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Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq ( n  = 6) and exome sequencing ( n  = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted. Vestibular schwannomas are benign tumours which can lead to neurological symptoms and morbidity. Here, the authors use single cell RNA-seq and ATAC-seq to identify Schwann cell subtypes in the tumour microenvironment which mimic a nerve injury phenotype.

Antihypertensive medicines are effective in reducing adverse cardiovascular events. Our aim was to compare hypertension awareness, treatment, and control, and how they have changed over time, in high-income countries. We used data from people aged 40–79 years who participated in 123 national health examination surveys from 1976 to 2017 in 12 high-income countries: Australia, Canada, Finland, Germany, Ireland, Italy, Japan, New Zealand, South Korea, Spain, the UK, and the USA. We calculated the proportion of participants with hypertension, which was defined as systolic blood pressure of 140 mm Hg or more, or diastolic blood pressure of 90 mm Hg or more, or being on pharmacological treatment for hypertension, who were aware of their condition, who were treated, and whose hypertension was controlled (ie, lower than 140/90 mm Hg). Data from 526 336 participants were used in these analyses. In their most recent surveys, Canada, South Korea, Australia, and the UK had the lowest prevalence of hypertension, and Finland the highest. In the 1980s and early 1990s, treatment rates were at most 40% and control rates were less than 25% in most countries and age and sex groups. Over the time period assessed, hypertension awareness and treatment increased and control rate improved in all 12 countries, with South Korea and Germany experiencing the largest improvements. Most of the observed increase occurred in the 1990s and early-mid 2000s, having plateaued since in most countries. In their most recent surveys, Canada, Germany, South Korea, and the USA had the highest rates of awareness, treatment, and control, whereas Finland, Ireland, Japan, and Spain had the lowest. Even in the best performing countries, treatment coverage was at most 80% and control rates were less than 70%. Hypertension awareness, treatment, and control have improved substantially in high-income countries since the 1980s and 1990s. However, control rates have plateaued in the past decade, at levels lower than those in high-quality hypertension programmes. There is substantial variation across countries in the rates of hypertension awareness, treatment, and control. Wellcome Trust and WHO.

T cell receptor cross-reactivity allows a fixed T cell repertoire to respond to a much larger universe of potential antigens. Recent work has emphasized the importance of peptide structural and chemical homology, as opposed to sequence similarity, in T cell receptor cross-reactivity. Surprisingly, though, T cell receptors can also cross-react between ligands with little physiochemical commonalities. Studying the clinically relevant receptor DMF5, we demonstrate that cross-recognition of such divergent antigens can occur through mechanisms that involve heretofore unanticipated rearrangements in the peptide and presenting MHC protein, including binding-induced peptide register shifts and extensions from MHC peptide binding grooves. Moreover, cross-reactivity can proceed even when such dramatic rearrangements do not translate into structural or chemical molecular mimicry. Beyond demonstrating new principles of T cell receptor cross-reactivity, our results have implications for efforts to predict and control T cell specificity and cross-reactivity and highlight challenges associated with predicting T cell reactivities.

Since 2013, the Centers for Disease Control and Prevention (CDC) has hosted an annual influenza season forecasting challenge. The 2015–2016 challenge consisted of weekly probabilistic forecasts of multiple targets, including fourteen models submitted by eleven teams. Forecast skill was evaluated using a modified logarithmic score. We averaged submitted forecasts into a mean ensemble model and compared them against predictions based on historical trends. Forecast skill was highest for seasonal peak intensity and short-term forecasts, while forecast skill for timing of season onset and peak week was generally low. Higher forecast skill was associated with team participation in previous influenza forecasting challenges and utilization of ensemble forecasting techniques. The mean ensemble consistently performed well and outperformed historical trend predictions. CDC and contributing teams will continue to advance influenza forecasting and work to improve the accuracy and reliability of forecasts to facilitate increased incorporation into public health response efforts.

The Community Land Model (CLM) is the land component of the Community Earth System Model (CESM) and is used in several global and regional modeling systems. In this paper, we introduce model developments included in CLM version 5 (CLM5), which is the default land component for CESM2. We assess an ensemble of simulations, including prescribed and prognostic vegetation state, multiple forcing data sets, and CLM4, CLM4.5, and CLM5, against a range of metrics including from the International Land Model Benchmarking (ILAMBv2) package. CLM5 includes new and updated processes and parameterizations: (1) dynamic land units, (2) updated parameterizations and structure for hydrology and snow (spatially explicit soil depth, dry surface layer, revised groundwater scheme, revised canopy interception and canopy snow processes, updated fresh snow density, simple firn model, and Model for Scale Adaptive River Transport), (3) plant hydraulics and hydraulic redistribution, (4) revised nitrogen cycling (flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake), (5) global crop model with six crop types and time‐evolving irrigated areas and fertilization rates, (6) updated urban building energy, (7) carbon isotopes, and (8) updated stomatal physiology. New optional features include demographically structured dynamic vegetation model (Functionally Assembled Terrestrial Ecosystem Simulator), ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Conclusive establishment of improvement or degradation of individual variables or metrics is challenged by forcing uncertainty, parametric uncertainty, and model structural complexity, but the multivariate metrics presented here suggest a general broad improvement from CLM4 to CLM5. Plain Language Summary The Community Land Model (CLM) is the land component of the widely used Community Earth System Model (CESM). Here, we introduce model developments included in CLM version 5 (CLM5), the default land component for CESM2 which will be used for the Coupled Model Intercomparison Project (CMIP6). CLM5 includes many new and updated processes including (1) hydrology and snow features such as spatially explicit soil depth, canopy snow processes, a simple firn model, and a more mechanistic river model, (2) plant hydraulics and hydraulic redistribution, (3) revised nitrogen cycling with flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake, (4) expansion to six crop types (global) and time‐evolving irrigated areas and fertilization rates, (5) improved urban building energy model, and (6) carbon isotopes. New optional features include a demographically structured dynamic vegetation model, ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Model performance is generally improved for most assessed variables and metrics, though clear establishment of improvement or degradation is challenging due to model complexity as well as observational data limitations. Nonetheless, CLM5 is increasingly suited for research into a broad range of societally relevant scientific questions related to the terrestrial system. Key Points Updated Community Land Model has more hydrological and ecological process fidelity and more comprehensive representation of land management. The model is systematically evaluated using International Land Model Benchmarking system and shows marked improvement over prior versions.

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.