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The Multidisciplinary Observatory for Study of the Arctic Climate (MOSAiC) expedition consisted of a year-long drifting survey of the Central Arctic Ocean. The ecosystems component of MOSAiC included the sampling of molecular data, with metagenomes collected from a diverse range of environments. The generation of metagenome-assembled-genomes (MAGs) from metagenomes are a starting point for genome-resolved analyses. This dataset presents a catalogue of MAGs recovered from a set of 73 samples from MOSAiC, including 2407 prokaryotic and 56 eukaryotic MAGs, as well as annotations of a near complete eukaryotic MAG using the Joint Genome Institute (JGI) annotation pipeline. The metagenomic samples are from the surface ocean, chlorophyll maximum, mesopelagic and bathypelagic, within leads and under-ice ocean, as well as melt ponds, ice ridges, and first- and second-year sea ice. This set of MAGs can be used to benchmark microbial biodiversity in the Central Arctic Ocean, compare individual strains across space and time, and to study changes in Arctic microbial communities from the winter to summer, at a genomic level. more...

Aspergillus nidulans is an important model organism for eukaryotic biology and the reference for the section Nidulantes in comparative studies. In this study, we de novo sequenced the genomes of 25 species of this section. Whole-genome phylogeny of 34 Aspergillus species and Penicillium chrysogenum clarifies the position of clades inside section Nidulantes. Comparative genomics reveals a high genetic diversity between species with 684 up to 2433 unique protein families. Furthermore, we categorized 2118 secondary metabolite gene clusters (SMGC) into 603 families across Aspergilli, with at least 40 % of the families shared between Nidulantes species. Genetic dereplication of SMGC and subsequent synteny analysis provides evidence for horizontal gene transfer of a SMGC. Proteins that have been investigated in A. nidulans as well as its SMGC families are generally present in the section Nidulantes, supporting its role as model organism. The set of genes encoding plant biomass-related CAZymes is highly conserved in section Nidulantes, while there is remarkable diversity of organization of MAT-loci both within and between the different clades. This study provides a deeper understanding of the genomic conservation and diversity of this section and supports the position of A. nidulans as a reference species for cell biology. more...

Quantifying ecosystem services provided by mobile species like insectivorous bats remains a challenge, particularly in understanding where and how these services vary over space and time. Bats are known to offer valuable ecosystem services, such as mitigating insect pest damage to crops, reducing pesticide use, and reducing nuisance pest populations. However, determining where bats forage is difficult to monitor. In this study, we use a weather-radar-based bat-monitoring algorithm to estimate bat foraging distributions during the peak season of 2019 in Californias Northern Central Valley. This region is characterized by valuable agricultural crops and significant populations of both crop and nuisance pests, including midges, moths, mosquitos, and flies. Our results show that bat activity is high but unevenly distributed, with rice fields experiencing significantly elevated activity compared to other land cover types. Specifically, bat activity over rice fields is 1.5 times higher than over any other land cover class and nearly double that of any other agricultural land cover. While irrigated rice fields may provide abundant prey, wetland and water areas showed less than half the bat activity per hectare compared to rice fields. Controlling for land cover type, we found bat activity significantly associated with higher flying insect abundance, indicating that bats forage in areas where crop and nuisance pests are likely to be found. This study demonstrates the effectiveness of radar-based bat monitoring in identifying where and when bats provide ecosystem services. more...

BackgroundDespite the established link between social support and cardiovascular disease (CVD) outcomes, few studies have examined racial/ethnic variation in these associations. This study utilized data from the Multi-Ethnic Study of Atherosclerosis (MESA) to investigate racial/ethnic differences in perceived social support and in the link between support and incident hard CVD events and mortality.MethodParticipants (N = 6,814) were 45-84 years of age who identified as White, Black, Hispanic/Latino, or Chinese without known clinical CVD at baseline (2000-2002). Racial/ethnic differences in perceived support (overall, emotional, informational, and instrumental) were tested using multiple regression with adjustments for demographic, socioeconomic, lifestyle/psychosocial, and clinical risk factors, and immigration history. Racial/ethnic differences in the association between perceived support and incident CVD events or mortality were tested using Cox proportional hazards models with progressive adjustments for the same covariates.ResultsAt baseline, the mean age was 62.15 years (SD = 10.23); 38.5% identified as White, 27.8% as Black, 22.0% as Hispanic/Latino, and 11.8% as Chinese. Black and Hispanic/Latino participants reported higher levels of overall support, emotional support, and informational support than White participants (p's more...

A significant challenge on an exascale computer is the speed at which we compute results exceeds by many orders of magnitude the speed at which we save these results. Therefore the Exascale Computing Project (ECP) ALPINE project focuses on providing exascale-ready visualization solutions including in situ processing. In situ visualization and analysis runs as the simulation is run, on simulations results are they are generated avoiding the need to save entire simulations to storage for later analysis. The ALPINE project made post hoc visualization tools, ParaView and VisIt, exascale ready and developed in situ algorithms and infrastructures. The suite of ALPINE algorithms developed under ECP includes novel approaches to enable automated data analysis and visualization to focus on the most important aspects of the simulation. Many of the algorithms also provide data reduction benefits to meet the I/O challenges at exascale. ALPINE developed a new lightweight in situ infrastructure, Ascent. more...

This Roadmap article provides a succinct, comprehensive overview of the state of electronic structure (ES) methods and software for molecular and materials simulations. Seventeen distinct sections collect insights by 51 leading scientists in the field. Each contribution addresses the status of a particular area, as well as current challenges and anticipated future advances, with a particular eye towards software related aspects and providing key references for further reading. Foundational sections cover density functional theory and its implementation in real-world simulation frameworks, Green’s function based many-body perturbation theory, wave-function based and stochastic ES approaches, relativistic effects and semiempirical ES theory approaches. Subsequent sections cover nuclear quantum effects, real-time propagation of the ES, challenges for computational spectroscopy simulations, and exploration of complex potential energy surfaces. The final sections summarize practical aspects, including computational workflows for complex simulation tasks, the impact of current and future high-performance computing architectures, software engineering practices, education and training to maintain and broaden the community, as well as the status of and needs for ES based modeling from the vantage point of industry environments. Overall, the field of ES software and method development continues to unlock immense opportunities for future scientific discovery, based on the growing ability of computations to reveal complex phenomena, processes and properties that are determined by the make-up of matter at the atomic scale, with high precision. more...

