Association of ratios of visceral fat area/subcutaneous fat area and muscle area/standard body weight at T12 CT level with the prognosis of acute respiratory distress syndrome.

Background: It is well-known that body composition metrics can influence the prognosis of various diseases. This study investigated how body composition metrics predict acute respiratory distress syndrome (ARDS) prognosis, focusing on the ratio of visceral fat area (VFA) to subcutaneous fat area (SFA), SFA to standard body weight (SBW), VFA to SBW, and muscle area (MA) to SBW. These metrics were assessed at the level of the twelfth thoracic vertebra (T12 computed tomography [CT] level) to determine their correlation with the outcomes of ARDS. The goal was to utilize these findings to refine and personalize treatment strategies for ARDS. Methods: Patients with ARDS admitted to the intensive care units (ICUs) of three hospitals from January 2016 to July 2023 were enrolled in this study. Within 24 hours of ARDS onset, we obtained chest CT scans to measure subcutaneous fat, visceral fat, and muscle area at the T12 level. We then compared these ratios between survivors and non-survivors. Logistic regression was employed to identify prognostic risk factors. Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal cutoff for predictors of in-hospital mortality. Based on this cutoff, patients with ARDS were stratified. To reduce confounding factors, 1:1 propensity score matching (PSM) was applied. We conducted analyses of clinical feature and prognostic differences pre- and post-PSM between the stratified groups. Additionally, Kaplan-Meier survival curves were generated to compare the survival outcomes of these groups. Results: Of 258 patients with ARDS, 150 survived and 108 did not. Non-survivors had a higher VFA/SFA ratio (P <0.001) and lower SFA/SBW and MA/SBW ratios (both P <0.001). Key risk factors were high VFA/SFA ratio (OR=2.081; P=0.008), age, acute physiology and chronic health evaluation (APACHE) II score, and lactate levels, while MA/SBW and albumin were protective. Patients with a VFA/SFA ratio ≥0.73 were associated with increased mortality, while those with an MA/SBW ratio >1.55 cm²/kg had lower mortality, both pre- and post-PSM (P=0.001 and P <0.001, respectively). Among 170 patients with pulmonary-origin ARDS, 87 survived and 83 did not. The non-survivor group showed a higher VFA/SFA ratio (P <0.001) and lower SFA/SBW and MA/SBW (P=0.003, P <0.001, respectively). Similar risk and protective factors were observed in this cohort. For VFA/SFA, a value above the cutoff of 1.01 predicted higher mortality, while an MA/SBW value below the cutoff of 1.48 cm²/kg was associated with increased mortality (both P <0.001 pre-/post-PSM). Conclusions: Among all patients with ARDS, the VFA to SFA ratio, MA to SBW ratio at the T12 level, age, APACHE II score, and lactate levels emerged as independent risk factors for mortality.

Progress and trends of research on mineral elements for depression.

Objective: To explore the research progress and trends on mineral elements and depression. Methods: After querying the MeSH database and referring to the search rules, the search terms were selected and optimized to obtain the target literature collection. We analyzed the general characteristics of the literature, conducted network clustering and co-occurrence analysis, and carried out a narrative review of crucial literature. Results: Bipolar disorder was a dominant topic in the retrieved literature, which saw a significant increase in 2010 and 2019-2020. Most studies focused on mineral elements, including lithium, calcium, magnesium, zinc, and copper. The majority of journals and disciplines were in the fields of psychiatry, neuropsychology, neuropharmacology, nutrition, medical informatics, chemistry, and public health. The United States had the highest proportion in terms of paper sources, most-cited articles, high-frequency citations, frontier citations, and high centrality citation. Regarding the influence of academic institutions, the top five were King's College London, the Chinese Academy of Sciences, University of Barcelona, INSERM, and Heidelberg University. Frontier keywords included bipolar disorder, drinking water, (neuro)inflammation, gut microbiota, and systematic analysis. Research on lithium response, magnesium supplementation, and treatment-resistant unipolar depression increased significantly after 2013. Conclusion: Global adverse events may have indirectly driven the progress in related research. Although the literature from the United States represents an absolute majority, its influence on academic institutions is relatively weaker. Multiple pieces of evidence support the efficacy of lithium in treating bipolar disorder (BD). A series of key discoveries have led to a paradigm shift in research, leading to increasingly detailed studies on the role of magnesium, calcium, zinc, and copper in the treatment of depression. Most studies on mineral elements remain diverse and inconclusive. The potential toxicity and side effects of some elements warrant careful attention.

