TMC7 deficiency causes acrosome biogenesis defects and male infertility in mice.

Transmembrane channel-like (TMC) proteins are a highly conserved ion channel family consisting of eight members (TMC1-TMC8) in mammals. TMC1/2 are components of the mechanotransduction channel in hair cells, and mutations of TMC1/2 cause deafness in humans and mice. However, the physiological roles of other TMC proteins remain largely unknown. Here, we show that Tmc7 is specifically expressed in the testis and that it is required for acrosome biogenesis during spermatogenesis. Tmc7-/- mice exhibited abnormal sperm head, disorganized mitochondrial sheaths, and reduced number of elongating spermatids, similar to human oligo-astheno-teratozoospermia. We further demonstrate that TMC7 is colocalized with GM130 at the cis-Golgi region in round spermatids. TMC7 deficiency leads to aberrant Golgi morphology and impaired fusion of Golgi-derived vesicles to the developing acrosome. Moreover, upon loss of TMC7 intracellular ion homeostasis is impaired and ROS levels are increased, which in turn causes Golgi and endoplasmic reticulum stress. Taken together, these results suggest that TMC7 is required to maintain pH and ion homeostasis, which is needed for acrosome biogenesis. Our findings unveil a novel role for TMC7 in acrosome biogenesis during spermiogenesis.

Specialists regulate microbial network and community assembly in subtropical seagrass sediments under differing land use conditions.

Microorganisms in the sediment play a pivotal role in the functioning and stability of seagrass ecosystems and their dynamics are influenced by the nutrient acquisition strategies of host plants. While the distinct impacts of microbial generalists and specialists on community dynamics are recognized, their distribution patterns and ecological roles within seagrass ecosystems remain largely unexplored. To address this issue, we conducted an analysis of community assembly processes and co-occurrence relationships of both microbial generalists and specialists within sediment profiles (0-100 cm) from seagrass habitats subjected to differing land use conditions. The results revealed that seagrasses in Yifeng Estuary experienced the large proportion of cultivated land and exhibited higher organic carbon content in the 0-20 cm surface sediment layer. Nitrogen-cycling bacteria were predominantly associated with seagrasses from Yifeng Estuary, whereas Vibrio spp. was more prevalent in seagrasses from Liusha Bay. Notably, seagrass Halophia beccarii (YHB) in Yifeng Estuary harbored higher niche breadths for both microbial generalist and specialist compared to Halodule uninervis (LHU) and Halophia ovalis (LHO) from Liusha Bay. Stochastic processes were pivotal in shaping seagrass sediment microbial communities, with a higher immigration rate observed in YHB, suggesting greater microbial turnover in this area. Additionally, YHB sediment presented lower drift and higher dispersal limitation among generalists compared to LHU and LHO, whereas the pattern was reversed among specialists. Specialists were found to play a crucial role in shaping microbial interactions within YHB sediment, with genera Halioglobus identified as keystone species in the network. The specialists were further found to significantly influence microbial ß-diversity in seagrass sediment directly. Overall, our findings illustrated how microbial generalists and specialists were distributed in seagrass sediments in response to land use changes and provided new insights into the potential roles of microbial regulation in degraded seagrass ecosystems.

Using surface runoff to reveal the mechanisms of landscape patterns driving on various forms of nitrogen in non-point source pollution.

Non-point source (NPS) pollution directly threatens river water quality, constrains sustainable economic development, and poses hazards to human health. Comprehension of the impact factors on NPS pollution is essential for scientific river water quality management. Despite the landscape pattern being considered to have a significant impact on NPS pollution, the driving mechanism of landscape patterns on NPS pollution remains unclear. Therefore, this study coupled multi-models including the Soil and Water Assessment Tool (SWAT), Random Forest, and Partial Least Squares Structural Equation Modeling (PLS-SEM) to construct the connection between landscape patterns, NPS pollution, and surface runoff. The results suggested that increased runoff during the wet season enhances the link between landscape patterns and NPS pollution, and the explained NPS pollution variation by landscape pattern increased from 59.6 % (dry season) to 84.9 % (wet season). Furthermore, from the impact pathways, we find that the sink landscape pattern can significantly and indirectly influence NPS pollution by regulating surface runoff during the wet season (0.301*). Meanwhile, the sink and source landscape patterns significantly and directly impact NPS pollution during different seasons. Moreover, we further find that the percentage of paddy land use (Pad_PLAND) and grassland patch density (Gra_PD) metrics can significantly predict the dissolved total nitrogen (DTN) and nitrate nitrogen (NO3--N) variation. Thus, controlling the runoff migration process by guiding the rational evolution of watershed landscape patterns is an important development direction for watershed NPS pollution management.