INTRODUCTION: A large proportion of patients with inflammatory bowel disease (IBD) experience IBD-related inflammatory conditions outside of the gastrointestinal tract, termed extraintestinal manifestations (EIMs) which further decreases quality of life and, in extreme cases, can be life threatening. The pathogenesis of EIMs remains unknown, and although gut microbiota alterations are a well-known characteristic of patients with IBD, its relationship with EIMs remains sparsely investigated. This study aimed to compare the gut microbiota of patients with IBD with and without EIMs. METHODS: A total of 131 Danish patients with IBD were included in the study, of whom 86 had a history of EIMs (IBD-EIM) and 45 did not (IBD-C). Stool samples underwent 16S rRNA sequencing. Amplicon sequence variants (ASVs) were mapped to the Silva database. Diversity indices and distance matrices were compared between IBD-EIM and IBD-C. Differentially abundant ASVs were identified using a custom multiple model statistical analysis approach, and modules of co-associated bacteria were identified using sparse correlations for compositional data (SparCC) and related to patient EIM status. RESULTS: Patients with IBD and EIMs exhibited increased disease activity, body mass index, increased fecal calprotectin levels and circulating monocytes and neutrophils. Microbiologically, IBD-EIM exhibited lower fecal microbial diversity than IBD-C (Mann-Whitneys test, p = .01) and distinct fecal microbiota composition (permutational multivariate analysis of variance; weighted UniFrac, R2 = 0.018, p = .01). A total of 26 ASVs exhibited differential relative abundances between IBD-EIM and IBD-C, including decreased Agathobacter and Blautia and increased Eggerthella lenta in the IBD-EIM group. SparCC analysis identified 27 bacterial co-association modules, three of which were negatively related to EIM (logistic regression, p more...

OBJECTIVE: The potential for choline metabolism to influence the development of diabetes has received increased attention. Previous studies on circulating choline metabolites and incident diabetes have been conducted in samples of older adults, often with a high prevalence of risk factors. RESEARCH DESIGN AND METHODS: Participants were from year 15 of follow-up (2000-2001) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 3,133, aged 33-45 years) with plasma choline metabolite (choline, betaine, and trimethylamine N-oxide [TMAO]) data. We quantified associations between choline metabolites and 15-year risk of incident diabetes (n = 387) among participants free of diabetes at baseline using Cox proportional hazards regression models adjusted for sociodemographics, health behaviors, and clinical variables. RESULTS: Betaine was inversely associated with 15-year risk of incident diabetes (hazard ratio 0.76 [95% CI 0.67, 0.88] per 1-SD unit betaine), and TMAO was positively associated with 15-year risk of incident diabetes (1.11 [1.01, 1.22] per 1-SD unit). Choline was not significantly associated with 15-year risk of incident diabetes (1.05 [0.94, 1.16] per 1-SD). CONCLUSIONS: Our findings are consistent with other published literature supporting a role for choline metabolism in diabetes. Our study extends the current literature by analyzing a racially diverse population-based cohort of early middle-aged individuals in whom preventive activities may be most relevant. more...

Advances in x-ray free electron lasers have made ultrafast scattering a powerful method for investigating molecular reaction kinetics and dynamics. Accurate measurement of the ground-state, static scattering signals of the reacting molecules is pivotal for these pump-probe x-ray scattering experiments as they are the cornerstone for interpreting the observed structural dynamics. This article presents a data calibration procedure, designed for gas-phase x-ray scattering experiments conducted at the Linac Coherent Light Source x-ray Free-Electron Laser at SLAC National Accelerator Laboratory, that makes it possible to derive a quantitative dependence of the scattering signal on the scattering vector. A self-calibration algorithm that optimizes the detector position without reference to a computed pattern is introduced. Angle-of-scattering corrections that account for several small experimental non-idealities are reported. Their implementation leads to near quantitative agreement with theoretical scattering patterns calculated with ab-initio methods as illustrated for two x-ray photon energies and several molecular test systems. more...

We applied reaction microscopy to elucidate fast non-adiabatic dissociation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV with synchrotron radiation. For the very rare D+ + O+ + D breakup channel, the particle momenta, angular, and energy distributions of electrons and ions, measured in coincidence, reveal distinct electronic dication states and their dissociation pathways via spin-orbit coupling and charge transfer at crossings and seams on the potential energy surfaces. Notably, we could distinguish between direct and fast sequential dissociation scenarios. For the latter case, our measurements reveal the geometry and orientation of the deuterated water molecule with respect to the polarization vector that leads to this rare 3-body molecular breakup channel. Aided by multi-reference configuration-interaction calculations, the dissociation dynamics could be traced on the relevant potential energy surfaces and particularly their crossings and seams. This approach also unraveled the ultrafast time scales governing these processes. more...

The development of biomaterials capable of regulating cellular processes and guiding cell fate decisions has broad implications in tissue engineering, regenerative medicine, and cell-based assays for drug development and disease modeling. Recent studies have shown that three-dimensional (3D) nanoscale physical cues such as nanotopography can modulate various cellular processes like adhesion and endocytosis by inducing nanoscale curvature on the plasma and nuclear membranes. Two-dimensional (2D) biochemical cues such as protein micropatterns can also regulate cell function and fate by controlling cellular geometries. Development of biomaterials with precise control over nanoscale physical and biochemical cues can significantly influence programming cell function and fate. In this study, we utilized a laser-assisted micropatterning technique to manipulate the 2D architectures of cells on 3D nanopillar platforms. We performed a comprehensive analysis of cellular and nuclear morphology and deformation on both nanopillar and flat substrates. Our findings demonstrate the precise engineering of single cell architectures through 2D micropatterning on nanopillar platforms. We show that the coupling between the nuclear and cell shape is disrupted on nanopillar surfaces compared to flat surfaces. Furthermore, our results suggest that cell elongation on nanopillars enhances nanopillar-induced endocytosis. We believe our platform serves as a versatile tool for further explorations into programming cell function and fate through combined physical cues that create nanoscale curvature on cell membranes and biochemical cues that control the geometry of the cell. more...

One of the key factors influencing aging and morbidity is the overall antioxidant status and regenerative capacity. In examining contributors to the antioxidant status, we analyzed the thiamine status in felines and the influence of age, gender, and body condition score. We measured erythrocytic B1-dependent specific transketolase (STKT) activity, an enzyme in the pentose phosphate pathway, in a group of 60 sexually intact, healthy, and specific pathogen-free felines (44 females, 16 males, aged 1–17 years) with thiamine diphosphate (TDP; 0.3 and 3 mM) and without it. Only two parameters (STKT activity with and without 0.3 mM TDP) decreased with age. After adjusting for age, statistical thresholds were established using these and other age-independent parameters, identifying 15 felines with subclinical thiamine deficiency. The red blood cell proteomics analysis revealed that the pentose phosphate shunt, glycolysis, and oxidative stress response were the most affected pathways in deficient felines, confirming the above diagnosis. Age emerged as the primary factor associated with thiamine deficiency, supported by the enrichment of neurodegenerative diseases with a proteotoxicity component; five young-adult felines showed marginal or acute B1 deficiency, and six were adult-mature with a more chronic deficiency, possibly linked to cognitive decline, all with an underweight to ideal body condition scores. Only three senior-adult felines were deficient and overweight-obese. Detecting thiamine deficiency emphasizes the need for more accurate reference values, the establishment of advanced preventive or therapeutic measures to enhance the well-being of aging companion animals, and potential extensions to human health, particularly concerning cognitive function. more...

