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Increasing drought frequency and severity in a warming climate threaten forest ecosystems with widespread tree deaths. Canopy structure is important in regulating tree mortality during drought, but how it functions remains controversial. Here, we show that the interplay between tree size and forest structure explains drought-induced tree mortality during the 2012-2016 California drought. Through an analysis of over one million trees, we find that tree mortality rate follows a negative-positive-negative piecewise relationship with tree height, and maintains a consistent negative relationship with neighborhood canopy structure (a measure of tree competition). Trees overshadowed by tall neighboring trees experienced lower mortality, likely due to reduced exposure to solar radiation load and lower water demand from evapotranspiration. Our findings demonstrate the significance of neighborhood canopy structure in influencing tree mortality and suggest that re-establishing heterogeneity in canopy structure could improve drought resiliency. Our study also indicates the potential of advances in remote-sensing technologies for silvicultural design, supporting the transition to multi-benefit forest management.

In order to study the pollution characteristics and source contributions of PM2.5 at Lin'an, located in Hangzhou City, the PM2.5 component online monitoring was conducted from December 23, 2021, to February 28, 2022, and the sources apportionment of PM2.5 was conducted using positive matrix factorization (PMF). The mean concentration of PM2.5 was 53.91 μg·m-3 in winter, with NO3- and organic matter contributing the most, which accounted for 31.07% and 19.66%, respectively. NOR, SOR and SOC analysis showed that the secondary formation of PM2.5 was obvious in winter, which contributed largely to local PM2.5. Source apportionment showed that the air of Lin'an in winter was mainly affected by seven sources, namely secondary nitrate (52%), secondary sulfate (16%), vehicle exhaust (14%), coal (6%), dust (5%), industrial (5%) and biomass combustion (2%). During the episode, the contribution of secondary nitrate and vehicle exhaust increased, suggesting that local governments should control the impact of vehicle exhaust emissions on PM2.5 during pollution periods.(为研究杭州市临安区PM2.5的污染特征及来源，于2021年12月23日至2022年2月28日在线监测临安区的PM2.5，并运用正交矩阵因子分解法（PMF）进行来源解析。结果表明，观测期间临安区PM2.5平均质量浓度为53.91 μg·m-3，NO3-和有机物对PM2.5的贡献较大，分别占31.07%和19.66%。氮氧化率（NOR）、硫氧化率（SOR）和二次有机物（SOC）浓度的分析结果表明，临安区冬季PM2.5的二次转化较明显，对PM2.5有重要贡献。来源解析结果表明，临安区冬季PM2.5主要有七类来源，分别为二次硝酸盐（52%）、二次硫酸盐（16%）、机动车尾气（14%）、燃煤（6%）、扬尘（5%）、工业排放（5%）和生物质燃烧（2%）。在污染过程中，二次硝酸盐和机动车尾气的贡献有所上升，建议当地政府在污染期间控制机动车尾气排放，降低PM2.5浓度。)

Grasslands are one of the largest coupled human-nature terrestrial ecosystems on Earth, and severe anthropogenic-induced grassland ecosystem function declines have been reported recently. Understanding factors influencing grassland ecosystem functions is critical for making sustainable management policies. Canopy structure is an important factor influencing plant growth through mediating within-canopy microclimate (e.g., light, water, and wind), and it is found coordinating tightly with plant species diversity to influence forest ecosystem functions. However, the role of canopy structure in regulating grassland ecosystem functions along with plant species diversity has been rarely investigated. Here, we investigated this problem by collecting field data from 170 field plots distributed along an over 2000 km transect across the northern agro-pastoral ecotone of China. Aboveground net primary productivity (ANPP) and resilience, two indicators of grassland ecosystem functions, were measured from field data and satellite remote sensing data. Terrestrial laser scanning data were collected to measure canopy structure (represented by mean height and canopy cover). Our results showed that plant species diversity was positively correlated to canopy structural traits, and negatively correlated to human activity intensity. Canopy structure was a significant indicator for ANPP and resilience, but their correlations were inconsistent under different human activity intensity levels. Compared to plant species diversity, canopy structural traits were better indicators for grassland ecosystem functions, especially for ANPP. Through structure equation modeling analyses, we found that plant species diversity did not have a direct influence on ANPP under human disturbances. Instead, it had a strong indirect effect on ANPP by altering canopy structural traits. As to resilience, plant species diversity had both a direct positive contribution and an indirect contribution through mediating canopy cover. This study highlights that canopy structure is an important intermediate factor regulating grassland diversity-function relationships under human disturbances, which should be included in future grassland monitoring and management.

Genome-wide association studies (GWAS) successfully identified multiple sclerosis (MS) susceptibility variants. Despite this notable progress, understanding the biological context of these associations remains challenging, due in part to the complexity of linking GWAS results to causative genes and cell types. Here, we aimed to address this gap by integrating GWAS data with single-cell and bulk chromatin accessibility data and histone modification profiles from immune and nervous systems. MS-GWAS associations are significantly enriched in regulatory regions of microglia and peripheral immune cell subtypes, especially B cells and monocytes. Cell-specific polygenic risk scores were developed to examine the cumulative impact of the susceptibility genes on MS risk and clinical phenotypes, showing significant associations with risk and brain white matter volume. The findings reveal enrichment of GWAS signals in B cell and monocyte/microglial cell-types, consistent with the known pathology and presumed targets of effective MS therapeutics.

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.

BACKGROUND: The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods. METHODS: We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls. RESULTS: We identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk. RESULTS: The results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

Intratumoral Tregs are key mediators of cancer immunotherapy resistance, including anti-programmed cell death (ligand) 1 [anti-PD-(L)1] immune checkpoint blockade (ICB). The mechanisms driving Treg infiltration into the tumor microenvironment (TME) and the consequence on [CD8.sup.+] T cell exhaustion remain elusive. Here, we report that heat shock protein gp96 (also known as GRP94) was indispensable for Treg tumor infiltration, primarily through the roles of gp96 in chaperoning integrins. Among various gp96-dependent integrins, we found that only LFA-1 ([alpha]L integrin), and not [alpha]V, CD103 ([alpha]E), or [beta]7 integrin, was required for Treg tumor homing. Loss of Treg infiltration into the TME by genetic deletion of gp96/LFA-1 potently induced rejection of tumors in multiple ICB-resistant murine cancer models in a [CD8.sup.+] T cell-dependent manner, without loss of self-tolerance. Moreover, gp96 deletion impeded Treg activation primarily by suppressing IL-2/STAT5 signaling, which also contributed to tumor regression. By competing for intratumoral IL-2, Tregs prevented the activation of [CD8.sup.+] tumor-infiltrating lymphocytes, drove thymocyte selection-associated high mobility group box protein (TOX) induction, and induced bona fide [CD8.sup.+] T cell exhaustion. By contrast, Treg ablation led to striking [CD8.sup.+] T cell activation without TOX induction, demonstrating clear uncoupling of the 2 processes. Our study reveals that the gp96/LFA-1 axis plays a fundamental role in Treg biology and suggests that Treg-specific gp96/LFA-1 targeting represents a valuable strategy for cancer immunotherapy without inflicting autoinflammatory conditions., Introduction Regulatory T cells (Tregs) are characterized by high expression of IL-2 receptor a chain (CD25) and the transcription factor Foxp3, and their function in suppressing the effector immune response [...]

The omni-directional mobile manipulator robot (OMMR) is a class of a new robot with activating operating capability, which is composed of one or more manipulators mounted on a mobile platform. However, after the manipulator is installed on the mobile platform, the coupling effect between the manipulator and the mobile platform will significantly increase the complexity of the dynamic behavior of the whole system, involving the dynamic interaction between the ground and the mobile platform, the mobile platform and the manipulator, the manipulator and the operating environment, which brings great difficulties to the modeling of the system. Based on establishing the kinematics and statics models of OMMR, this study presents a simplified modeling approach of OMMR system dynamics. Based on this dynamic model, the vehicle-manipulator interaction model is established, and its interaction is analyzed. Simulation and experiments verify the correctness of the vehicle-manipulator interaction model, indirectly prove the rationality and effectiveness of the proposed OMMR system dynamics modeling approach, and provide model data for motion planning and control of robots.

ObjectiveATXN1 encodes the polyglutamine protein ataxin-1, which we have demonstrated exerting an immunomodulatory function in the context of central nervous system (CNS) autoimmunity, in addition to its classical role in the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1). In this study, we dissected the contribution of DNA methylation to the regulation of ATXN1 in multiple sclerosis (MS).MethodsWe interrogated a DNA methylation dataset previously generated via bisulfate DNA sequencing (BS-seq) in sorted peripheral immune cytotypes (CD4+ and CD8+ T cells, CD19+ B cells, and CD14+ monocytes) isolated from untreated MS patients at symptoms onset.ResultsHere, we report that ATXN1 undergoes hypo-methylation at four distinct regions upon MS, exclusively in B cells. We also highlight how these differentially methylated sites overlap with other regulatory epigenetic marks and MS risk variants. Lastly, we employ luciferase assays to assess the functionality of these regions, showing that the loss of methylation leads to an increase in ATXN1 expression.InterpretationAltogether, these findings provide biological insights into ataxin-1 regulation in the immune system as well as into the molecular mechanisms underlying MS risk.