommodation of difference, has been unhealthy for autonomy-based liberalism and has led liberalism more broadly toward cultural relativism, be it in the guise of liberal multiculturalism or critiques of cosmopolitan distributive-justice theories. Robert Taylor believes that it is time to redeem A Theory of Justice’s implicit promise of a universalistic, comprehensive Kantian liberalism. Reconstructing Rawls on Kantian foundations leads to some unorthodox conclusions about justice as fairness, to be sure: for example, it yields a more civic-humanist reading of the priority of political liberty, a more Marxist reading of the priority of fair equality of opportunity, and a more ascetic or antimaterialist reading of the difference principle. It nonetheless leaves us with a theory that is still recognizably Rawlsian and reveals a previously untraveled road out of Theory—a road very different from the one Rawls himself ultimately followed.
Methods for site-selective transformations of hydroxyl groups in carbohydrate derivatives are reviewed. The construction of oligosaccharides of defined connectivity hinges on such transformations, ...which are also needed for the preparation of modified or non-natural sugar derivatives, the installation of naturally occurring postglycosylation modifications, the selective labeling or conjugation of carbohydrate derivatives, and the preparation of therapeutic agents or research tools for glycobiology. The review begins with a discussion of intrinsic factors and processes that can influence selectivity in reactions of unprotected or partially protected carbohydrate derivatives, followed by a description of transformations that engage two OH groups in cyclic adducts (acetals, ketals, boronic esters, and related species). An overview of the various classes of site-selective transformations of OH groups in sugars is then provided: the reactions discussed include esterification, thiocarbonylation, alkylation, glycosylation, arylation, silylation, phosphorylation, sulfonylation, sulfation, and oxidation. Emphasis is placed on recently developed methods that employ reagent or catalyst control to achieve otherwise challenging transformations or site-selectivities.
Analysis of somatic mutations provides insight into the mutational processes that have shaped the cancer genome, but such analysis currently requires large cohorts. We develop deconstructSigs, which ...allows the identification of mutational signatures within a single tumor sample.
Application of deconstructSigs identifies samples with DNA repair deficiencies and reveals distinct and dynamic mutational processes molding the cancer genome in esophageal adenocarcinoma compared to squamous cell carcinomas.
deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine.
Reading in many alphabetic writing systems depends on both item-specific knowledge used to read irregular words (sew, yacht) and generative spelling-sound knowledge used to read pseudowords (tew, ...yash). Research into the neural basis of these abilities has been directed largely by cognitive accounts proposed by the dual-route cascaded and triangle models of reading. We develop a framework that enables predictions for neural activity to be derived from cognitive models of reading using 2 principles: (a) the extent to which a model component or brain region is engaged by a stimulus and (b) how much effort is exerted in processing that stimulus. To evaluate the derived predictions, we conducted a meta-analysis of 36 neuroimaging studies of reading using the quantitative activation likelihood estimation technique. Reliable clusters of activity are localized during word versus pseudoword and irregular versus regular word reading and demonstrate a great deal of convergence between the functional organization of the reading system put forward by cognitive models and the neural systems activated during reading tasks. Specifically, left-hemisphere activation clusters are revealed reflecting orthographic analysis (occipitotemporal cortex), lexical and/or semantic processing (anterior fusiform, middle temporal gyrus), spelling-sound conversion (inferior parietal cortex), and phonological output resolution (inferior frontal gyrus). Our framework and results establish that cognitive models of reading are relevant for interpreting neuroimaging studies and that neuroscientific studies can provide data relevant for advancing cognitive models. This article thus provides a firm empirical foundation from which to improve integration between cognitive and neural accounts of the reading process.
The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the solid form. Because an amorphous solid has a higher chemical potential than the corresponding ...crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an amorphous solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the “amorphous solubility” of drugs formulated as amorphous solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The “amorphous solubility” of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration (“amorphous solubility”) of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.