Impaired IL-27 signaling aggravates macrophage senescence and sensitizes premature ovarian insufficiency induction by high-fat diet.

Premature ovarian insufficiency (POI) critically affects female reproductive health, with obesity being a significant and recognized risk factor. Interleukin-27 (IL-27), known for its role in immune modulation and inflammation, has garnered attention in metabolic syndrome research. Nonetheless, the role of these immunometabolic factors on the initiation of POI remains to be unraveled. Our investigation delves into the influence of impaired IL-27 signaling on POI induction, particularly under the challenge of a high-fat diet (HFD). We analyzed patients' serum profiles and established a correlation of increased serum triglycerides with decreased IL-27 levels in POI cases. Experiments on C57BL/6 mice lacking the IL-27 receptor alpha (Il27ra-/-) revealed that when subjected to HFD, these mice developed hallmark POI symptoms. This includes escalated lipid deposition in both liver and ovarian tissues, increased ovarian macrophages cellular aging, and diminished follicle count, all pointing to compromised ovarian function. These findings unveil a novel pathway wherein impaired IL-27 signaling potentiates the onset of POI in the presence of HFD. Understanding the intricate interplay between IL-27, metabolic alterations, and immune dysregulation sheds light on potential therapeutic avenues for managing POI, offering hope for improved reproductive health outcomes.

ResSAT: Enhancing Spatial Transcriptomics Prediction from H&E- Stained Histology Images with Interactive Spot Transformer.

Spatial transcriptomics (ST) revolutionizes RNA quantification with high spatial resolution. Hematoxylin and eosin (H&E) images, the gold standard in medical diagnosis, offer insights into tissue structure, correlating with gene expression patterns. Current methods for predicting spatial gene expression from H&E images often overlook spatial relationships. We introduce ResSAT (Residual networks - Self-Attention Transformer), a framework generating spatially resolved gene expression profiles from H&E images by capturing tissue structures and using a self-attention transformer to enhance prediction.Benchmarking on 10× Visium datasets, ResSAT significantly outperformed existing methods, promising reduced ST profiling costs and rapid acquisition of numerous profiles.

ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

Effects of environmental phenols on eGFR: machine learning modeling methods applied to cross-sectional studies.

Purpose: Limited investigation is available on the correlation between environmental phenols' exposure and estimated glomerular filtration rate (eGFR). Our target is established a robust and explainable machine learning (ML) model that associates environmental phenols' exposure with eGFR. Methods: Our datasets for constructing the associations between environmental phenols' and eGFR were collected from the National Health and Nutrition Examination Survey (NHANES, 2013-2016). Five ML models were contained and fine-tuned to eGFR regression by phenols' exposure. Regression evaluation metrics were used to extract the limitation of the models. The most effective model was then utilized for regression, with interpretation of its features carried out using shapley additive explanations (SHAP) and the game theory python package to represent the model's regression capacity. Results: The study identified the top-performing random forest (RF) regressor with a mean absolute error of 0.621 and a coefficient of determination of 0.998 among 3,371 participants. Six environmental phenols with eGFR in linear regression models revealed that the concentrations of triclosan (TCS) and bisphenol S (BPS) in urine were positively correlated with eGFR, and the correlation coefficients were ß = 0.010 (p = 0.026) and ß = 0.007 (p = 0.004) respectively. SHAP values indicate that BPS (1.38), bisphenol F (BPF) (0.97), 2,5-dichlorophenol (0.87), TCS (0.78), BP3 (0.60), bisphenol A (BPA) (0.59) and 2,4-dichlorophenol (0.47) in urinary contributed to the model. Conclusion: The RF model was efficient in identifying a correlation between phenols' exposure and eGFR among United States NHANES 2013-2016 participants. The findings indicate that BPA, BPF, and BPS are inversely associated with eGFR.

Unlocking potential of oxytocin: improving intracranial lymphatic drainage for Alzheimer's disease treatment.