Imiquimod inhibits U87 cell proliferation and migration in vitro through inhibition of STAT-3/NF-κB signalling pathway.

Imiquimod, known for its immune-modulating properties, has emerged as a potential anti-cancer agent. The U87 glioblastoma cell line, known for its high malignancy and poor prognosis, presents a significant challenge in neuro-oncology. Targeting the STAT-3/NF-κB pathways offers a promising therapeutic strategy for glioblastoma treatment. Imiquimod potentially inhibits these oncogenic signaling routes to suppress U87 cell proliferation and migration. We investigated the effect of imiquimod (IMQ) on U87 cell growth using CCK-8 and cell scratch assays. Western blotting analyzed protein levels of STAT-3, p-STAT-3, NF-κB and p-NF-κB, while flow cytometry assessed U87 cell apoptosis rates. ELISA detected cellular inflammatory factor levels. In vivo experiments further evaluated IMQ's impact on U87 cell growth. Findings suggest that IMQ suppresses U87 cell growth and movement, inhibits STAT-3 and NF-κB phosphorylation and accelerates apoptosis. ELISA assays indicated that IMQ reduced local inflammation. Adding a STAT-3 inhibitor yielded similar effects to IMQ, altering cell proliferation, migration and apoptosis. Overall, IMQ appears to inhibit U87 cell proliferation and migration, inducing programmed cell death through STAT-3 modulation.

Targeting Macrophage Phenotypes and Metabolism as Novel Therapeutic Approaches in Atherosclerosis and Related Cardiovascular Diseases.

PURPOSE OF THE REVIEW: Macrophage accumulation and activation function as hallmarks of atherosclerosis and have complex and intricate dynamics throughout all components and stages of atherosclerotic plaques. In this review, we focus on the regulatory roles and underlying mechanisms of macrophage phenotypes and metabolism in atherosclerosis. We highlight the diverse range of macrophage phenotypes present in atherosclerosis and their potential roles in progression and regression of atherosclerotic plaque. Furthermore, we discuss the challenges and opportunities in developing therapeutic strategies for preventing and treating atherosclerotic cardiovascular disease. RECENT FINDINGS: Dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypealters the immuno-inflammatory response during atherosclerosis progression, leading to plaque initiation, growth, and ultimately rupture. Altered metabolism of macrophage is a key feature for their function and the subsequent progression of atherosclerotic cardiovascular disease. The immunometabolism of macrophage has been implicated to macrophage activation and metabolic rewiring of macrophages within atherosclerotic lesions, thereby shifting altered macrophage immune-effector and tissue-reparative function. Targeting macrophage phenotypes and metabolism are potential therapeutic strategies in the prevention and treatment of atherosclerosis and atherosclerotic cardiovascular diseases. Understanding the precise function and metabolism of specific macrophage subsets and their contributions to the composition and growth of atherosclerotic plaques could reveal novel strategies to delay or halt development of atherosclerotic cardiovascular diseases and their associated pathophysiological consequences. Identifying biological stimuli capable of modulating macrophage phenotypes and metabolism may lead to the development of innovative therapeutic approaches for treating patients with atherosclerosis and coronary artery diseases.

Chemosynthetic alphaproteobacterial diazotrophs reside in deep-sea cold-seep bottom waters.