Extreme weather has a direct and significant impact on buildings and infrastructure, resulting in billions of dollars of damage each year. This problem continues to grow as climate patterns change and buildings are exposed to new and different hazards than what they were designed to withstand. In order to better plan for the long-range sustainment, restoration, modernization, and eventual recapitalization of these buildings, organizations with large building portfolios, such as the U.S. Department of Defense (DoD), must have an awareness of the risks that these extreme weather events present. This research aimed to develop an approach to estimate condition loss and reduction in service life for the components of a building due to extreme weather hazards, to understand the risks that may be present in certain buildings and building systems. To achieve this objective, a damage association matrix was developed that categorizes climate hazards, the damage modes that they produce, and the individual component types impacted. This damage matrix formally links state-of-the-art climate model output, which provides projections of the probability of various climate hazards with a damage effects model that quantifies the consequence on component-level condition and service life. This method is applied to an actual portfolio of buildings in a particular geographic location and with a pre-defined component inventory that comprises the building. This approach can be aggregated to the system-, facility-, and site-level thus helping support billions of dollars in recapitalization decisions related to restoration/modernization of facilities. more...

Pump–probe experiments with subfemtosecond resolution are the key to understanding electronic dynamics in quantum systems. Here we demonstrate the generation and control of subfemtosecond pulse pairs from a two-colour X-ray free-electron laser. By measuring the delay between the two pulses with an angular streaking diagnostic, we characterize the group velocity of the X-ray free-electron laser and show control of the pulse delay down to 270 as. We confirm the application of this technique to a pump–probe measurement in core-ionized para-aminophenol. These results reveal the ability to perform pump–probe experiments with subfemtosecond resolution and atomic site specificity. more...

Estimates of the economic impact of widespread, long duration (WLD) power interruptions can be used to prioritize and justify significant investments in power system resilience. This report presents estimates of this type for WLDs originating within the Commonwealth Edison (ComEd) service territory. The intended audience for this research includes utility executives and technical staff, regulators, and government agencies.This project involved surveying ComEd customers to understand how they might respond when confronted with a WLD power interruption. The research team used the survey responses to calibrate a state-of-the-art regional economic model (“POET”) to estimate economic impacts to households and 38 industry sectors across 17 impacted micro-regions (individual counties or aggregations of counties) within ComEd’s service territory and beyond. We ran one-day, three-day, and 14-day interruption duration scenarios each with varying geographic extents as well as estimated the benefits of deploying additional backup generation across the service territory. The results were then compared to a “business as usual” scenario assuming that no interruption occurred. There are six key findings from this analysis:-There may be significant losses to gross output (business revenue), gross domestic product, and household consumption during WLD interruptions, especially multi-day interruptions that occur across all of ComEd, Cook county, or the suburbs of Chicago.-The wholesale trade and transportation sectors appear to be highly sensitive to power interruptions—losses to these sectors are large relative to the losses observed across the entire economy.-Several sector-region combinations—e.g., the transportation sector in Cook county—are very sensitive to interruptions.-High-income households experience proportionately larger losses to consumption during a one-day power interruption, but low-income households experience proportionately larger losses during the longest power interruptions.-Increasing the amount of backup generation deployed across ComEd’s service territory provides significant net benefits to system-wide gross domestic product, gross output, and household consumption relative to the existing amount of backup generation already being used.-Some micro-regions (e.g., Dekalb and Kendall counties), sectors (e.g., wholesale trade, transportation), and low-income households in Cook county may especially benefit from targeted resilience interventions.We recommend that decision-makers consider running cost-benefit analyses using each of the economic metrics presented in this report independent of one another to evaluate the robustness of the insights that each of these estimates may provide. In addition to this report, we developed a tool that will allow ComEd staff and other decision-makers to visualize the full suite of results using an easy-to-interpret, user interface. We hope that the findings from this research effort will provide valuable insights to ComEd, policymakers across Illinois, and other stakeholders who have an interest in the resilience of the power system. more...

Intermuscular adipose tissue (IMAT) is a relatively understudied adipose depot located between muscle fibers. IMAT content increases with age and BMI and is associated with metabolic and muscle degenerative diseases; however, an understanding of the biological properties of IMAT and its interplay with the surrounding muscle fibers is severely lacking. In recent years, single-cell and nuclei RNA sequencing have provided us with cell type-specific atlases of several human tissues. However, the cellular composition of human IMAT remains largely unexplored due to the inherent challenges of its accessibility from biopsy collection in humans. In addition to the limited amount of tissue collected, the processing of human IMAT is complicated due to its proximity to skeletal muscle tissue and fascia. The lipid-laden nature of the adipocytes makes it incompatible with single-cell isolation. Hence, single nuclei RNA sequencing is optimal for obtaining high-dimensional transcriptomics at single-cell resolution and provides the potential to uncover the biology of this depot, including the exact cellular composition of IMAT. Here, we present a detailed protocol for nuclei isolation and library preparation of frozen human IMAT for single nuclei RNA sequencing. This protocol allows for the profiling of thousands of nuclei using a droplet-based approach, thus providing the capacity to detect rare and low-abundant cell types. more...

Survival and growth strategies of Antarctic endolithic microbes residing in Earth's driest and coldest desert remain virtually unknown. From 109 endolithic microbiomes, 4539 metagenome-assembled genomes were generated, 49.3 % of which were novel candidate bacterial species. We present evidence that trace gas oxidation and atmospheric chemosynthesis may be the prevalent strategies supporting metabolic activity and persistence of these ecosystems at the fringe of life and the limits of habitability. more...

Traditional methods for assessing the resource adequacy (RA) of a power system are becoming obsolete due to emerging trends such as the increasing deployment of variable renewable energy and storage. Consequently, analysts are recommending that RA be assessed using a Monte Carlo simulation approach that models chronological power system operations over many instances of possible operating conditions. However, this approach is necessarily more complex and computationally demanding, which is an obstacle to real-world implementation. In this study, we investigate which operational details of power systems are important to capture in order to accurately evaluate a system's RA, versus details that add complexity but do not meaningfully affect RA results. To do so, we develop a probabilistic RA assessment framework by adapting an existing production cost model and apply it to a case study based on the IEEE Reliability Test System. Our results indicate that multi-year data, storage dispatch, and transmission limits are key details to incorporate. Accurate RA results can be obtained using non-economic dispatch strategies as long as they are coordinated with detailed operational strategies. We also demonstrate how popular expectation-based RA metrics can mask important differences in the characteristics of loss of load events. more...

