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Background Stroke, as a major chronic non-communicable disease, seriously affects the health of the nation and imposes a heavy burden on patients, families and society. Alcohol consumption is common in China, and there is a close relationship between alcohol intake and stroke incidence, but the relationship between alcohol intake and stroke incidence is still controversial. Objective To investigate the relationship between alcohol intake and risk of stroke. Methods PubMed, Web of Science, Cochrane Library, Embase, CNKI, VIP, Wanfang Data, and SinoMed were searched for prospective cohort studies on the relationship between alcohol intake and risk of stroke from inception to December 2023. Literature screening, data extraction, and literature quality evaluation were performed independently by 2 researchers. Stata/MP 17.0 was used for dose-response meta-analysis. Results A total of 16 papers with 548 595 study subjects were included. Meta-analysis results showed that alcohol intake was associated with the risk of stroke (RR=1.17, 95%CI=1.10-1.26, P40 g increased the risk of stroke by 35% (RR=1.35, 95%CI=1.23-1.49, P

The characterization of product-related variants in monoclonal antibodies involves identifying and quantifying the size and charge of variants that can impact the activity, efficacy, and safety of the antibodies. These variants represent distinct molecular forms that may arise from processes such as fragmentation, dimerization, aggregation, or post-translational modifications. The characterization of variants typically involves isolating the relevant species using a semi-preparative scale HPLC system and analyzing them using various analytical techniques and biological assays. The commonly used analytical techniques include size-exclusion and ion-exchange chromatography, light scattering, mass spectrometry, capillary isoelectric focusing, and capillary electrophoresis-sodium dodecyl sulfate with ultraviolet or laser-induced fluorescence detection, among others. Additionally, functional assessments are performed using cell-based assays and binding assays to assess the biological activities of the variants. Identifying product-related variants through characterization enables the recognition of impurities that compromise the quality and safety of the drug., RECOMBINANT MONOCLONAL ANTIBODIES (mAbs) are biotherapeutics known for their high selectivity in binding to target antigens and inducing an immune response. Multiple structural variants may arise in mAbs due to [...]

In non-neuronal cells, clathrin has established roles in endocytosis, with clathrin cages enclosing plasma membrane infoldings, followed by rapid disassembly and reuse of monomers. However, in neurons, clathrin is conveyed in slow axonal transport over days to weeks, and the underlying transport/targeting mechanisms, mobile cargo structures, and even its precise presynaptic localization and physiologic role are unclear. Combining live imaging, photobleaching/conversion, mass spectrometry, electron microscopy, and super-resolution imaging, we found that unlike in dendrites, where clathrin cages rapidly assemble and disassemble, in axons, clathrin and related proteins organize into stable "transport packets" that are unrelated to endocytosis and move intermittently on microtubules, generating an overall slow anterograde flow. At synapses, multiple clathrin packets abut synaptic vesicle (SV) clusters, and clathrin packets also exchange between synaptic boutons in a microtubule-dependent "superpool." Within synaptic boundaries, clathrin is surprisingly dynamic, continuously exchanging between local clathrin assemblies, and its depletion impairs SV recycling. Our data provide a conceptual framework for understanding clathrin trafficking and presynaptic targeting that has functional implications.

Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of "sporadic" cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced nitrosative stress triggers protein aggregation and cell-to-cell spread. In patient brains with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), aggregation of the RNA-binding protein TDP-43 constitutes a major component of aberrant cytoplasmic inclusions. We identify a pathological signaling cascade whereby reactive nitrogen species cause S-nitrosylation of TDP-43 (forming SNO-TDP-43) to facilitate disulfide linkage and consequent TDP-43 aggregation. Similar pathological SNO-TDP-43 levels occur in postmortem human FTD/ALS brains and in cell-based models, including human-induced pluripotent stem cell (hiPSC)-derived neurons. Aggregated TDP-43 triggers additional nitrosative stress, representing positive feed forward leading to further SNO-TDP-43 formation and disulfide-linked oligomerization/aggregation. Critically, we show that these redox reactions facilitate cell spreading in vivo and interfere with the TDP-43 RNA-binding activity, affecting SNMT1 and phospho-(p)CREB levels, thus contributing to neuronal damage in ALS/FTD disorders.