Nitrogen (N)-fixing organisms, also known as diazotrophs, play a crucial role in N-limited ecosystems by controlling the production of bioavailable N. The carbon-dominated cold-seep ecosystems are inherently N-limited, making them hotspots of N fixation. However, the knowledge of diazotrophs in cold-seep ecosystems is limited compared to other marine ecosystems. In this study, we used multi-omics to investigate the diversity and catabolism of diazotrophs in deep-sea cold-seep bottom waters. Our findings showed that the relative abundance of diazotrophs in the bacterial community reached its highest level in the cold-seep bottom waters compared to the cold-seep upper waters and non-seep bottom waters. Remarkably, more than 98% of metatranscriptomic reads aligned on diazotrophs in cold-seep bottom waters belonged to the genus Sagittula, an alphaproteobacterium. Its metagenome-assembled genome, named Seep-BW-D1, contained catalytic genes (nifHDK) for nitrogen fixation, and the nifH gene was actively transcribed in situ. Seep-BW-D1 also exhibited chemosynthetic capability to oxidize C1 compounds (methanol, formaldehyde, and formate) and thiosulfate (S2O32-). In addition, we observed abundant transcripts mapped to genes involved in the transport systems for acetate, spermidine/putrescine, and pectin oligomers, suggesting that Seep-BW-D1 can utilize organics from the intermediates synthesized by methane-oxidizing microorganisms, decaying tissues from cold-seep benthic animals, and refractory pectin derived from upper photosynthetic ecosystems. Overall, our study corroborates that carbon-dominated cold-seep bottom waters select for diazotrophs and reveals the catabolism of a novel chemosynthetic alphaproteobacterial diazotroph in cold-seep bottom waters. IMPORTANCE: Bioavailable nitrogen (N) is a crucial element for cellular growth and division, and its production is controlled by diazotrophs. Marine diazotrophs contribute to nearly half of the global fixed N and perform N fixation in various marine ecosystems. While previous studies mainly focused on diazotrophs in the sunlit ocean and oxygen minimum zones, recent research has recognized cold-seep ecosystems as overlooked N-fixing hotspots because the seeping fluids in cold-seep ecosystems introduce abundant bioavailable carbon but little bioavailable N, making most cold seeps inherently N-limited. With thousands of cold-seep ecosystems detected at continental margins worldwide in the past decades, the significant role of cold seeps in marine N biogeochemical cycling is emphasized. However, the diazotrophs in cold-seep bottom waters remain poorly understood. Through multi-omics, this study identified a novel alphaproteobacterial chemoheterotroph belonging to Sagittula as one of the most active diazotrophs residing in cold-seep bottom waters and revealed its catabolism.

Multi-site and long-term estimation of phosphorus dynamics for paddy surface water in China based on new MLEpaddy-P.

Paddy surface water serves as the primary source of artificial drainage and rainfall runoff leading to phosphorus (P) loss from paddy fields. The quantification of P dynamics in paddy surface water on a large scale is challenging due to the spatiotemporal heterogeneity of influencing factors and the limitations of field measurements. Based on 1226 data sets from 33 field sites covering the three main rice-growing regions of China (the Southeast Coast, the Yangtze River Basin, and the Northeast Plain), we analyzed the spatiotemporal characteristics of P attenuation in paddy surface water and its influencing factors. A new multi-site and long-term phosphorus estimation model for paddy (MLEpaddy-P) was proposed to evaluate the total phosphorus (TP) dynamics at national scale by improving the initial concentration (C0) and attenuation coefficient (k) of the first-order kinetic model (Ct=C0∙e-k(t-1)). Our study showed that: (1) Fertilizer amounts, soil organic matter content, soil Olsen-P content, soil pH, and soil total phosphorus are the primary factors affecting the variation of C0 and k; (2) Yangtze River Basin possessed the highest C0 (6.87 ± 12.97 mg/L) and high k ≤ 7 (0.262 in 1-7 days after fertilization), followed by Southeast Coast (4.15 ± 5.33 mg/L; 0.263) and Northeast Plain (1.33 ± 1.50 mg/L; 0.239), respectively; (3) MLEpaddy-P performed well in daily TP dynamics estimation at national scale with R2 of 0.74-0.85; (4) Middle and lower reaches of the Yangtze River Basin were the critical regions with high TP concentration due to high fertilizer amount and soil Olsen-P content. The new universal model realizes the multi-site and long-term estimation of P dynamics while greatly saving multi-site monitoring costs. This study provides a basis for early warning and targeted control of P loss from paddies.

Increased anaerobic conditions promote the denitrifying nitrogen removal potential and limit anammox substrate acquisition within paddy irrigation and drainage units.

Microbial nitrogen (N) removal is crucial for purifying surface water quality in paddy irrigation and drainage units (IDUs). However, the spatiotemporal microbial N removal potential characteristics within these IDUs and the effects of changing anaerobic conditions on this potential remain insufficiently studied. In this study, we investigated the microbial N removal potential of conventional rice-wheat rotation and anaerobically enhanced rice-crayfish rotation IDUs using field measurements, isotope tracing techniques, and quantitative PCR. Our findings reveal that paddy fields were identified as hotspots for anammox activity, contributing to 76.0 %-97.4 % of the total anammox N removal potential in the IDU, while denitrification processes in ditches accounted for 43.5 %-77.4 % of the IDU's denitrification potential. During the rice transplanting period, the anammox N removal potential peaked, representing 35.8 % and 71.8 % of the total anammox N removal potential of the paddy fields in rice-wheat and rice-crayfish IDUs, respectively. An increase in anaerobic conditions diminished the anammox N removal potential while amplifying denitrification capabilities. The N removal potential in paddy fields decreased with increasing depth, contrasting with the relative stability in ditches. Spatiotemporal fluctuations in N removal potentials within these units are influenced by Fe2+ concentration, carbon and N content, WFPS, and pH levels. This study provides a scientific basis for improving nitrogen removal and water quality treatment in IDUs.

Spatial variability in blue carbon storage and sequestration of seagrass meadows in southern China.

Although seagrass meadows are intense carbon sinks, information on the regional variability in seagrass blue carbon stocks and carbon sequestration remains limited. We estimated the organic carbon (Corg) stocks and carbon accumulation rates (CAR) of seven seagrass meadows along the subtropical coast of China's Zhanjiang City and analyzed the driving factors of variability in sediment Corg stocks in three seagrass meadows. Results showed that most Corg (99.83 %) was stored in the sediments, and the contribution of living biomass was minor. The average Corg stocks of living biomass and sediments across all sites were 0.04 ± 0.01 and 42.03 ± 25.07 Mg C ha-1, respectively, which were significantly lower than the world average (2.52 ± 0.48 and 194.2 Mg C ha-1). The sediment Corg stocks of the upper 1 m ranged from 24.26 to 157.12 Mg C ha-1 with substantial variability among sites: Liusha Bay (64.93 ± 22.31 Mg C ha-1) > Donghai Island (33.8 ± 10.65 Mg C ha-1) > Dongshen Ferry (27.35 ± 4.15 Mg C ha-1). The average sediment CAR was 53.47 g C m-2 yr-1, and the total CAR of 864.18 ha seagrass meadows was 260.76 ± 4.86 Mg C yr-1 in these studied sites. Physicochemical factors, such as high moisture content, salinity, CaCO3 content, and low dry bulk density, jointly inhibited the mineralization rate of Corg in sediments. Our study provides data from understudied regions to a growing dataset on seagrass carbon stocks and sequestration rates and highlights the significance of local and regional differences in seagrass blue carbon storage to accurately assess the climate change mitigation potential of seagrass ecosystems.

Long-term responses of internal environment dynamics in a freshwater lake to variations in external nutrient inputs: A model simulation approach.