Apoptosis linked Gene-2 (ALG-2) is a multifunctional intracellular Ca2+ sensor and the archetypal member of the penta-EF hand protein family. ALG-2 functions in the repair of damage to both the plasma and lysosome membranes and in COPII-dependent budding at endoplasmic reticulum exit sites (ERES). In the presence of Ca2+, ALG-2 binds to ESCRT-I and ALIX in membrane repair and to SEC31A at ERES. ALG-2 also binds directly to acidic membranes in the presence of Ca2+ by a combination of electrostatic and hydrophobic interactions. By combining giant unilamellar vesicle-based experiments and molecular dynamics simulations, we show that charge-reversed mutants of ALG-2 at these locations disrupt membrane recruitment. ALG-2 membrane binding mutants have reduced or abrogated ERES localization in response to Thapsigargin-induced Ca2+ release but still localize to lysosomes following lysosomal Ca2+ release. In vitro reconstitution shows that the ALG-2 membrane-binding defect can be rescued by binding to ESCRT-I. These data thus reveal the nature of direct Ca2+-dependent membrane binding and its interplay with Ca2+-dependent protein binding in the cellular functions of ALG-2. more...

BACKGROUND: Muscle density is inversely associated with all-cause mortality, but associations with cardiovascular disease (CVD) risk are not well understood. This study evaluated the association between muscle density and muscle area and incident total CVD, coronary heart disease (CHD), and stroke in diverse men and women. METHODS AND RESULTS: Adult participants (N=1869) in the Multi-Ethnic Study of Atherosclerosis Ancillary Body Composition Study underwent computer tomography scans of the L2-L4 region of the abdomen. Muscle was quantified by density (Hounsfield units) and area in cm2. Sex-stratified Cox proportional hazard models assessed associations between incident total CVD, incident CHD, and incident stroke across sex-specific percentiles of muscle area and density, which were entered simultaneously into the model. Mean age for men and women at baseline were 64.1 and 65.1 years, respectively, and median follow-up time was 10.3 years. For men, associations between muscle density and incident CVD were inverse but not significant in fully adjusted models (P trend=0.15). However, there was an inverse association between density and CHD (P trend=0.02; HR, 0.26 for 95th versus 10th percentile), and no association with stroke (P trend=0.78). Conversely, for men, there was a strong positive association between muscle area and incident CVD (HR, 4.19 for 95th versus 10th percentile; P trend more...

STUDY OBJECTIVES: To test associations between neighborhood social, built, and ambient environment characteristics and multidimensional sleep health in Hispanic/Latino adults. METHODS: Data were from San Diego-based Hispanic/Latino adults mostly of Mexican heritage enrolled in the Hispanic Community Health Study/Study of Latinos (N = 342). Home addresses were geocoded to ascertain neighborhood characteristics of greenness, walkability (density of intersections, retail spaces, and residences), socioeconomic deprivation (e.g. lower income, lower education), social disorder (e.g. vacant buildings, crime), traffic density, and air pollution (PM 2.5) in the Study of Latinos Communities and Surrounding Areas Study. Sleep dimensions of regularity, satisfaction, alertness, timing, efficiency, and duration were measured by self-report or actigraphy approximately 2 years later. Multivariable regression models accounting for study design (stratification and clustering) were used to examine associations of neighborhood variables with individual sleep dimensions and a multidimensional sleep health composite score. RESULTS: Neighborhood characteristics were not significantly associated with the multidimensional sleep health composite, and there were few significant associations with individual sleep dimensions. Greater levels of air pollution (B = 9.03, 95% CI: 1.16, 16.91) were associated with later sleep midpoint, while greater social disorder (B = -6.90, 95% CI: -13.12, -0.67) was associated with earlier sleep midpoint. Lower walkability was associated with more wake after sleep onset (B = -3.58, 95% CI: -7.07, -0.09). CONCLUSIONS: Living in neighborhoods with lower walkability and greater air pollution was associated with worse sleep health, but otherwise findings were largely null. Future research should test these hypotheses in settings with greater variability and investigate mechanisms of these associations. more...

Human-wildlife conflict is an important factor in the modern biodiversity crisis and has negative effects on both humans and wildlife (such as property destruction, injury, or death) that can impede conservation efforts for threatened species. Effectively addressing conflict requires an understanding of where it is likely to occur, particularly as climate change shifts wildlife ranges and human activities globally. Here, we examine how projected shifts in cropland density, human population density, and climatic suitability-three key drivers of human-elephant conflict-will shift conflict pressures for endangered Asian and African elephants to inform conflict management in a changing climate. We find that conflict risk (cropland density and/or human population density moving into the 90th percentile based on current-day values) increases in 2050, with a larger increase under the high-emissions regional rivalry SSP3 - RCP 7.0 scenario than the low-emissions sustainability SSP1 - RCP 2.6 scenario. We also find a net decrease in climatic suitability for both species along their extended range boundaries, with decreasing suitability most often overlapping increasing conflict risk when both suitability and conflict risk are changing. Our findings suggest that as climate changes, the risk of conflict with Asian and African elephants may shift and increase and managers should proactively mitigate that conflict to preserve these charismatic animals. more...

INTRODUCTION: Antibrush border antibody disease (ABBA) is an autoimmune tubulointerstitial kidney disease that primarily affects older individuals and results in progressive kidney failure. It is rare with only 20 reported cases. Here, we describe a case series to further define the clinicopathologic spectrum and natural history, and to inform management. METHODS: We identified 67 patients with ABBA who underwent kidney biopsy, including 65 native and 2 transplants. Demographics, clinical findings, and laboratory data were obtained. Histopathologic data included light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2, CUBN, and AMN. Follow-up data, including treatment(s), laboratory values, and outcomes, were available from 51 patients. RESULTS: Patients with ABBA were predominantly male with a median age of 72 years. Median serum creatinine was 2.7 mg/dl, proteinuria was 2.8 g/day, and hematuria was present in two-thirds of the patients. Tubular injury with LRP2-positive tubular basement membrane (TBM) deposits were seen in 94.2% of patients. Thirty-eight patients (56.7%) had a second kidney disease, commonly glomerular diseases with high-grade proteinuria. These diseases included podocytopathies, membranous nephropathy (MN), IgA nephropathy, diabetic glomerulopathy, lupus nephritis (LN), crescentic glomerulonephritis (GN), tubulointerstitial nephritis, and involvement by lymphoma. The majority of patients were treated with immunosuppression. Of those patients with follow-up, 29.4% achieved remission, 70.6% had no response, and 52.8% required dialysis or were deceased. Untreated patients were at the highest risk. CONCLUSION: ABBA is a rare autoimmune kidney disease that often occurs with other kidney diseases. Although the overall prognosis of ABBA is poor, there is potential benefit from immunosuppression. more...

Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. KRAS activity is closely coupled to protein dynamics and is regulated through two interconverting conformations: state 1 (inactive, effector binding deficient) and state 2 (active, effector binding enabled). Here, we use 31P NMR to delineate the differences in state 1 and state 2 populations present in WT and common KRAS oncogenic mutants (G12C, G12D, G12V, G13D, and Q61L) bound to its natural substrate GTP or a commonly used nonhydrolyzable analog GppNHp (guanosine-5-[(β,γ)-imido] triphosphate). Our results show that GppNHp-bound proteins exhibit significant state 1 population, whereas GTP-bound KRAS is primarily (90% or more) in state 2 conformation. This observation suggests that the predominance of state 1 shown here and in other studies is related to GppNHp and is most likely nonexistent in cells. We characterize the impact of this differential conformational equilibrium of oncogenic KRAS on RAF1 kinase effector RAS-binding domain and intrinsic hydrolysis. Through a KRAS G12C drug discovery, we have identified a novel small-molecule inhibitor, BBO-8956, which is effective against both GDP- and GTP-bound KRAS G12C. We show that binding of this inhibitor significantly perturbs state 1-state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1-RAS-binding domain is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action for this novel and active-conformation inhibitor. more...

Climate change is increasing the frequency and severity of short-term (~1 y) drought events-the most common duration of drought-globally. Yet the impact of this intensification of drought on ecosystem functioning remains poorly resolved. This is due in part to the widely disparate approaches ecologists have employed to study drought, variation in the severity and duration of drought studied, and differences among ecosystems in vegetation, edaphic and climatic attributes that can mediate drought impacts. To overcome these problems and better identify the factors that modulate drought responses, we used a coordinated distributed experiment to quantify the impact of short-term drought on grassland and shrubland ecosystems. With a standardized approach, we imposed ~a single year of drought at 100 sites on six continents. Here we show that loss of a foundational ecosystem function-aboveground net primary production (ANPP)-was 60% greater at sites that experienced statistically extreme drought (1-in-100-y event) vs. those sites where drought was nominal (historically more common) in magnitude (35% vs. 21%, respectively). This reduction in a key carbon cycle process with a single year of extreme drought greatly exceeds previously reported losses for grasslands and shrublands. Our global experiment also revealed high variability in drought response but that relative reductions in ANPP were greater in drier ecosystems and those with fewer plant species. Overall, our results demonstrate with unprecedented rigor that the global impacts of projected increases in drought severity have been significantly underestimated and that drier and less diverse sites are likely to be most vulnerable to extreme drought. more...

This paper identifies and evaluates issues in traditional resource adequacy (RA) assessment practices, and how adjusting these practices may affect and depend on existing institutional arrangements for planning and procurement. The paper proposes a technical-institutional roadmap that would allow regulators in vertically-integrated jurisdictions and system planners and operators in restructured jurisdictions to revise RA practices across a range of components.First, we compile a critical review of current RA assessment practices based on (1) interviews with RA practitioners and (2) a review of recent technical literature. We find that (i) RA may need to expand beyond capacity adequacy to ensure energy adequacy – relevant for energy-limited resources such as storage – and potentially some form of ancillary service adequacy (e.g. enough ramping-up and ramping-down capability in the system); (ii) chronological hourly simulations for all hours in the year are the current best practice; (iii) metrics and models used do not reflect economic criteria in system operation and loss of load; and (iv) there is a need to improve representation of weather dependencies and weather data.Second, we review planning and RA reports for several private and public entities that plan generation and/or transmission infrastructure in the continental U.S. to look for existing practices involving resilience assessments. We find no systematic treatment of the costs of extreme weather and other hazards, the benefits of resilience, and resilience metrics in planning analyses and no systematic treatment of resilience metrics, methods, and outcomes for resource adequacy purposes.Third, we create a technical framework for probabilistic RA assessment and use it to study how key choices about how to model power system operations affect the values that are obtained for RA metrics. We find that (i) non-economic dispatch schemes that ignore economic objectives can lead to accurate RA assessments when coordinated with detailed operational strategies; (ii) multi-year data is critical to capture a wide variety of system conditions; (iii) not incorporating transmission limits into RA assessment could lead to substantial underestimation of traditional “expected value” RA metrics; and (iv) new RA metrics that capture event-specific shortfall characteristics should be used as supplements to traditional metrics.Finally, we examine RA assessments and use this information to propose a guide of evolving industry standards for resource adequacy assessments in resource planning and transmission planning. We report minimum, best, and frontier practices for temporal resolution of assessments, metrics and targets, weather data, load forecasting, characterization of variable renewable resources, characterization of transmission and market transactions, RA modeling and integration with planning processes, and capacity accreditation. more...

BACKGROUND: Monitoring serum phosphorus concentrations is crucial in the management of chronic kidney disease in cats. The diurnal variation of serum phosphorus concentration may affect clinical assessment. HYPOTHESIS/OBJECTIVES: Characterize the diurnal variation of serum phosphorus concentration in cats and determine the associations between changes in serum phosphorus concentration and several metabolites of phosphorus metabolism. ANIMALS: Six apparently healthy, intact male, specific-pathogen-free cats were housed in a photoperiod, humidity, and temperature-controlled facility. METHODS: Blood sampling was performed hourly for 24 hours to obtain the serum concentrations of phosphorus, ionized calcium, parathyroid hormone, and calcidiol. Results were analyzed using linear mixed-effect models to determine the significance of diurnal variation and associations between serum phosphorus concentrations and other metabolites over time. RESULTS: Diurnal variation in serum phosphorus concentration was noted with an apex around 11:00 followed by gradually declining concentrations to reach the nadir around 23:00. The serum phosphorus concentration again increased through the early morning on the next day. An approximately 25% difference in serum phosphorus concentration at the apex and the nadir was documented. A non-linear relationship between the serum concentrations of phosphorus and ionized calcium over time was identified. CONCLUSIONS AND CLINICAL IMPORTANCE: Diurnal variations of serum phosphorus concentration and associations between the trending of serum phosphorus and ionized calcium concentrations were evident in a group of clinically healthy adult cats housed in a controlled environment. These findings can help in the interpretation of clinical and research data regarding calcium and phosphorus metabolism and kidney health in cats. more...

Aspergillus terreus has attracted interest due to its application in industrial biotechnology, particularly for the production of itaconic acid and bioactive secondary metabolites. As related species also seem to possess a prosperous secondary metabolism, they are of high interest for genome mining and exploitation. Here, we present draft genome sequences for six species from Aspergillus section Terrei and one species from Aspergillus section Nidulantes. Whole-genome phylogeny confirmed that section Terrei is monophyletic. Genome analyses identified between 70 and 108 key secondary metabolism genes in each of the genomes of section Terrei, the highest rate found in the genus Aspergillus so far. The respective enzymes fall into 167 distinct families with most of them corresponding to potentially unique compounds or compound families. Moreover, 53% of the families were only found in a single species, which supports the suitability of species from section Terrei for further genome mining. Intriguingly, this analysis, combined with heterologous gene expression and metabolite identification, suggested that species from section Terrei use a strategy for UV protection different to other species from the genus Aspergillus. Section Terrei contains a complete plant polysaccharide degrading potential and an even higher cellulolytic potential than other Aspergilli, possibly facilitating additional applications for these species in biotechnology. more...

This research explores the potential of machine learning (ML) in identifying vocal markers for schizophrenia. While previous research showed that voice-based ML models can accurately predict schizophrenia diagnosis and symptoms, it is unclear to what extent such ML markers generalize to different clinical subpopulations and languages: the assessment of generalization performance is however crucial for testing their clinical applicability.We systematically examined voice-based ML model performance on a large cross-linguistic dataset (3 languages: Danish, German, Chinese). Employing a rigorous pipeline to minimize overfitting, including cross-validated training sets and multilingual models, we assessed generalization on participants with schizophrenia and controls speaking the same or different languages. Model performance was comparable to state-of-the art findings (F1-score ~ 0.75) within the same language; however, models did not generalize well - showing a substantial decrease - when tested on new languages, and the performance of multilingual models was also generally low (F1-score ~ 0.50). more...

Efficiently managing agricultural irrigation is vital for food security today and into the future under climate change. Yet, evaluating agriculture's hydrological impacts and strategies to reduce them remains challenging due to a lack of field-scale data on crop water consumption. Here, we develop a method to fill this gap using remote sensing and machine learning, and leverage it to assess water saving strategies in California's Central Valley. We find that switching to lower water intensity crops can reduce consumption by up to 93%, but this requires adopting uncommon crop types. Northern counties have substantially lower irrigation efficiencies than southern counties, suggesting another potential source of water savings. Other practices that do not alter land cover can save up to 11% of water consumption. These results reveal diverse approaches for achieving sustainable water use, emphasizing the potential of sub-field scale crop water consumption maps to guide water management in California and beyond. more...

Limited studies are available on vitamin B6 status in domestic cats. To this end, we evaluated glutamate-oxaloacetate transaminase (GOT) activity in hemolysates with and without pyridoxal 5'-phosphate addition in two feline populations: a cohort of 60 healthy, domestic (sexually intact and specific pathogen-free) cats maintained under strictly controlled conditions with appropriate diets housed at the Feline Nutrition and Pet Care Center, and a cohort of 57 cats randomly selected between December 2022 to January 2023 that visited the Veterinary Medicine Teaching Hospital to seek care under different circumstances. The GOT activity expressed as the ratio with and without pyridoxal 5'-phosphate addition (primary activation ratio; PAR) decreased significantly with age in the healthy cohort. The PAR values normalized to age established a cut-off for vitamin B6 deficiency in both cohorts, identifying 17 of 101 animals as vitamin B6 deficient. Using machine learning, a partition-based model (decision tree) was built to identify the most important factors that predicted vitamin B6 deficiency while using the resulting tree to make predictions for new observations. This analysis, performed with all 101 cats, revealed that the diagnosis of an infectious, chronic or acute condition (0.55) was the main contributor, followed by age (0.26), and body condition score (optimal-overweight; 0.19). Thus, our study supports that vitamin B6 supplementation may be indicated in junior to adult animals diagnosed with an infectious, chronic, or acute conditions or healthy cats with body weight ranging from optimal to overweight. In older cats, even if healthy, underweight to optimal cats appear to be at risk of vitamin B6 deficiency. more...

The California Public Utilities Commission (CPUC) sought support for the development of database schema specifications for a bi-directional data portal that would foster cross-jurisdictional collaboration necessary to improve resilient energy infrastructure planning processes. This technical assistance activity involved Berkeley Lab researchers reviewing 34 local/tribal government hazard mitigation plans to assess (1) the natural hazards that communities are most concerned about; (2) the variety of–and terminology used to describe–critical community infrastructure; and (3) the availability of GIS information that could be incorporated into CPUC-mandated "Microgrid Planning Portals". In addition, we develop a common, but generic data taxonomy showing what fields to collect to encourage consolidating and sharing of this information in the future. Finally, we partnered with the Bishop Paiute tribal government to demonstrate the value of combining electricity infrastructure, natural hazard layers, and critical community infrastructure into a series of maps. The project demonstrated that a single system containing both electric utility and community infrastructure data—as well as information about natural hazards—will help the state of California, the IOUs, first responders, and long-term planners better prepare for—and thus lower their exposure to these ongoing and emerging hazards. The project also identified a number of challenges that will need to be overcome before it is possible to stand up a single system to display this information. more...

Transcriptional enhancers direct precise gene expression patterns during development and harbor the majority of variants associated with phenotypic diversity, evolutionary adaptations, and disease. Pinpointing which enhancer variants contribute to changes in gene expression and phenotypes is a major challenge. Here, we find that suboptimal or low-affinity binding sites are necessary for precise gene expression during heart development. Single-nucleotide variants (SNVs) can optimize the affinity of ETS binding sites, causing gain-of-function (GOF) gene expression, cell migration defects, and phenotypes as severe as extra beating hearts in the marine chordate Ciona robusta. In human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, a SNV within a human GATA4 enhancer increases ETS binding affinity and causes GOF enhancer activity. The prevalence of suboptimal-affinity sites within enhancers creates a vulnerability whereby affinity-optimizing SNVs can lead to GOF gene expression, changes in cellular identity, and organismal-level phenotypes that could contribute to the evolution of novel traits or diseases. more...

Hospitalist clinician-educators frequently work with medical students at the clinical level, but many early career educators may lack an understanding of how to effectively promote student learning and growth. We explore the role of hospitalists working with medical students in the clinical environment as it pertains to three overarching domains - clinical skills, systems-based healthcare, and career mentorship. more...

Administrative skills are essential tools for clinician educators to maximize success, however they are not considered a core component of a medical school or residency curriculum. This perspective describes domains of administrative skills that can be used with practical tools provided to increase productivity in clinical, academic, and leadership activities. more...

BackgroundBreast density is an important risk factor for breast cancer and is known to be associated with characteristics such as age, race, and hormone levels; however, it is unclear what factors contribute to changes in breast density in postmenopausal women over time. Understanding factors associated with density changes may enable a better understanding of breast cancer risk and facilitate potential strategies for prevention.MethodsThis study investigated potential associations between personal factors and changes in mammographic density in a cohort of 3,392 postmenopausal women with no personal history of breast cancer between 2011 and 2017. Self-reported information on demographics, breast and reproductive history, and lifestyle factors, including body mass index (BMI), alcohol intake, smoking, and physical activity, was collected by an electronic intake form, and breast imaging reporting and database system (BI-RADS) mammographic density scores were obtained from electronic medical records. Factors associated with a longitudinal increase or decrease in mammographic density were identified using Fisher's exact test and multivariate conditional logistic regression.Results7.9% of women exhibited a longitudinal decrease in mammographic density, 6.7% exhibited an increase, and 85.4% exhibited no change. Longitudinal changes in mammographic density were correlated with age, race/ethnicity, and age at menopause in the univariate analysis. In the multivariate analysis, Asian women were more likely to exhibit a longitudinal increase in mammographic density and less likely to exhibit a decrease compared to White women. On the other hand, obese women were less likely to exhibit an increase and more likely to exhibit a decrease compared to normal weight women. Women who underwent menopause at age 55 years or older were less likely to exhibit a decrease in mammographic density compared to women who underwent menopause at a younger age. Besides obesity, lifestyle factors (alcohol intake, smoking, and physical activity) were not associated with longitudinal changes in mammographic density.ConclusionsThe associations we observed between Asian race/obesity and longitudinal changes in BI-RADS density in postmenopausal women are paradoxical in that breast cancer risk is lower in Asian women and higher in obese women. However, the association between later age at menopause and a decreased likelihood of decreasing in BI-RADS density over time is consistent with later age at menopause being a risk factor for breast cancer and suggests a potential relationship between greater cumulative lifetime estrogen exposure and relative stability in breast density after menopause. Our findings support the complexity of the relationships between breast density, BMI, hormone exposure, and breast cancer risk. more...

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine. more...

We present an investigation of the relaxation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV. We focus on the very rare D+ + O+ + D reaction channel in which the sequential fragmentation mechanisms were found to dominate the dynamics. Aided by theory, the state-selective formation and breakup of the transient OD+(a1Δ, b1Σ+) is traced, and the most likely dissociation path-OD+: a1Δ or b1Σ+ → A 3Π → X 3Σ- → B 3Σ--involving a combination of spin-orbit and non-adiabatic charge transfer transitions is determined. The multi-step transition probability of this complex transition sequence in the intermediate fragment ion is directly evaluated as a function of the energy of the transient OD+ above its lowest dissociation limit from the measured ratio of the D+ + O+ + D and competing D+ + D+ + O sequential fragmentation channels, which are measured simultaneously. Our coupled-channel time-dependent dynamics calculations reproduce the general trends of these multi-state relative transition rates toward the three-body fragmentation channels. more...

DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain. Despite the crucial role of the BER pathway, insights into how this pathway is affected by aging in the human brain and the underlying regulatory mechanisms are very limited. By microarray analysis of four cortical brain regions from humans aged 20-99 years (n = 57), we show that the expression of core BER genes is largely downregulated during aging across brain regions. Moreover, we find that expression of many BER genes correlates positively with the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the human brain. In line with this, we identify binding sites for the BDNF-activated transcription factor, cyclic-AMP response element-binding protein (CREB), in the promoter of most BER genes and confirm the ability of BDNF to regulate several BER genes by BDNF treatment of mouse primary hippocampal neurons. Together, these findings uncover the transcriptional landscape of BER genes during aging of the brain and suggest BDNF as an important regulator of BER in the human brain. more...

BackgroundMany dog owners alter their dog's nutritional regimen after a diagnosis of cancer. There are limited data as to specific changes made and reasons behind these changes.Hypothesis/objectivesTo collect updated and detailed data on changes made by owners to their dog's diet and supplements after a cancer diagnosis.AnimalsResponses were collected from a survey of dog owners who brought their dogs to the UC Davis Veterinary Medical Teaching Hospital's Oncology Service for the first time after a cancer diagnosis. Dogs with recurrence or presenting for a second type of cancer were excluded.MethodsEligible owners were surveyed between December 2020 and March 2022. The survey contained 62 questions regarding diet, supplement use, and treats, and how these were altered after a cancer diagnosis. Responses were matched to medical record data.ResultsOne hundred twenty-eight surveys were retained for analysis, including 120 respondents that completed the survey. In response to a cancer diagnosis, 54.8% (95% CI; 45.7%-63.8%) of owners altered diets or supplements or both. The most common informational resource for dog diets was veterinarians (53.9%). Usage of home-prepared foods significantly increased after a cancer diagnosis (P = .03). There was no significant difference in commercial diet usage before or after a diagnosis (P = .25). Joint support products were the most common supplements given both before (37.4%) and after (35.0%) diagnosis.Conclusions and clinical importanceMany dog owners alter their dog's nutritional intake after a cancer diagnosis. These owners should be provided information relating to commonly observed alterations, including home-prepared foods and supplements. more...

We present the relaxation dynamics of deuterated water molecules via autoionization, initiated by the absorption of a 61 eV photon, producing the very rare D+ + O+ + D breakup channel. We employ the COLd target recoil ion momentum spectroscopy method to measure the 3D momenta of the ionic fragments and emitted electrons from the dissociating molecule in coincidence. We interpret the results using the potential energy surfaces extracted from multi-reference configuration interaction calculations. The measured particle energy distributions can be related to a super-excited monocationic state located above the double ionization threshold of D2O. The autoionized electron energy shows a sharp distribution centered around 0.5 eV, which is a signature of the atomic oxygen autoionization occurring in the direct and sequential dissociation processes of D2O+* at a large internuclear distance. In this way, an O+ radical fragment and a low-energy electron are created, both of which can trigger secondary reactions in their environment. more...

Schizophrenia is marked by deficits in facial affect processing associated with abnormalities in GABAergic circuitry, deficits also found in first-degree relatives. Facial affect processing involves a distributed network of brain regions including limbic regions like amygdala and visual processing areas like fusiform cortex. Pharmacological modulation of GABAergic circuitry using benzodiazepines like alprazolam can be useful for studying this facial affect processing network and associated GABAergic abnormalities in schizophrenia. Here, we use pharmacological modulation and computational modeling to study the contribution of GABAergic abnormalities toward emotion processing deficits in schizophrenia. Specifically, we apply principles from network control theory to model persistence energy - the control energy required to maintain brain activation states - during emotion identification and recall tasks, with and without administration of alprazolam, in a sample of first-degree relatives and healthy controls. Here, persistence energy quantifies the magnitude of theoretical external inputs during the task. We find that alprazolam increases persistence energy in relatives but not in controls during threatening face processing, suggesting a compensatory mechanism given the relative absence of behavioral abnormalities in this sample of unaffected relatives. Further, we demonstrate that regions in the fusiform and occipital cortices are important for facilitating state transitions during facial affect processing. Finally, we uncover spatial relationships (i) between regional variation in differential control energy (alprazolam versus placebo) and (ii) both serotonin and dopamine neurotransmitter systems, indicating that alprazolam may exert its effects by altering neuromodulatory systems. Together, these findings provide a new perspective on the distributed emotion processing network and the effect of GABAergic modulation on this network, in addition to identifying an association between schizophrenia risk and abnormal GABAergic effects on persistence energy during threat processing. more...

• Peak standing crop (PSC) and residual dry matter (RDM) are the primary measures of production and grazing intensity on California's annual rangelands. • One of the most common methods of monitoring forage metrics is to clip 1-ft2 quadrats. The USDA Forest Service, Bureau of Land Management, universities, and other land managers have been using this methodology since the 1930s. • We used best linear unbiased predictors (BLUEs) to determine 95% confidence intervals for PSC and RDM. For both PSC and RDM, as the number of samples taken increased from 1 to 10, the predictive ability also significantly increased. We found no evidence of increased predictive power past 10 samples. more...

This paper reports results from a large-scale randomized controlled trial assessing whether counter-stereotypical messaging and partisan cues can induce people to get COVID-19 vaccines. The study used a 27-s video compilation of Donald Trump's comments about the vaccine from Fox News interviews and presented the video to millions of U.S. YouTube users through a $100,000 advertising campaign in October 2021. Results indicate that the number of vaccines increased in the average treated county by 103 (with a one-tailed P value of 0.097). Based on this average treatment effect and totaling across our 1014 treated counties, the total estimated effect was 104,036 vaccines. more...

RATIONALE & OBJECTIVE: People with end-stage kidney disease (ESKD) have very low physical activity, and the degree of inactivity is strongly associated with morbidity and mortality. We assessed the feasibility and effectiveness of a 12-week intervention coupling a wearable activity tracker (FitBit) and structured feedback coaching versus wearable activity tracker alone on changes in physical activity in hemodialysis patients. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 55 participants with ESKD receiving hemodialysis who were able to walk with or without assistive devices recruited from a single academic hemodialysis unit between January 2019 and April 2020. INTERVENTIONS: All participants wore a Fitbit Charge 2 tracker for a minimum of 12 weeks. Participants were randomly assigned 1:1 to a wearable activity tracker plus a structured feedback intervention versus the wearable activity tracker alone. The structured feedback group was counseled weekly on steps achieved after randomization. OUTCOME: The outcome was step count, and the main parameter of interest was the absolute change in daily step count, averaged per week, from baseline to completion of 12 weeks intervention. In the intention-to-treat analysis, mixed-effect linear regression analysis was used to evaluate change in daily step count from baseline to 12-weeks in both arms. RESULTS: Out of 55 participants, 46 participants completed the 12-week intervention (23 per arm). The mean age was 62 (± 14 SD) years; 44% were Black, and 36% were Hispanic. At baseline, step count (structured feedback intervention: 3,704 [1,594] vs wearable activity tracker alone: 3,808 [1,890]) and other participant characteristics were balanced between the arms. We observed a larger change in daily step count in the structured feedback arm at 12 weeks relative to use of the wearable activity tracker alone arm (Δ 920 [±580 SD] versus Δ 281 [±186 SD] steps; between-group difference Δ 639 [±538 SD] steps; P more...

Economy-wide emissions drop 43 to 48% below 2005 levels by 2035 with accelerated clean energy deployment.

Learning, memory, and cognition are thought to require synaptic plasticity, specifically including hippocampal long-term potentiation and depression (LTP and LTD). LTP versus LTD is induced by high-frequency stimulation versus low-frequency, but stimulating β-adrenergic receptors (βARs) enables LTP induction also by low-frequency stimulation (1 Hz) or theta frequencies (∼5 Hz) that do not cause plasticity by themselves. In contrast to high-frequency stimulation-LTP, such βAR-LTP requires Ca2+-flux through L-type voltage-gated Ca2+-channels, not N-methyl-D-aspartate-type glutamate receptors. Surprisingly, we found that βAR-LTP still required a nonionotropic scaffolding function of the N-methyl-D-aspartate-type glutamate receptor: the stimulus-induced binding of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) to its GluN2B subunit that mediates CaMKII movement to excitatory synapses. In hippocampal neurons, β-adrenergic stimulation with isoproterenol (Iso) transformed LTD-type CaMKII movement to LTP-type movement, resulting in CaMKII movement to excitatory instead of inhibitory synapses. Additionally, Iso enabled induction of a major cell-biological feature of LTP in response to LTD stimuli: increased surface expression of GluA1 fused with super-ecliptic pHluorein. Like for βAR-LTP in hippocampal slices, the Iso effects on CaMKII movement and surface expression of GluA1 fused with super-ecliptic pHluorein involved L-type Ca2+-channels and specifically required β2-ARs. Taken together, these results indicate that Iso transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode. more...

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. more...

Public trust in medical institutions is essential for ensuring compliance with medical directives. However, the politicization of public health issues and the polarized nature of major news outlets suggest that partisanship and news consumption habits can influence medical trust. This study employed a survey with 858 participants and used regression analysis to assesses how news consumption habits and information assessment traits (IATs) influence trust in medical scientists. IATs included were conscientiousness, openness, need for cognitive closure (NFCC), and cognitive reflective thinking (CRT). News sources were classified on the basis of factuality and political bias. Initially, readership of liberally biased news was positively associated with medical trust (p < 0.05). However, this association disappeared when controlling for the news source's factuality (p = 0.28), while CRT (p < 0.05) was positively associated with medical trust. When controlling for conservatively biased news sources, factuality of the news source (p < 0.05) and NFCC (p < 0.05) were positively associated with medical trust. While partisan media bias may influence medical trust, these results suggest that those who have higher abilities to assess information and who prefer more credible news sources have a greater trust in medical scientists. more...

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE more...