Modulation of Cellular Tropism and Innate Antiviral Response by Viral Glycans

Arthropod-borne viruses (arboviruses) are a significant cause of human and animal disease worldwide. Multiple interactions between virus and the host innate immune system ultimately determine the pathogenesis and clinical outcome of the infection. Evidence is rapidly emerging that suggests viral glycans play a key role in viral pathogenesis by regulating host cell tropism and interactions with the host innate immune response. Glycan-mediated interactions are especially important for arboviruses which must adapt to variable glycosylation systems and cellular receptors within both vertebrate and invertebrate hosts. This review focuses on emerging evidence which supports a crucial role for viral glycans in mediating host cell tropism and regulating the innate antiviral response

Stria terminalis microstructure in humans predicts variability in orienting toward threat

Current concepts of the extended amygdala posit that basolateral to central amygdala projections mediate fear‐conditioned autonomic alerting, whereas projections to the bed nucleus of the stria terminalis mediate sustained anxiety. Using diffusion tensor imaging tractography in humans, we show that microstructure of the stria terminalis correlates with an orienting bias towards threat in a saccade decision task, providing the first evidence that this circuit supports decisions guiding evaluation of threatening stimuli

Generalized Sums over Histories for Quantum Gravity II. Simplicial Conifolds

This paper examines the issues involved with concretely implementing a sum over conifolds in the formulation of Euclidean sums over histories for gravity. The first step in precisely formulating any sum over topological spaces is that one must have an algorithmically implementable method of generating a list of all spaces in the set to be summed over. This requirement causes well known problems in the formulation of sums over manifolds in four or more dimensions; there is no algorithmic method of determining whether or not a topological space is an n-manifold in five or more dimensions and the issue of whether or not such an algorithm exists is open in four. However, as this paper shows, conifolds are algorithmically decidable in four dimensions. Thus the set of 4-conifolds provides a starting point for a concrete implementation of Euclidean sums over histories in four dimensions. Explicit algorithms for summing over various sets of 4-conifolds are presented in the context of Regge calculus. Postscript figures available via anonymous ftp at black-hole.physics.ubc.ca (137.82.43.40) in file gen2.ps.Comment: 82pp., plain TeX, To appear in Nucl. Phys. B,FF-92-

Helping and Cooperation in Children with Autism

Helping and cooperation are central to human social life. Here, we report two studies investigating these social behaviors in children with autism and children with developmental delay. In the first study, both groups of children helped the experimenter attain her goals. In the second study, both groups of children cooperated with an adult, but fewer children with autism performed the tasks successfully. When the adult stopped interacting at a certain moment, children with autism produced fewer attempts to re-engage her, possibly indicating that they had not formed a shared goal/shared intentions with her. These results are discussed in terms of the prerequisite cognitive and motivational skills and propensities underlying social behavior

Time From Symptom Onset to Treatment and Outcomes after Thrombolytic Therapy

OBJECTIVES: This study sought to examine the relations among patient characteristics, time to thrombolysis and outcomes in the international GUSTO-I trial. BACKGROUND: Studies have shown better left ventricular function and decreased infarct size as well as increased survival with earlier thrombolysis, but the relative benefits of various thrombolytic agents with earlier administration are uncertain. METHODS: We evaluated the relations of baseline characteristics to three prospectively defined time variables: symptom onset to treatment, symptom onset to hospital arrival (presentation delay) and hospital arrival to treatment (treatment delay). We also examined the relations of delays to clinical outcomes and to the relative 30-day mortality benefit with accelerated tissue-type plasminogen activator (t-PA) versus streptokinase. RESULTS: Female, elderly, diabetic and hypertensive patients had longer delays at all stages. Previous infarction or bypass surgery was an additional risk factor for treatment delay. Early thrombolysis was associated with lower overall mortality rate ( 4 h, 9.0%), but no additional relative benefit resulted from earlier treatment with accelerated t-PA versus streptokinase (p = 0.38). Longer presentation and treatment delays were both associated with increased mortality rate (presentation delay 4 h, 8.6%; treatment delay 90 min, 8.1%). As time to treatment increased, the incidence of recurrent ischemia or reinfarction decreased, but the rates of shock, heart failure and stroke increased. CONCLUSIONS: Earlier treatment resulted in better outcomes, regardless of thrombolytic strategy. Elderly, female and diabetic patients were treated later, adding to their already substantial risk

Prevalence of nonsuppressed viral load and associated factors among HIV-positive adults receiving antiretroviral therapy in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017): results from population-based nationally representative surveys.