Background: The impediment to ß-amyloid (Aß) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. Methods: The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. Results: Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aß from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. Conclusion: This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.

Ceas: An R package for Seahorse data analysis and visualization.

SUMMARY: Measuring cellular energetics is essential to understanding a matrix's (e.g. cell, tissue or biofluid) metabolic state. The Agilent Seahorse machine is a common method to measure real-time cellular energetics, but existing analysis tools are highly manual or lack functionality. The Cellular Energetics Analysis Software (ceas) R package fills this analytical gap by providing modular and automated Seahorse data analysis and visualization. AVAILABILITY AND IMPLEMENTATION: Ceas is available on CRAN (https://cran.r-project.org/package=ceas). Source code and installable tarballs are freely available for download at https://github.com/jamespeapen/ceas/releases/ under the MIT license. Package documentation may be found at https://jamespeapen.github.io/ceas/. ceas is implemented in R and is supported on macOS, Windows and Linux. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Dynamic evolution of MADS-box genes in extant ferns via large-scale phylogenomic analysis.

Introduction: Several studies of MADS-box transcription factors in flowering plants have been conducted, and these studies have indicated that they have conserved functions in floral organ development; MIKC-type MADS-box genes has been proved to be expanded in ferns, however, few systematic studies of these transcription factors have been conducted in non-seed plants. Although ferns and seed plants are sister groups, they exhibit substantial morphological differences. Methods: Here, we clarified the evolution of MADS-box genes across 71 extant fern species using available transcriptome, genome, and gene expression data. Results: We obtained a total of 2,512 MADS-box sequences, ranging from 9 to 89 per species. The most recent common ancestor (MRCA) of ferns contained approximately three type I genes and at least 5-6 type II MADS-box genes. The domains, motifs, expression of type I and type II proteins, and the structure of the both type genes were conserved in ferns as to other land plants. Within type II genes, MIKC*-type proteins are involved in gametophyte development in ferns; MIKCC-type proteins have broader expression patterns in ferns than in seed plants, and these protein sequences are likely conserved in extant seed plants and ferns because of their diverse roles in diploid sporophyte development. More than 90% of MADS-box genes are type II genes, and MIKCC genes, especially CRM1 and CRM6-like genes, have undergone a large expansion in leptosporangiate ferns; the diverse expression patterns of these genes might be related to the fuctional diversification and increased complexity of the plant body plan. Tandem duplication of CRM1 and CRM6-like genes has contributed to the expansion of MIKCC genes. Conclusion or Discussion: This study provides new insights into the diversity, evolution, and functions of MADS-box genes in extant ferns.

Activation of α7 Nicotinic Acetylcholine Receptor Improves Muscle Endurance by Upregulating Orosomucoid Expression and Glycogen Content in Mice.

There are presently no acknowledged therapeutic targets or official drugs for the treatment of muscle fatigue. The alpha7 nicotinic acetylcholine receptor (α7nAChR) is expressed in skeletal muscle, with an unknown role in muscle endurance. Here, we try to explore whether α7nAChR could act as a potential therapeutic target for the treatment of muscle fatigue. Results showed that nicotine and PNU-282987 (PNU), as nonspecific and specific agonists of α7nAChR, respectively, could both significantly increase C57BL6/J mice treadmill-running time in a time- and dose-dependent manner. The improvement effect of PNU on running time and ex vivo muscle fatigue index disappeared when α7nAChR deletion. RNA sequencing revealed that the differential mRNAs affected by PNU were enriched in glycolysis/gluconeogenesis signaling pathways. Further studies found that PNU treatment significantly elevates glycogen content and ATP level in the muscle tissues of α7nAChR+/+ mice but not α7nAChR-/- mice. α7nAChR activation specifically increased endogenous glycogen-targeting protein orosomucoid (ORM) expression both in vivo skeletal muscle tissues and in vitro C2C12 skeletal muscle cells. In ORM1 deficient mice, the positive effects of PNU on running time, glycogen and ATP content, as well as muscle fatigue index, were abolished. Therefore, the activation of α7nAChR could enhance muscle endurance via elevating endogenous anti-fatigue protein ORM and might act as a promising therapeutic strategy for the treatment of muscle fatigue.

Tropism-shifted AAV-PHP.eB-mediated bFGF gene therapy promotes varied neurorestoration after ischemic stroke in mice.

ABSTRACT: AAV-PHP.eB is an artificial adeno-associated virus (AAV) that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically. While AAV-PHP.eB has been used in various disease models, its cellular tropism in cerebrovascular diseases remains unclear. In the present study, we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor (bFGF) gene therapy. Mice were injected intravenously with AAV-PHP.eB either 14 days prior to (pre-stroke) or 1 day following (post-stroke) transient middle cerebral artery occlusion. Notably, we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen (mNG). This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A (Ly6A). Furthermore, AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke. Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.

A transient transcriptional activation governs unpolarized-to-polarized morphogenesis during embryo implantation.

During implantation, embryos undergo an unpolarized-to-polarized transition to initiate postimplantation morphogenesis. However, the underlying molecular mechanism is unknown. Here, we identify a transient transcriptional activation governing embryonic morphogenesis and pluripotency transition during implantation. In naive pluripotent embryonic stem cells (ESCs), which represent preimplantation embryos, we find that the microprocessor component DGCR8 can recognize stem-loop structures within nascent mRNAs to sequester transcriptional coactivator FLII to suppress transcription directly. When mESCs exit from naive pluripotency, the ERK/RSK/P70S6K pathway rapidly activates, leading to FLII phosphorylation and disruption of DGCR8/FLII interaction. Phosphorylated FLII can bind to transcription factor JUN, activating cell migration-related genes to establish poised pluripotency akin to implanting embryos. Resequestration of FLII by DGCR8 drives poised ESCs into formative pluripotency. In summary, we identify a DGCR8/FLII/JUN-mediated transient transcriptional activation mechanism. Disruption of this mechanism inhibits naive-poised-formative pluripotency transition and the corresponding unpolarized-to-polarized transition during embryo implantation, which are conserved in mice and humans.

Sleep Deprivation Triggers Mitochondrial DNA Release in Microglia to Induce Neural Inflammation: Preventative Effect of Hydroxytyrosol Butyrate.

Sleep deprivation (SD) triggers mitochondrial dysfunction and neural inflammation, leading to cognitive impairment and mental issues. However, the mechanism involving mitochondrial dysfunction and neural inflammation still remains unclear. Here, we report that SD rats exhibited multiple behavioral disorders, brain oxidative stress, and robust brain mitochondrial DNA (mtDNA) oxidation. In particular, SD activated microglia and microglial mtDNA efflux to the cytosol and provoked brain pro-inflammatory cytokines. We observed that the mtDNA efflux and pro-inflammatory cytokines significantly reduced with the suppression of the mtDNA oxidation. With the treatment of a novel mitochondrial nutrient, hydroxytyrosol butyrate (HTHB), the SD-induced behavioral disorders were significantly ameliorated while mtDNA oxidation, mtDNA release, and NF-κB activation were remarkably alleviated in both the rat brain and the N9 microglial cell line. Together, these results indicate that microglial mtDNA oxidation and the resultant release induced by SD mediate neural inflammation and HTHB prevents mtDNA oxidation and efflux, providing a potential treatment for SD-induced mental issues.

Multi-scale variational autoencoder for imputation of missing values in untargeted metabolomics using whole-genome sequencing data.

BACKGROUND: Missing data is a common challenge in mass spectrometry-based metabolomics, which can lead to biased and incomplete analyses. The integration of whole-genome sequencing (WGS) data with metabolomics data has emerged as a promising approach to enhance the accuracy of data imputation in metabolomics studies. METHOD: In this study, we propose a novel method that leverages the information from WGS data and reference metabolites to impute unknown metabolites. Our approach utilizes a multi-scale variational autoencoder to jointly model the burden score, polygenetic risk score (PGS), and linkage disequilibrium (LD) pruned single nucleotide polymorphisms (SNPs) for feature extraction and missing metabolomics data imputation. By learning the latent representations of both omics data, our method can effectively impute missing metabolomics values based on genomic information. RESULTS: We evaluate the performance of our method on empirical metabolomics datasets with missing values and demonstrate its superiority compared to conventional imputation techniques. Using 35 template metabolites derived burden scores, PGS and LD-pruned SNPs, the proposed methods achieved R2-scores > 0.01 for 71.55 % of metabolites. CONCLUSION: The integration of WGS data in metabolomics imputation not only improves data completeness but also enhances downstream analyses, paving the way for more comprehensive and accurate investigations of metabolic pathways and disease associations. Our findings offer valuable insights into the potential benefits of utilizing WGS data for metabolomics data imputation and underscore the importance of leveraging multi-modal data integration in precision medicine research.