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Staphylococcus aureus USA300 strains cause a highly inflammatory necrotizing pneumonia. The virulence of this strain has been attributed to its expression of multiple toxins that have diverse targets ...including ADAM10, NLRP3 and CD11b. We demonstrate that induction of necroptosis through RIP1/RIP3/MLKL signaling is a major consequence of S. aureus toxin production. Cytotoxicity could be prevented by inhibiting either RIP1 or MLKL signaling and S. aureus mutants lacking agr, hla or Hla pore formation, lukAB or psms were deficient in inducing cell death in human and murine immune cells. Toxin-associated pore formation was essential, as cell death was blocked by exogenous K+ or dextran. MLKL inhibition also blocked caspase-1 and IL-1β production, suggesting a link to the inflammasome. Rip3(-/-) mice exhibited significantly improved staphylococcal clearance and retained an alveolar macrophage population with CD200R and CD206 markers in the setting of acute infection, suggesting increased susceptibility of these leukocytes to necroptosis. The importance of this anti-inflammatory signaling was indicated by the correlation between improved outcome and significantly decreased expression of KC, IL-6, TNF, IL-1α and IL-1β in infected mice. These findings indicate that toxin-induced necroptosis is a major cause of lung pathology in S. aureus pneumonia and suggest the possibility of targeting components of this signaling pathway as a therapeutic strategy.
Despite the importance of precipitation phase to global hydroclimate simulations, many land surface models use spatially uniform air temperature thresholds to partition rain and snow. Here we show, ...through the analysis of a 29-year observational dataset (n = 17.8 million), that the air temperature at which rain and snow fall in equal frequency varies significantly across the Northern Hemisphere, averaging 1.0 °C and ranging from -0.4 to 2.4 °C for 95% of the stations. Continental climates generally exhibit the warmest rain-snow thresholds and maritime the coolest. Simulations show precipitation phase methods incorporating humidity perform better than air temperature-only methods, particularly at relative humidity values below saturation and air temperatures between 0.6 and 3.4 °C. We also present the first continuous Northern Hemisphere map of rain-snow thresholds, underlining the spatial variability of precipitation phase partitioning. These results suggest precipitation phase could be better predicted using humidity and air temperature in large-scale land surface model runs.
Abstract
UNITE (https://unite.ut.ee/) is a web-based database and sequence management environment for the molecular identification of fungi. It targets the formal fungal barcode—the nuclear ribosomal ...internal transcribed spacer (ITS) region—and offers all ∼1 000 000 public fungal ITS sequences for reference. These are clustered into ∼459 000 species hypotheses and assigned digital object identifiers (DOIs) to promote unambiguous reference across studies. In-house and web-based third-party sequence curation and annotation have resulted in more than 275 000 improvements to the data over the past 15 years. UNITE serves as a data provider for a range of metabarcoding software pipelines and regularly exchanges data with all major fungal sequence databases and other community resources. Recent improvements include redesigned handling of unclassifiable species hypotheses, integration with the taxonomic backbone of the Global Biodiversity Information Facility, and support for an unlimited number of parallel taxonomic classification systems.
The respiratory tract is exceptionally well defended against infection from inhaled bacteria, with multiple proinflammatory signaling cascades recruiting phagocytes to clear airway pathogens. ...However, organisms that efficiently activate damaging innate immune responses, such as those mediated by the inflammasome and caspase-1, may cause pulmonary damage and interfere with bacterial clearance. The extracellular, opportunistic pathogen Pseudomonas aeruginosa expresses not only pathogen-associated molecular patterns that activate NF-κB signaling in epithelial and immune cells, but also flagella that activate the NLRC4 inflammasome. We demonstrate that induction of inflammasome signaling, ascribed primarily to the alveolar macrophage, impaired P. aeruginosa clearance and was associated with increased apoptosis/pyroptosis and mortality in a murine model of acute pneumonia. Strategies that limited inflammasome activation, including infection by fliC mutants, depletion of macrophages, deletion of NLRC4, reduction of IL-1β and IL-18 production, inhibition of caspase-1, and inhibition of downstream signaling in IL-1R- or IL-18R-null mice, all resulted in enhanced bacterial clearance and diminished pathology. These results demonstrate that the inflammasome provides a potential target to limit the pathological consequences of acute P. aeruginosa pulmonary infection.
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