INTRODUCTION The global target for 2020 is that ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) will achieve viral load suppression (VLS). We examined VLS and its determinants among adults receiving ART for at least four months. METHODS We analysed data from the population-based HIV impact assessment (PHIA) surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017). PHIA surveys are nationally representative, cross-sectional household surveys. Data collection included structured interviews, home-based HIV testing and laboratory testing. Blood samples from PLHIV were analysed for HIV RNA, CD4 counts and recent exposure to antiretroviral drugs (ARVs). We calculated representative estimates for the prevalence of VLS (viral load <1000 copies/mL), nonsuppressed viral load (NVL; viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL) and rates of switching to second-line ART (protease inhibitors present) among PLHIV aged 15 to 59 years who participated in the PHIA surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe, initiated ART at least four months before the survey and were receiving ART at the time of the survey (according to self-report or ARV testing). We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second-line ART. RESULTS We included 9200 adults receiving ART of whom 88.8% had VLS and 11.2% had NVL including 8.2% who experienced VF and 3.0% who interrupted ART. Younger age, male sex, less education, suboptimal adherence, receiving nevirapine, HIV non-disclosure, never having married and residing in Zimbabwe, Lesotho or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female sex, shorter ART duration, higher CD4 count and alcohol use were associated with lower odds for VF and higher odds for interrupted ART. Many people with VF (44.8%) had CD4 counts <200 cells/µL, but few (0.31% per year) switched to second-line ART. CONCLUSIONS Countries are approaching global VLS targets for adults. Treatment support, in particular for younger adults, and people with higher CD4 counts, and switching of people to protease inhibitor- or integrase inhibitor-based regimens may further reduce NVL prevalence

Impact of the 2014–2016 marine heatwave on US and Canada West Coast fisheries: Surprises and lessons from key case studies

Marine heatwaves are increasingly affecting marine ecosystems, with cascading impacts on coastal economies, communities, and food systems. Studies of heatwaves provide crucial insights into potential ecosystem shifts under future climate change and put fisheries social-ecological systems through “stress tests” that expose both vulnerabilities and resilience. The 2014–16 Northeast Pacific heatwave was the strongest and longest marine heatwave on record and resulted in profound ecological changes that impacted fisheries, fisheries management, and human livelihoods. Here, we synthesize the impacts of the 2014–2016 marine heatwave on US and Canada West Coast fisheries and extract key lessons for preparing global fisheries science, management, and industries for the future. We set the stage with a brief review of the impacts of the heatwave on marine ecosystems and the first systematic analysis of the economic impacts of these changes on commercial and recreational fisheries. We then examine ten key case studies that provide instructive examples of the complex and surprising challenges that heatwaves pose to fisheries social-ecological systems. These reveal important insights into improving the resilience of monitoring and management and increasing adaptive capacity to future stressors. Key recommendations include: (1) expanding monitoring to enhance mechanistic understanding, provide early warning signals, and improve predictions of impacts; (2) increasing the flexibility, adaptiveness, and inclusiveness of management where possible; (3) using simulation testing to help guide management decisions; and (4) enhancing the adaptive capacity of fishing communities by promoting engagement, flexibility, experimentation, and failsafes. These advancements are important as global fisheries prepare for a changing oceanWe are grateful to Nate Mantua, Manuel Hidalgo, Kiva Oken, and Cori Lopazanski for feedback on manuscript drafts. We thank Jean Lee for sharing a non-confidential version of the Gulf of Alaska commercial fisheries landings data and Evan Damkjar and John Davidson for sharing non-confidential versions of British Columbia's commercial and recreational fisheries landings data. CMF was funded by The Nature Conservancy, California. BM was partially supported by the Future Seas II project under NOAA's Climate and Fisheries Adaptation Program (NA20OAR431050). The scientific results and conclusions, as well as any views or opinions expressed herein, are those of the author(s) and do not necessarily reflect the views of NOAA or the Department of Commerce.Ye

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD.'' All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations

Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82

G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments