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High throughput sequencing has accelerated the determination of genome sequences for thousands of human infectious disease pathogens and dozens of their vectors. The scale and scope of these data are enabling genotype-phenotype association studies to identify genetic determinants of pathogen virulence and drug/insecticide resistance, and phylogenetic studies to track the origin and spread of disease outbreaks. To maximize the utility of genomic sequences for these purposes, it is essential that metadata about the pathogen/vector isolate characteristics be collected and made available in organized, clear, and consistent formats. Here we report the development of the GSCID/BRC Project and Sample Application Standard, developed by representatives of the Genome Sequencing Centers for Infectious Diseases (GSCIDs), the Bioinformatics Resource Centers (BRCs) for Infectious Diseases, and the U.S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), informed by interactions with numerous collaborating scientists. It includes mapping to terms from other data standards initiatives, including the Genomic Standards Consortium's minimal information (MIxS) and NCBI's BioSample/BioProjects checklists and the Ontology for Biomedical Investigations (OBI). The standard includes data fields about characteristics of the organism or environmental source of the specimen, spatial-temporal information about the specimen isolation event, phenotypic characteristics of the pathogen/vector isolated, and project leadership and support. By modeling metadata fields into an ontology-based semantic framework and reusing existing ontologies and minimum information checklists, the application standard can be extended to support additional project-specific data fields and integrated with other data represented with comparable standards. The use of this metadata standard by all ongoing and future GSCID sequencing projects will provide a consistent representation of these data in the BRC resources and other repositories that leverage these data, allowing investigators to identify relevant genomic sequences and perform comparative genomics analyses that are both statistically meaningful and biologically relevant.

We developed a novel conceptualization of one component of creativity in narratives by integrating creativity theory and distributional semantics theory. We termed the new construct divergent semantic integration ( DSI ), defined as the extent to which a narrative connects divergent ideas. Across nine studies, 27 different narrative prompts, and over 3500 short narratives, we compared six models of DSI that varied in their computational architecture. The best-performing model employed Bidirectional Encoder Representations from Transformers (BERT), which generates context-dependent numerical representations of words (i.e., embeddings). BERT DSI scores demonstrated impressive predictive power, explaining up to 72% of the variance in human creativity ratings, even approaching human inter-rater reliability for some tasks. BERT DSI scores showed equivalently high predictive power for expert and nonexpert human ratings of creativity in narratives. Critically, DSI scores generalized across ethnicity and English language proficiency, including individuals identifying as Hispanic and L2 English speakers. The integration of creativity and distributional semantics theory has substantial potential to generate novel hypotheses about creativity and novel operationalizations of its underlying processes and components. To facilitate new discoveries across diverse disciplines, we provide a tutorial with code (osf.io/ath2s) on how to compute DSI and a web app ( osf.io/ath2s ) to freely retrieve DSI scores.

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures. The SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme provides a real-time risk assessment of SARS-CoV-2 variants with the potential to affect transmission, virulence and resistance to infection- and vaccine-induced immunity.

Alterations in GABAergic neurotransmission are implicated in several psychiatric illnesses, including schizophrenia. The Na-K-Cl and K-Cl cotransporters regulate intracellular chloride levels. Abnormalities in cotransporter expression levels could shift the chloride electrochemical gradient and impair GABAergic transmission. In this study, we performed Western blot analysis to investigate whether the Na-K-Cl and K-Cl cotransporter protein is abnormally expressed in the dorsal lateral prefrontal cortex and the anterior cingulate cortex in patients with schizophrenia versus a control group. We found decreased K-Cl cotransporter protein expression in the dorsal lateral prefrontal cortex, but not the anterior cingulate cortex, in subjects with schizophrenia, supporting the hypothesis of region level abnormal GABAergic function in the pathophysiology of schizophrenia. Subjects with schizophrenia off antipsychotic medication at the time of death had decreased K-Cl cotransporter protein expression compared to both normal controls and subjects with schizophrenia on antipsychotics. Our results provide evidence for KCC2 protein abnormalities in schizophrenia and suggest that antipsychotic medications might reverse deficits of this protein in the illness.