Lake restoration usually focuses on reducing external nutrient sources. However, when sediments contain nutrients accumulated over multiple years, internal nutrient release can delay restoration progress. In lake restoration and management, it is important to understand the dynamic relationship between nutrient concentrations in a lake and internal and external nutrient sources. In this study, we quantified external nutrient inputs through measurements and compared them with internal sediment release from simulation using the PCLake+ model. Additionally, we evaluated alterations in the internal nutrient release, lake nutrient concentrations, and algae biomass (chlorophyll-a) within the lake following varying degrees of reduction in external nutrient loads. The results demonstrate that the PCLake+ effectively simulated the lake's nutrient concentration and algae biomass. Based on the PCLake+ estimates, internal nutrient loads accounted for 51 % of the total nitrogen (N) and 80 % of the total phosphorus (P) loadings in Lake Erhai in 2019. In 2020, the total contributions were 43 % for TN and 72 % for TP. We simulated four scenarios where external nutrient inputs were reduced to 25 %, 50 %, 75 %, and 99.99 % of their original levels. The 40-year simulation showed that the lake's ecological system initially exhibited a fast internal response but reached equilibrium after eight years. P concentrations took longer to reach equilibrium compared to N concentrations, probably due to the stronger binding characteristics of P. To meet the water quality target in the future, it is necessary to reduce external N and P inputs into Lake Erhai by at least 23 % and 15 %, respectively, under current conditions. Although reducing external nutrient loads can indirectly lower internal nutrient loads, water management should address both external and internal loads simultaneously, as internal release cannot be effectively reduced by external reductions alone. Additionally, the lake's internal release may continue for several years, even with reductions in external inputs.

Study on the Aging Precipitation Behavior and Kinetics of Al-10.0Zn-3.0Mg-2.8Cu Alloy by Pre-Deformation Treatment.

In this paper, the effect of thermomechanical treatment process on the hardening behavior, grain microstructure, precipitated phase, and tensile mechanical properties of the new high-strength and high-ductility Al-10.0Zn-3.0Mg-2.8Cu alloy was studied, and the optimal thermomechanical treatment process was established. The strengthening and toughening mechanisms were revealed, which provided technical and theoretical guidance for the engineering application of this kind of high strength-ductility aluminum alloy. Al-10.0Zn-3.0Mg-2.8Cu alloy cylindrical parts with external longitudinal reinforcement were prepared by a composite extrusion deformation process (reciprocal upsetting + counter-extrusion) with a true strain up to 2.56, and the organizational evolution of the alloys during the extrusion deformation process and the influence of pre-stretching treatments on the subsequent aging precipitation behaviors and mechanical properties were investigated. The results show that firstly, the large plastic deformation promotes the fragmentation of coarse insoluble phases and the occurrence of dynamic recrystallization, which results in the elongation of the grains along the extrusion direction, and the volume fraction of recrystallization reaches 42.4%. Secondly, the kinetic study showed that the decrease in the activation energy of precipitation increased the nucleation sites, which further promoted the diffuse distribution of the second phase in the alloy and a higher number of nucleation sites, while limiting the coarsening of the precipitated phase. When the amount of pre-deformation was increased from 0% to 2%, the size of the matrix precipitated phase decreased from 5.11 µm to 4.1 µm, and when the amount of pre-deformation was increased from 2% to 7%, the coarsening of the matrix precipitated phase took place, and the size of the phase increased from 4.1 µm to 7.24 µm. The finalized heat treatment process for the deformation of the aluminum alloy tailframe was as follows: solution (475 °C/3 h) + 2% pre-stretching + aging (120 °C/24 h), at which the comprehensive performance of the alloy was optimized, with a tensile strength of 634.2 MPa, a yield strength of 571.0 MPa, and an elongation of 15.2%. The alloy was strengthened by both precipitation strengthening and dislocation strengthening. After 2% pre-stretching, the fracture surface starts to be dominated by dense tough nest structure, and most of them are small tough nests, and small and dense tough nests are the main reason for the increase in alloy toughness after 2% pre-stretching deformation.

Association between triglyceride-glucose related indices and all-cause and cause-specific mortality in the general population: a cohort study.

BACKGROUND: Although triglyceride-glucose (TyG) index is a reliable indicator of insulin resistance and cardiometabolic disease, its effectiveness in predicting mortality risk has not been adequately validated. We aimed to investigate the association between the TyG-related indices and all-cause and cause-specific mortality in the general population. METHODS: A total of 27,642 individuals were included from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. Three indicators were constructed, including the TyG index, TyG combined with waist-to-height ratio (TyG-WHtR), and TyG combined with waist circumference (TyG-WC). Mortality data was acquired through the linkage of NHANES data with National Death Index records. Weighted Cox proportional hazards models were used to estimate the independent association between the TyG-related indices and mortality. Nonlinear associations were explored using restricted cubic splines. RESULTS: Multivariable adjusted models showed a progressive increase in all-cause and cause-specific mortality across quartiles of the TyG-related indices. Compared with the lowest quartile of the TyG index, the highest quartile had adjusted hazard ratios of 1.26 (95% CI 1.04-1.52) for all-cause mortality, 1.38 (1.04-1.74) for cardiovascular mortality, and 1.23 (1.01-1.50) for non-cardiovascular mortality, respectively. For the TyG-WHtR index, the corresponding hazard ratios were 1.60 (1.25-2.05), 1.86 (1.26-2.50), and 1.48 (1.10-1.99), respectively. For the TyG-WC index, the corresponding hazard ratios were 1.42 (1.11-1.75), 1.48 (1.04-1.96), and 1.38 (1.05-1.72), respectively. The associations between the three TyG-related indices and all-cause, cardiovascular and non-cardiovascular mortality were J-shaped. Interaction tests revealed significant effect modification by age, low-density lipoprotein cholesterol (LDL-C) level, and statin use (all P values < 0.05). CONCLUSIONS: The TyG-related indices were independent predictors of all-cause and cause-specific mortality in the general population. Young individuals should be particularly vigilant, whereas low LDL-C levels and statin use are potentially protective.

Sources, fate and influencing factors of nitrate in farmland drainage ditches of the irrigation area.

Global irrigation areas face the contradictory challenges of controlling nitrate inputs and ensuring food-safe production. To prevent and control nitrate pollution in irrigation areas, the study using the Yellow River basin (Ningxia section) of China as a case study, employed nitrogen and oxygen dual isotope tracing and extensive field investigations to analyze the sources, fate, and influencing factors of nitrate in agricultural drainage ditches. The results of source tracing of nitrate showed that annual proportions of nitrate sources entering the Yellow River in the ditches are as follows: for manure & sewage, fertilizer, and natural sources, the ratios are 33%, 35%, and 32% overall. The results of nitrate fate showed that nitrates derived from nitrate fertilizer exhibit a lower residual rate in drainage ditches (ecological ditches) compared to ammonium fertilizer, which can undergo self-ecological restoration within one year. The results of influencing factors showed that crops with high water and nutrient requirements, such as vegetables, the nitrate pollution and environmental harm resulting from "exploitative cultivation" are five times more than normal cultivation practices in dryland and paddy fields, especially winter irrigation without crop interception exacerbates the leaching of nitrate from the soil. Therefore, nitrate management in irrigation areas should focus on preventing and controlling "exploitative cultivation" and losses during winter irrigation, while appropriately adjusting the application ratio of ammonium nitrogen fertilizers. The results of the study can guide strategies to mitigate nitrate pollution in irrigated areas such as livestock farming, fertilizer application, irrigation management, ditch optimization, and crop cultivation.

Mitochondrial DNA content and methylation in sperm of patients with asthenozoospermia.

PURPOSE: The aim of the current study was to investigate the mtDNA methylation levels and mtDNA copy numbers in the sperm of patients with asthenozoospermia and compare them to those observed in controls with normozoospermia. METHODS: Pyrosequencing analysis of the methylation levels of the mitochondrial D-loop and MT-CO1/chr1:631,907-632083/chrX:26,471,887-126,472,063 (hereinafter referred to as "MT-CO1-AVG") region and quantitative PCR analysis of the mtDNA copy number were performed on sperm from 30 patients with asthenozoospermia and 30 controls with normozoospermia. RESULTS: Compared with those of controls with normozoospermia, the methylation levels of D-loop and MT-CO1-AVG regions and mtDNA copy number were significantly higher in patients with asthenozoospermia. The methylation level of the D-loop region in patients with asthenozoospermia and controls with normozoospermia and that of MT-CO1-AVG region in patients with asthenozoospermia showed a decreasing tendency with increasing total sperm motility. A significant inverse correlation between the mtDNA copy number and total sperm motility was observed in patients with asthenozoospermia but not in controls with normozoospermia. In patients with asthenozoospermia, but not in controls with normozoospermia, we observed a significant inverse correlation between D-loop methylation levels and mtDNA copy number, while no significant correlation was observed between MT-CO1-AVG methylation levels and mtDNA copy number. CONCLUSION: These results reveal the occurrence of mtDNA methylation in human sperm and altered D-loop and MT-CO1-AVG methylation levels in patients with asthenozoospermia. Additional research is needed to determine the function of these features in the etiology and course of asthenozoospermia.

LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization.

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe-/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages.

Assessment of genes involved in lysosomal diseases using the ClinGen Clinical Validity framework.

Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs. Understanding the clinical validity of the role of a gene in a disease is critical for the development of genomic technologies, such as which genes to include on next generation sequencing panels, and the interpretation of results from exome and genome sequencing. To this aim, the ClinGen Lysosomal Diseases Gene Curation Expert Panel utilized a semi-quantitative framework incorporating genetic and experimental evidence to assess the clinical validity of the 56 LD-associated genes on the Lysosomal Disease Network's list. Here, we describe the results, and the key themes and challenges encountered.

Nitrous oxide emissions and soil profile responses to manure substitution in the North China Plain drylands.

Substituting synthetic fertilizers with manures in agriculture enhances soil properties and crop yield. However, the impact on nitrous oxide (N2O) emissions, especially from the soil profile, remains poorly understood. This study examined emissions from 2017 to 2019 on a well-established (>10-year) maize field site in the North China Plain. Three treatments were compared: 100 % synthetic nitrogen (NPK), 50 % synthetic fertilizer N + 50 % manure N substitution (50%MNS), and 100 % manure N substitution (100%MNS). N2O emissions were monitored for three years, and in 2019, N2O concentrations at 20 cm and 40 cm soil depths were analyzed in relation to surface N2O fluxes and environmental factors. The results showed manure substitution resulted in about 13.8 %-25.2 % (50%MNS) and 40.3 %-72.2 % (100%MNS) reduction in N2O emissions over the 3-year period compared with the NPK treatment. Throughout the maize growing season, the top-dressing accompanied by rainfall was responsible for the N2O emissions. The difference in N2O concentrations between all the treatments at 20 cm depth was insignificant, but at 40 cm depth the N2O concentrations were significantly higher for the 50%MNS treatment than the other treatments. The N2O fluxes and N2O concentration were not synchronized especially in NPK. The decoupled relationship between the N2O fluxes and the N2O concentration in the soil profile depth suggested the contribution of N2O produced in the soil profile to the surface N2O fluxes is limited. This study highlights that manure substitution is an efficient measure to reduce N2O emissions.

Interactive impact of landscape composition and configuration on river water quality under different spatial and seasonal scales.

Currently, the comprehensive effect of the landscape pattern on river water quality has been widely studied. However, the interactive influences of landscape type, namely composition (COM) and configuration (CON) on water quality variations, as well as the specific landscape driving types affecting water quality variations under different spatial and seasonal scales remain unclear. To further improve the effectiveness of landscape planning and water quality protection, this study collected monthly water samples from the Fengyu River Watershed in southwestern China from 2018 to 2021, the Biota-Environment Matching Analysis (Bioenv) was used to identify key metrics representing landscape COM and CON, respectively. Then, the multiple regression (MLR) and redundancy analysis (RDA) were used to explore the relationship between these landscape metrics and water quality. In addition, this study used a variation partitioning analysis (VPA) to quantify the interactive and independent influence of landscape COM and CON on water quality. Results revealed that construction land and the Shannon's diversity index (SHDI) were the key metrics of landscape COM and CON, respectively, for predicting water pollution concentrations. The interactive contribution was particularly sensitive to seasonal changes in riparian buffer areas (27.66 % to 48.73 %), while it remained relatively stable at the sub-watershed scale (38.22 % to 40.51 %). Moreover, landscape CON had a higher independent contribution to variations on water quality across most spatio-temporal scales. Overall, identifying and managing key landscape type and consequential metrics, matching with the spatio-temporal scale, holds promise for enhancing water quality conservation. Furthermore, this study provides valuable insights into the identification and selection of core landscape metrics.