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Microglia are critical in brain development and Alzheimer's disease (AD) etiology. Down syndrome (DS) is the most common genetic developmental disorder and risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglial functions during DS brain development and in AD in DS. Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. In response to human brain tissue-derived pathological tau, DS microglia undergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide in vivo evidence that human microglia respond to pathological tau by exhibiting dystrophic phenotypes. Targeting IFNARs may improve DS microglial functions and prevent senescence.

Introduction Chronic kidney disease (CKD) is a serious and growing public health issue, affecting approximately 14% of the population in the United States (1). It is the ninth leading cause [...], Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single- cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.

Grass endophytes (Epichloë) are important symbiotic microorganisms of perennial ryegrass, playing a vital role in plant resistance against various stresses. This study investigated the effects of grass endophyte on leaf spot disease caused by fungal pathogen Bipolaris sorokiniana and subsequent feeding preferences of aphids (Rhopalosiphum maidis) on perennial ryegrass, with a particular focus on how grass endophyte influence the interactions between pathogens and aphids. The results indicated that grass endophytes significantly increased the net photosynthetic efficiency of perennial ryegrass. The interactions among grass endophytes, pathogen, and aphids affected the activities of superoxide dismutase (SOD), peroxidases (POD), and catalase (CAT). Grass endophytes enhanced SOD and CAT activities in pathogen-infected ryegrass. While pathogen infection and aphid infestation decreased jasmonic acid (JA) and salicylic acid (SA) concentrations, grass endophyte increased SA levels. Correlation analysis revealed a negative relationship between shoot dry weight and plant transpiration rate, SOD, and CAT activities. Aphid feeding choice showed that grass endophytes attracted more aphid feeding when co-infected with pathogens. This preference correlated positively with H2O2 and SA levels but negatively with NO and JA concentrations. Overall, grass endophytes enhance perennial ryegrass resistance to leaf spot pathogens and aphids, offering a novel pest and disease management strategy in agriculture. [ABSTRACT FROM AUTHOR]

Astroglia are integral to brain development and the emergence of neurodevelopmental disorders. However, studying the pathophysiology of human astroglia using brain organoid models has been hindered by inefficient astrogliogenesis. In this study, we introduce a robust method for generating astroglia-enriched organoids through BMP4 treatment during the neural differentiation phase of organoid development. Our RNA sequencing analysis reveals that astroglia developed within these organoids exhibit advanced developmental characteristics and enhanced synaptic functions compared to those grown under traditional two-dimensional conditions, particularly highlighted by increased neurexin (NRXN)-neuroligin (NLGN) signaling. Cell adhesion molecules, such as NRXN and NLGN, are essential in regulating interactions between astroglia and neurons. We further discovered that brain organoids derived from human embryonic stem cells (hESCs) harboring the autism-associated NLGN3 R451C mutation exhibit increased astrogliogenesis. Notably, the NLGN3 R451C astroglia demonstrate enhanced branching, indicating a more intricate morphology. Interestingly, our RNA sequencing data suggest that these mutant astroglia significantly upregulate pathways that support neural functions when compared to isogenic wild-type astroglia. Our findings establish a novel astroglia-enriched organoid model, offering a valuable platform for probing the roles of human astroglia in brain development and related disorders. [ABSTRACT FROM AUTHOR]

Carbon emissions trading pilots are an essential environmental regulation tool for incentivizing companies to reduce carbon emissions and a critical initiative for achieving "dual carbon" targets. This study, based on 2366 observations of 169 high-carbon listed companies on the Shanghai and Shenzhen stock exchanges from 2009 to 2022, uses double machine learning analysis to examine the impact and mechanisms of pilot policy on the low-carbon competitiveness of high-carbon industry-listed companies. The empirical results show that, first, pilot policy significantly enhances the low-carbon competitiveness of high-carbon industry-listed companies, and this conclusion holds after considering a series of robustness checks. Second, mechanism analysis indicates that alleviating green financing constraints and enhancing total factor productivity are pathways through which pilot policy influences low-carbon competitiveness. Heterogeneity analysis shows that the policy effects are stronger for state-owned enterprises, small- and medium-sized enterprises, and companies in eastern regions. Further analysis reveals that pilot policy enhances low-carbon competitiveness and increase enterprise value. Based on the study's conclusions, the government should ensure the incentivizing effect of pilot policy, promote expansion of the carbon emissions trading market, assist enterprises in overcoming green financing constraints, improve total factor productivity, and formulate tailored policies according to the development levels and resource endowments of regions and companies. [ABSTRACT FROM AUTHOR]

The article explores the application of transformer‐based large models for trajectory decision‐making in complex decision systems, focusing on multiagent nodes in a topological structure. By leveraging the capabilities of large models, the proposed approach enhances decision‐making in model‐free control environments characterized by numerous agents, diverse internal tasks, and unknown conditions. The proposed framework integrates advanced transformer models with a sophisticated decision‐making framework to enhance the efficiency, safety, and reliability of multiagent operations in dynamic environments. The results demonstrate the superior performance of the transformer model, achieving a trajectory decision‐making accuracy of 97.8%, significantly outperforming other models such as long short‐term memory (LSTM), gate recurrent unit (GRU), and traditional approaches. The visualizations highlight the close alignment between the true and predicted outcomes of complex decision‐making systems, showcasing the model's ability to capture complex dependencies and interactions within the multiagent environment. High task completion rates and low collision rates further underscore the effectiveness of the decision‐making framework in optimizing agent coordination and ensuring safe operations. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to construct an event-triggered finite-time fault-tolerant formation tracking controller, which can achieve a time-varying formation control for multiple unmanned aerial vehicles (UAVs) during actuator failures and external perturbations. Design/methodology/approach: First, this study developed the formation tracking protocol for each follower using UAV formation members, defining the tracking inaccuracy of the UAV followers' location. Subsequently, this study designed the multilayer event-triggered controller based on the backstepping method framework within finite time. Then, considering the actuator failures, and added self-adaptive thought for fault-tolerant control within finite time, the event-triggered closed-loop system is subsequently shown to be a finite-time stable system. Furthermore, the Zeno behavior is analyzed to prevent infinite triggering instances within a finite time. Finally, simulations are conducted with external disturbances and actuator failure conditions to demonstrate formation tracking controller performance. Findings: It achieves improved performance in the presence of external disturbances and system failures. Combining limited-time adaptive control and event triggering improves system stability, increase robustness to disturbances and calculation efficiency. In addition, the designed formation tracking controller can effectively control the time-varying formation of the leader and followers to complete the task, and by adding a fixed-time observer, it can effectively compensate for external disturbances and improve formation control accuracy. Originality/value: A formation-following controller is designed, which can handle both external disturbances and internal actuator failures during formation flight, and the proposed method can be applied to a variety of formation control scenarios and does not rely on a specific type of UAV or communication network. [ABSTRACT FROM AUTHOR]

Introduction African Americans represent 13% of the US population, and yet 35% of patients on chronic dialysis are African American (1, 2). This excess chronic kidney disease (CKD) risk can [...], Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOLI-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.

Introduction More than 1 in 10 people in the US suffers from chronic kidney disease (CKD). CKD is one of the strongest risk factors for cardiovascular death. The annual mortality [...], Genome-wide association studies (GWAS) for kidney function identified hundreds of risk regions; however, the causal variants, target genes, cell types, and disease mechanisms remain poorly understood. Here, we performed transcriptome- wide association studies (TWAS), summary Mendelian randomization, and MetaXcan to identify genes whose expression mediates the genotype effect on the phenotype. Our analyses identified Dachshund homolog 1 (DACH1), a cell-fate determination factor. GWAS risk variant was associated with lower DACH1 expression in human kidney tubules. Human and mouse kidney single- cell open chromatin data (snATAC-Seq) prioritized estimated glomerular filtration rate (eGFR) GWAS variants located on an intronic regulatory region in distal convoluted tubule cells. CRISPR-Cas9-mediated gene editing confirmed the role of risk variants in regulating DACH1 expression. Mice with tubule-specific Dach1 deletion developed more severe renal fibrosis both in folic acid and diabetic kidney injury models. Mice with tubule-specific Dach1 overexpression were protected from folic acid nephropathy. Single-cell RNA sequencing, chromatin immunoprecipitation, and functional analysis indicated that DACH1 controls the expression of cell cycle and myeloid chemotactic factors, contributing to macrophage infiltration and fibrosis development. In summary, integration of GWAS, TWAS, single-cell epigenome, expression analyses, gene editing, and functional validation in different mouse kidney disease models identified DACH1 as a kidney disease risk gene.

Schizophrenia is a severe psychiatric disorder. Among the globe, almost 70% of people with schizophrenia would experience hallucinations that make them feel insecure and progressively weakened. Etiologies and treatments of this perilous disease, therefore, are supposed to be studied in depth. Although the exact causes are still unknown, scientists highly suggest that this disorder results from the combination of genes and environments. For genetic influences, genes such as NR3C2, Dysbindin-1 (DTNBP1), Neuritin-1 (NRN1), KPNB3, and KPNA3 play insignificant roles in the development of schizophrenia. For environmental influences, researchers collected data from different aspects to infer the causes of schizophrenia. The reasons, including season of birth, urbanization, are not related to schizophrenia causation. Furthermore, if pharmacological interventions such as chlorpromazine, followed by some psychotherapy at an early stage, schizophrenia has a chance of being cured and not relapsing. Many drugs on the market target G-protein-coupled receptors. To improve their bioavailability, a new technique called lipid-based self-nanoemulsifying drug delivery systems formulations assists with the absorption of them.

Exhaust manifold is a main heated component of engine,which has poor working conditions. High levels of thermal load can lead to deformation even cracking,which affect its normal working and reliability and durability. Aiming at the high thermal load of a high pressure common rail diesel engine,different fluid-solid coupling models was built and the temperature distribution and thermal stress of the engine exhaust manifold was stimulated and the influence of different structural factors on the exhaust manifold thermal load was calculated and analyzed. Results show that: the maximum temperature of the exhaust manifold changed from 805. 2 ℃ to 820. 8 ℃ as the outlet length increased,the maximum temperature of the exhaust manifold changed from 805. 2 ℃ to 819. 4 ℃ as the outlet diameter increasing,and the maximum temperature of the exhaust manifold dropped to 784. 0 ℃ as the outlet transferred to the body symmetry position. Structure factors such as exhaust outlet position,outlet length and outlet diameter had a great influence on the exhaust manifold thermal load. The maximum thermal stress value was 326. 21 MPa of the case of 21 mm outlet length and 5 mm outlet diameter outlet with the non-symmetry outlet position; the minimum thermal stress value was 174. 1 MPa of the case of 19 mm outlet length and 5mm outlet diameter with the non-symmetry outlet position.

The primary cause of hazy weather is PM2.5, and forecasting PM2.5 concentrations can aid in managing and preventing hazy weather. This paper proposes a novel spatiotemporal prediction model called SpatioTemporal-Informer (ST-Informer) in response to the shortcomings of spatiotemporal prediction models commonly used in studies for long-input series prediction. The ST-Informer model implements parallel computation of long correlations and adds an independent spatiotemporal embedding layer to the original Informer model. The spatiotemporal embedding layer captures the complex dynamic spatiotemporal correlations among the input information. In addition, the ProbSpare Self-Attention mechanism in this model can focus on extracting important contextual information of spatiotemporal data. The ST-Informer model uses weather and air pollutant concentration data from numerous stations as its input data. The outcomes of the trials indicate that (1) The ST-Informer model can sharply capture the peaks and sudden changes in PM2.5 concentrations. (2) Compared to the current models, the ST-Informer model shows better prediction performance while maintaining high-efficiency prediction (MAE≈7.50μg/m3,RMSE≈4.31μg/m3,R2≈0.88). (3) The ST-Informer model has universal applicability, and the model was applied to the concentration of other pollutants prediction with good results. [ABSTRACT FROM AUTHOR]