Potassium chloride (KCl) is often used to supply K for potato (Solanum tuberosum L.) production; it is the least costly K fertilizer. However, crop uptake of Cl can reduce diagnostic petiole NO3–N and reduce tuber specific gravity. This trial evaluated the effect of K fertilizer source (KCl vs. sulfate of potash [SOP] and sulfate of potash magnesia [KMag]) and fertilizer application timing on Cl, S, N, and K in soil, petioles, and whole plant biomass. Fertilizers were applied at 224 kg K2O ha–1 at three application timings: 210 d before planting (fall preplant), 14 d before planting (spring preplant), or 35 d after planting (Layby) to a sandy loam soil in Hermiston, OR. Nitrogen fertilizer was applied by overhead sprinklers during the growing season. Potassium source and timing had minimal effect on crop S, N, and K uptake. Crop Cl response reflected a fertilizer source × timing interaction. Fall‐applied KCl did not increase plant Cl above that observed for KMag and SOP treatments. Spring or summer‐applied KCl increased plant Cl concentrations. The most likely explanation for this response pattern was leaching of Cl below rooting depth with fall fertilizer application. Findings of importance for potato production practices in our region included: (a) fall‐applied Cl was not taken up by the crop, and so did not represent a risk to potato tuber quality; (b) elevated concentrations of petiole Cl from preplant or in‐season KCl application did not affect petiole NO3–N. Core Ideas Delaying KCl application increased Cl in soil, petioles, and biomass. Crop Cl uptake was minimized by applying KCl preplant in fall. Elevated petiole Cl did not affect petiole NO3‐N.

Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19. Here, the authors show that SARS-CoV-2 infection causes gut microbiome dysbiosis and gut epithelial cell alterations in a mouse model, and correlate dysbiosis observed in COVID-19 patients with blood stream infections, matching reads of bacterial sequences from stool samples to organisms found in the blood.

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n  = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk. Environmental influences during prenatal development may have implications for health and disease later in life. Here, Czamara et al. assess DNA methylation in cord blood from new-born under various models including environmental and genetic effects individually and their additive or interaction effects.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons. Now, Valentin Gribkoff and his colleagues show some preliminary evidence that the drug dexpramipexole may have clinical activity in a small placebo-controlled trial in patients with ALS. Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death 1 , 2 , 3 . Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis 4 , 5 , 6 , 7 , 8 , 9 . Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS 10 , 11 . We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6 R )-4,5,6,7-tetrahydro- N 6-propyl-2,6-benzothiazole-diamine) 12 , 13 , 14 in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d −1 ) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single-blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d −1 or 300 mg d −1 as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant ( P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS.

The Palomar Transient Factory (PTF) is a fully-automated, wide-field survey aimed at a systematic exploration of the optical transient sky. The transient survey is performed using a new 8.1 square degree camera installed on the 48 inch Samuel Oschin telescope at Palomar Observatory; colors and light curves for detected transients are obtained with the automated Palomar 60 inch telescope. PTF uses 80% of the 1.2 m and 50% of the 1.5 m telescope time. With an exposure of 60 s the survey reaches a depth of m g ′  ≈ 21.3 m g ′ ≈ 21.3 and m R  ≈ 20.6 m R ≈ 20.6 (5σ, median seeing). Four major experiments are planned for the five-year project: (1) a 5 day cadence supernova search; (2) a rapid transient search with cadences between 90 s and 1 day; (3) a search for eclipsing binaries and transiting planets in Orion; and (4) a 3π sr deep H-alpha survey. PTF provides automatic, real-time transient classification and follow-up, as well as a database including every source detected in each frame. This paper summarizes the PTF project, including several months of on-sky performance tests of the new survey camera, the observing plans, and the data reduction strategy. We conclude by detailing the first 51 PTF optical transient detections, found in commissioning data.

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes 1 , 2 . Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease 3 , 4 , suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns 5 – 8 , the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) 9 , 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2 . Experimental validation of three variants, combined with previous work 10 , confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery. Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery.