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BackgroundAnti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus.MethodsThis is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak.FindingsSixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response.InterpretationA distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.FundingThis work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

The abrupt transition from face-to-face (F2F) to online learning during the COVID-19 pandemic impacted students' learning experiences in many ways. This survey-based study investigated the perceptions of 117 university students enrolled in beginner, intermediate, and advanced foreign language courses (French, Italian, Portuguese, Spanish) of their learning experiences in the F2F mode relative to the online mode. Quantitative and qualitative data were collected through a questionnaire with Likert-scale and open-ended questions that related to four language skills (listening, reading, speaking, and writing), student engagement (participation, comfort asking questions, and peer interactions), and overall learning experience. The results revealed significant differences in participants' perceptions across all dimensions and may be used to inform future foreign language curriculum development and teaching in any instructional mode.

The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin β5) as the essential integrin α/β pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the β-propeller domain of ITGAV for integrin αVβ5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the β-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVβ5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.

Lawrence Berkeley National Laboratory and the National Renewable Energy Laboratory provided technical assistance to the South Carolina Office of Regulatory Staff to examine how Duke Energy’s Integrated System Operations Planning (ISOP) framework interacts with other electricity planning processes in South Carolina. While this report was prepared for the South Carolina ORS, the information contained herein may be useful to audiences in other states who are interested in IDP, including public utility commissions, state energy offices, other state agencies, utilities, and stakeholders. The report discusses how to access the ISOP process diagram created for the report, provides observations about Duke Energy’s ISOP from our interviews and review of publicly available materials; and assesses ISOP, based on best practices for integrated distribution planning.

The water cycle is an important component of the earth system and it plays a key role in many facets of society, including energy production, agriculture, and human health and safety. In this study, the Energy Exascale Earth System Model version 1 (E3SMv1) is run with low-resolution (roughly 110 km) and high-resolution (roughly 25 km) configurations—as established by the High Resolution Model Intercomparison Project protocol—to evaluate the atmospheric and terrestrial water budgets over the conterminous United States (CONUS) at the large watershed scale. The warm season water cycle slows down in the HR experiment relative to the LR, with decreasing fluxes of precipitation, evapotranspiration, atmospheric moisture convergence, and runoff. The reductions in these terms exacerbate biases for some watersheds, while reducing them in others. For example, precipitation biases are exacerbated at HR over the Eastern and Central CONUS watersheds, while precipitation biases are reduced at HR over the Western CONUS watersheds. The most pronounced changes with resolution to the water cycle come from reductions in precipitation and evapotranspiration. The reduction in evapotranspiration reduces the biases across nearly all of the CONUS. Additional exploratory metrics show improvements to water cycle extremes (both in precipitation and streamflow), fractional contributions of different storm types to total precipitation, and mountain snowpack.

Moderate red wine intake has been associated with lower cardiovascular mortality, due in part to the intake of polyphenols and anthocyanins, whose content can vary from varietal and year of harvest. This study assessed the vascular effects in response to a single intake of 2015 and 2018 Zweigelt red wines from Hokkaido, Japan. Healthy men were randomly assigned to consume 240 mL each of a red wine, or a sparkling white grape juice as a control in a randomized three-arm cross-over design with a 7 day washout between arms. The augmentation index (AI; a measure of arterial stiffness) and AI at 75 beats/min (AI75), reactive hyperemia index, systolic and diastolic blood pressure (SBP and DBP, respectively), and platelet reactivity were assessed at baseline and two and four hours after each beverage intake. Changes from the baseline were analyzed using a linear mixed model. Significant treatment effects (p = 0.02) were observed, with AI 13% lower after the intake of the 2015 or 2018 vintages compared to the control. Intake of the 2018 vintage reduced SBP and DBP (-4.1 mmHg and -5.6 mmHg, respectively; p = 0.02) compared to the 2015 wine and the control drink. The amount of hydroxytyrosol in the 2018 wine was almost twice the amount as in the 2015 wine, which may help explain the variable blood pressure results. Future studies exploring the vascular effects of the same red wine from different vintage years and different phenolic profiles are warranted.

Consumption of nuts and berries are considered part of a healthy eating pattern. Nuts and berries contain a complex nutrient profile consisting of essential vitamins and minerals, fiber, polyunsaturated fatty acids, and phenolics in quantities that improve physiological outcomes. The spectrum of health outcomes that may be impacted by the consumptions of nuts and berries includes cardiovascular, gut microbiome, and cognitive, among others. Recently, new insights regarding the bioactive compounds found in both nuts and berries have reinforced their role for use in precision nutrition efforts. However, challenges exist that can affect the generalizability of outcomes from clinical studies, including inconsistency in study designs, homogeneity of test populations, variability in test products and control foods, and assessing realistic portion sizes. Future research centered on precision nutrition and multi-omics technologies will yield new insights. These and other topics such as funding streams and perceived risk-of-bias were explored at an international nutrition conference focused on the role of nuts and berries in clinical nutrition. Successes, challenges, and future directions with these foods are presented here.

This study explores how work-integrated learning (WIL) in higher education contexts translates for Indigenous Australian students and subsequent notions of their employability. Through a mixed methods survey, the paper identifies problematic issues that exist in current comprehensions of Indigenous Australian graduate employability readiness; and validates the Indigenous student voice via Western methods. Insights from Indigenous Australian students highlight themes of cultural safety and individualized approaches to employability promotion, amongst others. Survey results inform recommendations for tertiary institutions to consider regarding WIL reform.

Message matching within MPI is an important performance consideration for applications that utilize two-sided semantics. In this work, we present an instrumentation of the CrayMPI library that allows the collection of detailed message-matching statistics as well as an implementation of hashed matching in software. We use this functionality to profile key DOE applications with complex communication patterns to determine under what circumstances an application might benefit from hardware offload capabilities within the NIC to accelerate message matching. We find that there are several applications and libraries that exhibit sufficiently long match list lengths to motivate a Binned Message Matching approach.

Lutein, zeaxanthin, and meso-zeaxanthin are three xanthophyll carotenoid pigments that selectively concentrate in the center of the retina. Humans cannot synthesize lutein and zeaxanthin, so these compounds must be obtained from the diet or supplements, with meso-zeaxanthin being converted from lutein in the macula. Xanthophylls are major components of macular pigments that protect the retina through the provision of oxidant defense and filtering of blue light. The accumulation of these three xanthophylls in the central macula can be quantified with non-invasive methods, such as macular pigment optical density (MPOD). MPOD serves as a useful tool for assessing risk for, and progression of, age-related macular degeneration, the third leading cause of blindness worldwide. Dietary surveys suggest that the dietary intakes of lutein and zeaxanthin are decreasing. In addition to low dietary intake, pregnancy and lactation may compromise the lutein and zeaxanthin status of both the mother and infant. Lutein is found in modest amounts in some orange- and yellow-colored vegetables, yellow corn products, and in egg yolks, but rich sources of zeaxanthin are not commonly consumed. Goji berries contain the highest known levels of zeaxanthin of any food, and regular intake of these bright red berries may help protect against the development of age-related macular degeneration through an increase in MPOD. The purpose of this review is to summarize the protective function of macular xanthophylls in the eye, speculate on the compounds' role in maternal and infant health, suggest the establishment of recommended dietary values for lutein and zeaxanthin, and introduce goji berries as a rich food source of zeaxanthin.

Neural network models have recently made striking progress in natural language processing, but they are typically trained on orders of magnitude more language input than children receive. What can these neural networks, which are primarily distributional learners, learn from a naturalistic subset of a single child's experience? We examine this question using a recent longitudinal dataset collected from a single child, consisting of egocentric visual data paired with text transcripts. We train both language-only and vision-and-language neural networks and analyze the linguistic knowledge they acquire. In parallel with findings from Jeffrey Elman's seminal work, the neural networks form emergent clusters of words corresponding to syntactic (nouns, transitive and intransitive verbs) and semantic categories (e.g., animals and clothing), based solely on one child's linguistic input. The networks also acquire sensitivity to acceptability contrasts from linguistic phenomena, such as determiner-noun agreement and argument structure. We find that incorporating visual information produces an incremental gain in predicting words in context, especially for syntactic categories that are comparatively more easily grounded, such as nouns and verbs, but the underlying linguistic representations are not fundamentally altered. Our findings demonstrate which kinds of linguistic knowledge are learnable from a snapshot of a single child's real developmental experience.

This paper provides an overview of the United States (US) Department of Energy's (DOE's) Energy Exascale Earth System Model version 2 (E3SMv2) fully coupled regionally refined model (RRM) and documents the overall atmosphere, land, and river results from the Coupled Model Intercomparison Project 6 (CMIP6) DECK (Diagnosis, Evaluation, and Characterization of Klima) and historical simulations - a first-of-its-kind set of climate production simulations using RRM. The North American (NA) RRM (NARRM) is developed as the high-resolution configuration of E3SMv2 with the primary goal of more explicitly addressing DOE's mission needs regarding impacts to the US energy sector facing Earth system changes. The NARRM features finer horizontal resolution grids centered over NA, consisting of 25→100¯km atmosphere and land, a 0.125 river-routing model, and 14→60¯km ocean and sea ice. By design, the computational cost of NARRM is 1/43× of the uniform low-resolution (LR) model at 100¯km but only 1/4¯10¯%-20¯% of a globally uniform high-resolution model at 25¯km. A novel hybrid time step strategy for the atmosphere is key for NARRM to achieve improved climate simulation fidelity within the high-resolution patch without sacrificing the overall global performance. The global climate, including climatology, time series, sensitivity, and feedback, is confirmed to be largely identical between NARRM and LR as quantified with typical climate metrics. Over the refined NA area, NARRM is generally superior to LR, including for precipitation and clouds over the contiguous US (CONUS), summertime marine stratocumulus clouds off the coast of California, liquid and ice phase clouds near the North Pole region, extratropical cyclones, and spatial variability in land hydrological processes. The improvements over land are related to the better-resolved topography in NARRM, whereas those over ocean are attributable to the improved air-sea interactions with finer grids for both atmosphere and ocean and sea ice. Some features appear insensitive to the resolution change analyzed here, for instance the diurnal propagation of organized mesoscale convective systems over CONUS and the warm-season land-atmosphere coupling at the southern Great Plains. In summary, our study presents a realistically efficient approach to leverage the fully coupled RRM framework for a standard Earth system model release and high-resolution climate production simulations.

Abstraction enables humans to distill a cascade of sensory experiences into a useful format for making sense of the world and generalizing to new contexts. In developing theories of how these various forms of abstraction are discovered and used, cognitive scientists have proposed a multitude of representational formats with different properties to capture behavioral data and neural activity. However, because abstraction manifests in human cognition and behavior in so many ways, individual communities within cognitive science have generally studied these specific forms of abstraction under domain-specific representational assumptions. The goal of this workshop is to facilitate the search for unifying principles governing how humans learn, discover, and use abstractions in different domains, by providing a venue for the exchange of theoretical and empirical insights between research communities.