Background: Mitochondrial dysfunction in the retina can induce apoptosis of retinal capillary cells, leading to diabetic retinopathy (DR). This study aimed to explore key genes related to programmed cell death (PCD) and mitochondria in DR via bioinformatic analysis. Methods: A differential analysis was performed to identify differentially expressed genes (DEGs) between DR and control samples using the GSE94019 dataset from the Gene Expression Omnibus (GEO) database. Pearson correlation analysis was then utilized to select genes linked to mitochondrial function and PCD (M-PCD). Candidate genes were identified by overlapping DR-DEGs and M-PCD genes, followed by functional annotation. Mendelian randomization (MR) analysis was employed to identify genes with causal relationships to DR. Key genes were identified through protein-protein interaction (PPI) analysis using six algorithms (DEgree, DMNC, EPC, MCC, Genes are BottleNeck, and MNC) within Cytoscape software. The expression patterns of these genes were validated using GSE94019 and GSE60436 datasets, as well as RT-qPCR. Enrichment analysis provided insights into the function and pathways of these key genes in DR. Differential immune cell profiles were determined via immune infiltration analysis, followed by exploring the relationships between immune cells, cytokines, and the identified genes. Correlations between key genes and apoptosis genes were also examined. In vivo experiments using RT-PCR, immunohistochemistry (IHC), and western blot analysis confirmed that MYC and SLC7A11 expression was significantly elevated in DR rat retinal tissues. Results: From 658 candidate genes, 12 showed significant causal associations with DR. MYC and SLC7A11 were particularly notable, showing upregulated expression in DR samples and involvement in apoptosis and diabetes-related pathways. These genes were significantly associated with apoptotic genes and correlated positively with altered immune cell types and cytokines, suggesting a link between immune response and DR pathogenesis. In vivo findings confirmed that MYC and SLC7A11 expression was elevated in DR rat retinal tissues. Conclusion: Key genes (MYC and SLC7A11) associated with mitochondrial function and PCD in DR were identified, offering insights into DR's pathological mechanisms and potential targets for diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Accurately identifying the distribution of vineyard cultivation is of great significance for the development of the grape industry and the optimization of planting structures. Traditional remote sensing techniques for vineyard identification primarily depend on machine learning algorithms based on spectral features. However, the spectral reflectance similarities between grapevines and other orchard vegetation lead to persistent misclassification and omission errors across various machine learning algorithms. As a perennial vine plant, grapes are cultivated using trellis systems, displaying regular row spacing and distinctive strip-like texture patterns in high-resolution satellite imagery. This study selected the main oasis area of Turpan City in Xinjiang, China, as the research area. First, this study extracted both spectral and texture features based on GF-6 satellite imagery, subsequently employing the Boruta algorithm to discern the relative significance of these remote sensing features. Then, this study constructed vineyard information extraction models by integrating spectral and texture features, using machine learning algorithms including Naive Bayes (NB), Support Vector Machines (SVMs), and Random Forests (RFs). The efficacy of various machine learning algorithms and remote sensing features in extracting vineyard information was subsequently evaluated and compared. The results indicate that three spectral features and five texture features under a 7 × 7 window have significant sensitivity to vineyard recognition. These spectral features include the Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI), and Normalized Difference Water Index (NDWI), while texture features include contrast statistics in the near-infrared band (B4_CO) and the variance statistic, contrast statistic, heterogeneity statistic, and correlation statistic derived from NDVI images (NDVI_VA, NDVI_CO, NDVI_DI, and NDVI_COR). The RF algorithm significantly outperforms both the NB and SVM models in extracting vineyard information, boasting an impressive accuracy of 93.89% and a Kappa coefficient of 0.89. This marks a 12.25% increase in accuracy and a 0.11 increment in the Kappa coefficient over the NB model, as well as an 8.02% enhancement in accuracy and a 0.06 rise in the Kappa coefficient compared to the SVM model. Moreover, the RF model, which amalgamates spectral and texture features, exhibits a notable 13.59% increase in accuracy versus the spectral-only model and a 14.92% improvement over the texture-only model. This underscores the efficacy of the RF model in harnessing the spectral and textural attributes of GF-6 imagery for the precise extraction of vineyard data, offering valuable theoretical and methodological insights for future vineyard identification and information retrieval efforts. [ABSTRACT FROM AUTHOR]

Grey matter (GM) atrophies are observed in multiple sclerosis, neuromyelitis optica spectrum disorders [NMOSD; both anti-aquaporin-4 antibody-positive (AQP4+) and -negative (AQP4−) subtypes] and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4− NMOSD and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicentre cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4− NMOSD, 47 patients with MOGAD and 2169 healthy control subjects. First, interregional GM atrophy profiles across the cortical and subcortical regions were determined using Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4− NMOSD or MOGAD and healthy controls. The GM atrophy profiles were then spatially correlated with the gene expression levels extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical-feature relevant GM atrophy using a subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden and cognitive function. Multiple sclerosis showed a severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed an obvious widespread pattern of GM atrophy, predominately located in occipital cortex as well as cerebellum. AQP4− NMOSD showed a mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD, had spatial correlations with GM atrophy profile, while no atrophy profile-related gene expression was found in AQP4− NMOSD. Virtual histology of clinical feature-relevant GM atrophy pointed mainly to the shared neuronal and endothelial cells, among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings may help the differential diagnoses of these diseases and promote the use of optimal therapeutic strategies. [ABSTRACT FROM AUTHOR]

Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d+/- retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of light-induced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.

The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.

The abundant variety of yeasts and their diverse applications have essential roles in traditional Mexican alcoholic beverage fermentation processes. During our investigation of yeast diversity associated with Pulque, 41 yeast strains were characterized. Among them, 31 strains were eight known species belonging to seven genera. According to morphological and phylogenetic analyses (ITS and LSU rDNA), ten unidentified yeast strains were identified to be three novel species and proposed: Starmerella elongatum sp. nov., Kazachstania paragamospora sp. nov. and Pichia teotihuacanensis sp. nov. Our study has resulted in the isolation of yeast species not previously detected in Pulque, expanding our knowledge of the diversity of its associated yeast communities. [ABSTRACT FROM AUTHOR]

Soil pH is crucial for the quality of the farmland and crop growth. The objective of this study is to analyze the spatial and temporal variations of farmland soil pH in Xinjiang (XJ), and to provide a scientific basis for soil improvement and agricultural production optimization. Based on soil pH data from XJ farmland in two periods, 2008~2010 and 2019~2021, geostatistical methods and kriging spatial interpolation techniques were employed to analyze the spatiotemporal changes in soil pH and to investigate the relationship between relevant influencing factors and pH over more than a decade. The results indicate that the spatiotemporal distribution of soil pH in XJ farmlands is uneven. Between 2019 and 2021, the average soil pH was 8.11, generally being on the higher side, with a coefficient of variation (CV) of 3.85%, indicating minimal spatial variability. In the farmland soil of Southern Xinjiang (S-XJ), the average pH value was 8.17, significantly higher than that of Northern Xinjiang (N-XJ), which was 8.10, demonstrating a spatial pattern of "higher in the south, lower in the north". Over the past decade, soil pH in XJ has significantly increased from 8.11 to 8.13, with a 0.05 unit increase in the north and a 0.01 unit increase in the south (p < 0.05). Regionally, Altay saw the largest increase of 0.22 units, while Bortala Mongol Autonomous Prefecture (Bortala) experienced the most significant decrease, dropping by 0.59 units. Furthermore, this study found that factors such as topography, nutrients, and irrigation methods all have certain influences on the spatial distribution of soil pH in XJ farmland, while variations in climate factors and fertilization levels may affect its long-term temporal changes. These research findings will provide new insights for adjusting and updating agricultural management measures related to soil pH regulation in XJ. [ABSTRACT FROM AUTHOR]

Recent studies have pointed to protein S-nitrosylation as a critical regulator of cellular redox homeostasis. For example, S-nitrosylation of peroxiredoxin-2 (Prx2), a peroxidase widely expressed in mammalian neurons, inhibits both enzymatic activity and protective function against oxidative stress. Here, using in vitro and in vivo approaches, we identify a role and reaction mechanism of the reductase sulfiredoxin (Srxn1) as an enzyme that denitrosylates (thus removing -SNO) from Prx2 in an ATP-dependent manner. Accordingly, by decreasing S-nitrosylated Prx2 (SNO-Prx2), overexpression of Srxn1 protects dopaminergic neural cells and human-induced pluripotent stem cell (hiPSC)-derived neurons from NO-induced hypersensitivity to oxidative stress. The pathophysiological relevance of this observation is suggested by our finding that SNO-Prx2 is dramatically increased in murine and human Parkinson's disease (PD) brains. Our findings therefore suggest that Srxn1 may represent a therapeutic target for neurodegenerative disorders such as PD that involve nitrosative/oxidative stress.

Actin cables, composed of actin filament bundles nucleated by formins, mediate intracellular transport for cell polarity establishment and maintenance. We previously observed that metaphase cells preferentially promote actin cable assembly through cyclin-dependent kinase 1 (Cdk1) activity. However, the relevant metaphase Cdk1 targets were not known. Here we show that the highly conserved actin filament crosslinking protein fimbrin is a critical Cdk1 target for actin cable assembly regulation in budding yeast. Fimbrin is specifically phosphorylated on threonine 103 by the metaphase cyclin-Cdk1 complex, in vivo and in vitro. On the basis of conformational simulations, we suggest that this phosphorylation stabilizes fimbrin's N-terminal domain, and modulates actin filament binding to regulate actin cable assembly and stability in cells. Overall, this work identifies fimbrin as a key target for cell cycle regulation of actin cable assembly in budding yeast, and suggests an underlying mechanism.