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Abstract The increasing availability of biobanks is changing the way individuals are identified for genomic research. This study assesses the validity of a self-reported clinical diagnosis of schizophrenia. The study included 1744 clinically-ascertained participants with schizophrenia or schizoaffective disorder depressed-type (SA-D) diagnosed by self-report and/or research interview and 1453 UK Biobank participants with self-reported and/or medical record diagnosis of schizophrenia or SA-D. Unaffected controls included a total of 501,837 participants. We assessed the positive predictive values (PPV) of self-reported clinical diagnoses against research interview and medical record diagnoses. Polygenic risk scores (PRS) and phenotypes relating to demographics, education and employment were compared across diagnostic groups. The variance explained (r2) in schizophrenia PRS for each diagnostic group was compared to samples in the Psychiatric Genomics Consortium (PGC). In the clinically-ascertained participants, the PPV of self-reported schizophrenia for a research diagnosis of schizophrenia was 0.70, which increased to 0.81 after expanding the research diagnosis to schizophrenia or SA-D. In UK Biobank, the PPV of self-reported schizophrenia for a medical record diagnosis was 0.74. Compared to participants who self-reported, participants with a clinically-ascertained research diagnosis were younger and more likely to have a high school qualification. Participants with a medical record diagnosis in UK Biobank were less likely to be employed or have a high school qualification than those who self-reported. Schizophrenia PRS did not differ between participants that had a diagnosis from self-report, research diagnosis or medical records. Polygenic liability r2, for all diagnosis definitions, fell within the distribution of PGC schizophrenia cohorts. Self-reported measures of schizophrenia are justified in genomic research to maximise sample size and reduce the burden of in-depth interviews on participants, although within sample validation of diagnoses is recommended.

Abstract Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

A major challenge in sustainability science is identifying targets that maximize ecosystem benefits to humanity while minimizing the risk of crossing critical system thresholds. One critical threshold is the biomass at which populations become so depleted that their population growth rates become negative-depensation. Here, we evaluate how the value of monitoring information increases as a natural resource spends more time near the critical threshold. This benefit emerges because higher monitoring precision promotes higher yield and a greater capacity to recover from overharvest. We show that precautionary buffers that trigger increased monitoring precision as resource levels decline may offer a way to minimize monitoring costs and maximize profits. In a world of finite resources, improving our understanding of the trade-off between precision in estimates of population status and the costs of mismanagement will benefit stakeholders that shoulder the burden of these economic and social costs.

BackgroundPsychiatric disorders are associated with cognitive impairment. We have developed a web-based, 9-task cognitive battery to measure the core domains affected in people with psychiatric disorders. To date, this assessment has been used to collect data on a clinical sample of participants with psychiatric disorders. ObjectiveThe aims of this study were (1) to establish a briefer version of the battery (called the Cardiff Online Cognitive Assessment [CONCA]) that can give a valid measure of cognitive ability (“g”) and (2) to collect normative data and demonstrate CONCA’s application in a health population sample. MethodsBased on 6 criteria and data from our previous study, we selected 5 out of the original 9 tasks to include in CONCA. These included 3 core tasks that were sufficient to derive a measure of “g” and 2 optional tasks. Participants from a web-based national cohort study (HealthWise Wales) were invited to complete CONCA. Completion rates, sample characteristics, performance distributions, and associations between cognitive performance and demographic characteristics and mental health measures were examined. ResultsA total of 3679 participants completed at least one CONCA task, of which 3135 completed all 3 core CONCA tasks. Performance on CONCA was associated with age (B=–0.05, SE 0.002; P

Summary: Neural crest cells are multipotent cells that delaminate from the neuroepithelium, migrating throughout the embryo. Aberrant migration causes developmental defects. Animal models are improving our understanding of neural crest anomalies, but in vivo migration behaviors are poorly understood. Here, we demonstrate that murine neural crest cells display actin-based lamellipodia and filopodia in vivo. Using neural crest-specific knockouts or inhibitors, we show that the serine-threonine kinase glycogen synthase kinase-3 (GSK3) and the cytoskeletal regulator lamellipodin (Lpd) are required for lamellipodia formation while preventing focal adhesion maturation. Lpd is a substrate of GSK3, and phosphorylation of Lpd favors interactions with the Scar/WAVE complex (lamellipodia formation) at the expense of VASP and Mena interactions (adhesion maturation and filopodia formation). This improved understanding of cytoskeletal regulation in mammalian neural crest migration has general implications for neural crest anomalies and cancer.

BackgroundCognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.MethodsWe combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases.ResultsPRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS.ConclusionsCognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

Abstract Noncanonical epitopes presented by Human Leucocyte Antigen class I (HLA-I) complexes to CD8+ T cells attracted the spotlight in the research of novel immunotherapies against cancer, infection and autoimmunity. Proteasomes, which are the main producers of HLA-I-bound antigenic peptides, can catalyze both peptide hydrolysis and peptide splicing. The prediction of proteasome-generated spliced peptides is an objective that still requires a reliable (and large) database of non-spliced and spliced peptides produced by these proteases. Here, we present an extended database of proteasome-generated spliced and non-spliced peptides, which was obtained by analyzing in vitro digestions of 80 unique synthetic polypeptide substrates, measured by different mass spectrometers. Peptides were identified through invitroSPI method, which was validated through in silico and in vitro strategies. The peptide product database contains 16,631 unique peptide products (5,493 non-spliced, 6,453 cis-spliced and 4,685 trans-spliced peptide products), and a substrate sequence variety that is a valuable source for predictors of proteasome-catalyzed peptide hydrolysis and splicing. Potential artefacts and skewed results due to different identification and analysis strategies are discussed.

The data is collected through laboratory experiments on a dynamic common pool resource game, where, in an infinitely repeated number of rounds (i.e., game ended randomly), individuals made decisions about whether to exert a high or a low effort level to extract resources. Experiments were conducted using the student sample (consent provided and ethics approved) at the University of Hawaiʻi at Mānoa. A total of 8 sessions, 2 for each of the 4 treatments, were run with exactly 20 participants within a session. Individuals made decisions in groups of 10. Communication between any participant was not allowed. A session is randomly assigned (1) to vary whether the inflow of resources at the beginning of each round is high or low, and (2) to allow participants to either financially punish or socially punish defectors. A financial punishment resulted to a loss in profit for the punished while a social punishment displayed the words “You have extracted too much! You're being greedy!” on the computer screen of the punished. Individuals were assigned subject ID numbers and interacted using their subject IDs. The data is useful in understanding how resource inflow and type of punishment affects individual resource extraction behavior. The data could also be combined with other publicly available common pool resource datasets for a meta-analysis on individual behavior in the commons.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. Aims Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. Method As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. Results We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. Conclusions DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Abstract Escherichia coli is a Gram-negative bacterium that colonises the human intestine and virulent strains can cause severe diarrhoeal and extraintestinal diseases. The protein SslE is secreted by a range of pathogenic and commensal E. coli strains. It can degrade mucins in the intestine, promotes biofilm maturation and it is a major determinant of infection in virulent strains, although how it carries out these functions is not well understood. Here, we examine SslE from the commensal E. coli Waksman and BL21 (DE3) strains and the enterotoxigenic H10407 and enteropathogenic E2348/69 strains. We reveal that SslE has a unique and dynamic structure in solution and in response to acidification within mature biofilms it can form a unique aggregate with amyloid-like properties. Furthermore, we show that both SslE monomers and aggregates bind DNA in vitro and co-localise with extracellular DNA (eDNA) in mature biofilms, and SslE aggregates may also associate with cellulose under certain conditions. Our results suggest that interactions between SslE and eDNA are important for biofilm maturation in many E. coli strains and SslE may also be a factor that drives biofilm formation in other SslE-secreting bacteria.

Abstract Evaluation of the economic impacts of marine protected areas is hampered by the fact that it is impossible to observe what would have happened if the protected area had never been closed to fishing (the counterfactual). Catch reports and vessel tracks are used to perform an analysis of the potential negative economic impacts of establishing the Northeast Canyons and Seamounts Marine National Monument (located off the east coast of the United States of America) on three commercially important fisheries that were identified as having potential to be harmed. I conclude that there was little to no negative impact on any of the fisheries. I also test for, but find no evidence of, a Blue Paradox effect. Due to political factors largely unrelated to fisheries status, the protected area was reopened to commercial fishing on June 5th, 2020. I use this event, which was reversed sixteen months later, to test whether there were any economic benefits from reopening. I do not observe an increase in catch, a reduction in distance traveled, or an increase in relative fishing effort inside the protected area (compared to historical trends), consistent with the post-closure findings.

Physiological and premature aging are frequently associated with an accumulation of prelamin A, a precursor of lamin A, in the nuclear envelope of various cell types. Here, we aimed to underpin the hitherto unknown mechanisms by which prelamin A alters myonuclear organization and muscle fiber function. By experimentally studying membrane-permeabilized myofibers from various transgenic mouse lines, our results indicate that, in the presence of prelamin A, the abundance of nuclei and myosin content is markedly reduced within muscle fibers. This leads to a concept by which the remaining myonuclei are very distant from each other and are pushed to function beyond their maximum cytoplasmic capacity, ultimately inducing muscle fiber weakness.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

ABSTRACT Human immunodeficiency virus type-1 (HIV-1) infection is potently inhibited by human myxovirus resistance 2 (MX2/MxB), which binds to the viral capsid and blocks the nuclear import of viral DNA. We have recently shown that phosphorylation is a key regulator of MX2 antiviral activity, with phosphorylation of serine residues at positions 14, 17, and 18 repressing MX2 function. Here, we extend the study of MX2 posttranslational modifications and identify serine and threonine phosphorylation in all domains of MX2. By substituting these residues with aspartic acid or alanine, hence mimicking the presence or absence of a phosphate group, respectively, we identified key positions that control MX2 antiviral activity. Aspartic acid substitutions of residues Ser306 or Thr334 and alanine substitutions of Thr343 yielded proteins with substantially reduced antiviral activity, whereas the presence of aspartic acid at positions Ser28, Thr151, or Thr343 resulted in enhanced activity: referred to as hypermorphic mutants. In some cases, these hypermorphic mutations, particularly when paired with other MX2 mutations (e.g., S28D/T151D or T151D/T343A) acquired the capacity to inhibit HIV-1 capsid mutants known to be insensitive to wild-type MX2, such as P90A or T210K, as well as MX2-resistant retroviruses such as equine infectious anemia virus (EIAV) and murine leukemia virus (MLV). This work highlights the complexity and importance of MX2 phosphorylation in the regulation of antiviral activity and in the selection of susceptible viral substrates. IMPORTANCE Productive infection by human immunodeficiency virus type-1 (HIV-1) requires the import of viral replication complexes into the nuclei of infected cells. Myxovirus resistance 2 (MX2/MxB) blocks this step, halting nuclear accumulation of viral DNA and virus replication. We recently demonstrated how phosphorylation of a stretch of three serines in the amino-terminal domain of MX2 inhibits the antiviral activity. Here, we identify additional positions in MX2 whose phosphorylation status reduces or enhances antiviral function (hypomorphic and hypermorphic variants, respectively). Importantly, hypermorphic mutant proteins not only increased inhibitory activity against wild-type HIV-1 but can also exhibit antiviral capabilities against HIV-1 capsid mutant viruses that are resistant to wild-type MX2. Furthermore, some of these proteins were also able to inhibit retroviruses that are insensitive to MX2. Therefore, we propose that phosphorylation comprises a major element of MX2 regulation and substrate determination.

Abstract The discovery of compounds and proteins from plants has greatly contributed to modern medicine. Vernonia amygdalina Del. (Compositae) is used by humans and primates for a variety of conditions including parasitic infection. This paper describes the serendipitous discovery that V. amygdalina extract was able to bind to, and functionally inhibit, active TGFβ1. The binding agent was isolated and identified as chlorophyll a-b binding protein AB96. Given that active TGFβ1 contributes to the pathology of many infectious diseases, inhibiting these processes may explain some of the benefits associated with the ingestion of this species. This is the first plant-derived cytokine-neutralizing protein to be described and paves the way for further such discoveries.

Marine protected areas (MPAs) have been identified as one of the most effective tools to halt marine biodiversity loss. However, conflicting evidence from disparate, small-scale studies obfuscate a cohesive global picture of the role that MPAs can play in enhancing local fisheries through spillover benefits. We conducted a global analysis of trophy-size fish catches as a proxy for spillover occurring outside of fully protected MPAs, focusing on time series of recreational angling catch records. We show that the accumulation of recreational fishing records accelerates close to MPAs (compared to reference areas) and that this effect grows stronger over time. Our results provide a standardized global assessment of one of the benefits MPAs provide to recreational anglers. [ABSTRACT FROM AUTHOR]

There are concerns that expansion of marine protected areas could have negative effects on the fishing industry. Here Lynham et al. demonstrate that the expansion of two of the world’s largest protected areas did not have a negative impact on catch rates in the Hawaii longline fishery.

BackgroundCognitive impairments are features of many psychiatric disorders and affect functioning. A barrier to cognitive research on psychiatric disorders is the lack of large cross-disorder data sets. However, the collection of cognitive data can be logistically challenging and expensive. Web-based collection may be an alternative; however, little is known about who does and does not complete web-based cognitive assessments for psychiatric research. ObjectiveThe aims of this study are to develop a web-based cognitive battery for use in psychiatric research, validate the battery against the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and compare the characteristics of the participants who chose to take part with those of the individuals who did not participate. MethodsTasks were developed by The Many Brains Project and selected to measure the domains specified by the MATRICS initiative. We undertook a cross-validation study of 65 participants with schizophrenia, bipolar disorder, depression, or no history of psychiatric disorders to compare the web-based tasks with the MATRICS Consensus Cognitive Battery. Following validation, we invited participants from 2 large ongoing genetic studies, which recruited participants with psychiatric disorders to complete the battery and evaluated the demographic and clinical characteristics of those who took part. ResultsCorrelations between web-based and MATRICS tasks ranged between 0.26 and 0.73. Of the 961 participants, 887 (92.3%) completed at least one web-based task, and 644 (67%) completed all tasks, indicating adequate completion rates. Predictors of web-based participation included being female (odds ratio [OR] 1.3, 95% CI 1.07-1.58), ethnicity other than White European (OR 0.66, 95% CI 0.46-0.96), higher levels of education (OR 1.19, 95% CI 1.11-1.29), diagnosis of an eating disorder (OR 2.17, 95% CI 1.17-4) or depression and anxiety (OR 5.12, 95% CI 3.38-7.83), and absence of a diagnosis of schizophrenia (OR 0.59, 95% CI 0.35-0.94). Lower performance on the battery was associated with poorer functioning (B=−1.76, SE 0.26; P

Wildfires are worsening in Canada and globally, partly due to climate change. The government of Canada is designing and building WildFireSat, the world’s first purpose-built operational satellite system for wildfire monitoring. It will provide new fire intelligence to support decision-making. It takes time for fire management agencies to use new information: to understand it and its implications, change processes, develop training, and modify computer systems. Preparing for the system’s prelaunch will allow agencies to benefit more rapidly from the new information. We present (1) an assessment of the readiness of 12 Canadian fire management agencies to integrate WildFireSat information and (2) guidance for reducing readiness gaps. We used survey and other data to score readiness indicators for three readiness components: understanding, organization, and information technology. We weighted the influence of each indicator score on each component. We modelled scoring and weighting uncertainties and used Monte Carlo simulation to generate distributions of aggregated agency readiness. The results indicated that most agencies have a moderate level of readiness while others have a higher level of readiness. Cluster analysis was used to group agencies by similarity in multiple dimensions. Strategies for increasing readiness are highlighted. This identifies opportunities for agencies and the WildFireSat team to collaborate on enhancing readiness for the forthcoming WildFireSat data products.