Genome-wide data reveal bi-direction and asymmetrical hybridization origin of a fern species Microlepia matthewii.

Introduction: Natural hybridization is common and plays a crucial role in driving biodiversity in nature. Despite its significance, the understanding of hybridization in ferns remains inadequate. Therefore, it is imperative to study fern hybridization to gain a more comprehensive understanding of fern biodiversity. Our study delves into the role of hybridization in shaping fern species, employing Microlepia matthewii as a case study to investigate its origins of hybridization. Methods: We performed double digest Genotyping-by-sequencing (dd-GBS) on M. matthewii and its potential parent species, identifying nuclear and chloroplast SNPs. Initially, nuclear SNPs were employed to construct the three cluster analysis: phylogenetic tree, principal component analysis, and population structure analysis. Subsequently, to confirm whether the observed genetic mixture pattern resulted from hybridization, we utilized two methods: ABBA-BABA statistical values in the D-suite program and gene frequency covariance in the Treemix software to detect gene flow. Finally, we employed chloroplast SNPs to construct a phylogenetic tree, tracing the maternal origin. Results and discussion: The analysis of the nuclear SNP cluster revealed that M. matthewii possesses a genetic composition that is a combination of M. hancei and M. calvescens. Furthermore, the analysis provided strong evidence of significant gene flow signatures from the parental species to the hybrid, as indicated by the two gene flow analyses. The samples of M. matthewii cluster separately with M. hancei or M. calvescens on the chloroplast systematic tree. However, the parentage ratio significantly differs from 1:1, suggesting that M. matthewii is a bidirectional and asymmetrical hybrid offspring of M. hancei and M. calvescens.

Sex differences in motor learning flexibility are accompanied by sex differences in mushroom spine pruning of the mouse primary motor cortex during adolescence.

Background: Although males excel at motor tasks requiring strength, females exhibit greater motor learning flexibility. Cognitive flexibility is associated with low baseline mushroom spine densities achieved by pruning which can be triggered by α4ßδ GABAA receptors (GABARs); defective synaptic pruning impairs this process. Methods: We investigated sex differences in adolescent pruning of mushroom spine pruning of layer 5 pyramidal cells of primary motor cortex (L5M1), a site essential for motor learning, using microscopic evaluation of Golgi stained sections. We assessed α4GABAR expression using immunohistochemical and electrophysiological techniques (whole cell patch clamp responses to 100 nM gaboxadol, selective for α4ßδ GABARs). We then compared performance of groups with different post-pubertal mushroom spine densities on motor learning (constant speed) and learning flexibility (accelerating speed following constant speed) rotarod tasks. Results: Mushroom spines in proximal L5M1 of female mice decreased >60% from PND35 (puberty onset) to PND56 (Pubertal: 2.23 ± 0.21 spines/10 µm; post-pubertal: 0.81 ± 0.14 spines/10 µm, P < 0.001); male mushroom spine density was unchanged. This was due to greater α4ßδ GABAR expression in the female (P < 0.0001) because α4 -/- mice did not exhibit mushroom spine pruning. Although motor learning was similar for all groups, only female wild-type mice (low mushroom spine density) learned the accelerating rotarod task after the constant speed task (P = 0.006), a measure of motor learning flexibility. Conclusions: These results suggest that optimal motor learning flexibility of female mice is associated with low baseline levels of post-pubertal mushroom spine density in L5M1 compared to male and female α4 -/- mice.

Crosstalk between skeletal muscle ratio and cholesterol metabolism disorders: a cross-section study.

BACKGROUND: Dysfunction of cholesterol metabolism may be associated with low skeletal muscle mass.  This study aimed to explore the relationship between skeletal muscle mass and cholesterol metabolic disorders in adults. METHODS: The data of a total of 5949 people with complete medical history data, biochemical data and body composition analysis were recruited. According to the serum cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and nonHDL, the population was divided into a disorder group and a normal group. Independent sample t tests, chi-square tests, Pearson's correlation analyses and binary logistic regression analyses were used to study the effect of body composition on abnormal cholesterol metabolism. According to BMI and sex, the population was divided into different subgroups, and binary logistic regression analysis was used to study the effect of the skeletal mass ratio on cholesteral metabolic disorders in different subgroups. RESULTS: There were significant differences in sex, alcohol consumption, body weight, BMI, skeletal muscle mass index (SMI) [total skeletal muscle mass (kg)/height 2 (m2)] and skeletal muscle mass ratio (SMR) [total skeletal muscle mass (kg)/weight (kg) *100] between the disorder group (hypercholesterolemia, hyper-LDL, lower-HDL and hyper-nonHDL) and the normal group. Pearson correlation analysis revealed that the SMR was negatively correlated, while the SMI was positively correlated with cholesterol metabolic disorders in both sexes. The overweight group was older and had a greater SMI, abnormal cholesteral metabolism ratio and lower SMR than the normal-weight group. In the normal-weight group, the SMR was an independent protective factor against different kinds of cholesteral metabolic disorders in both sexes, while the SMI was a risk factor. In the overweight subgroup, the protective effect on HDL and nonHDL metabolism remained in the male subgroup but disappeared in the female subgroup. However, the SMI was an independent risk factor for different kinds of cholesteral metabolic disorders in both sexes. CONCLUSIONS: SMR was an independent protective factor against cholesterol metabolic disorders in both males and females, especially in the normal weight group. SMI was an independent risk factor, especially in the overweight group.

Dissecting the shared genetic architecture between anti-Müllerian hormone and age at menopause based on genome-wide association study.

BACKGROUND: While the phenotypic association between anti-Müllerian hormoneand age at menopause has been widely studied, the role of anti-Müllerian hormone in predicting the age at menopause is currently controversial, and the genetic architecture or causal relationships underlying these 2 traits is not well understood. AIM: We aimed to explore the shared genetic architecture between anti-Müllerian hormone and age at menopause, to identify shared pleiotropic loci and genes, and to investigate causal association and potential causal mediators. STUDY DESIGN: Using summary statistics from publicly available genome-wide association studies on anti-Müllerian hormone (N=7049) and age at menopause (N=201,323) in Europeans, we investigated the global genetic architecture between anti-Müllerian hormone and age at menopause through linkage disequilibrium score regression. We employed pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation of Genetic Associations, multimarker analysis of GenoMic annotation, and colocalization analysis to identify loci and genes with pleiotropic effects. Tissue enrichment analysis based on Genotype-Tissue Expression data was conducted using the Linkage Disequilibrium Score for the specific expression of genes analysis. Functional genes that were shared were additionally identified through summary data-based Mendelian randomization. The relationship between anti-Müllerian hormone and age at menopause was examined through 2-sample Mendelian randomization, and potential mediators were further explored using colocalization and metabolite-mediated analysis. RESULTS: A positive genetic association (correlation coefficient=0.88, P=1.33×10-5) was observed between anti-Müllerian hormone and age at menopause. By using pleiotropic analysis under composite null hypothesis and Functional Mapping and Annotation of Genetic Associations, 42 significant pleiotropic loci were identified that were associated with anti-Müllerian hormone and age at menopause, and 10 of these (rs10734411, rs61913600, rs2277339, rs75770066, rs28416520, rs9796, rs11668344, rs403727, rs6011452, and rs62237617) had colocalized loci. Additionally, 245 significant pleiotropic genes were identified by multimarker analysis of GenoMic annotation. Genetic associations between anti-Müllerian hormone and age at menopause were markedly concentrated in various tissues including whole blood, brain, heart, liver, muscle, pancreas, and kidneys. Further, summary data-based Mendelian randomization analysis revealed 9 genes that may have a causative effect on both anti-Müllerian hormone and age at menopause. A potential causal effect of age at menopause on anti-Müllerian hormone was suggested by 2-sample Mendelian randomization analysis, with very-low-density lipoprotein identified as a potential mediator. CONCLUSION: Our study revealed a shared genetic architecture between anti-Müllerian hormone and age at menopause, providing a basis for experimental investigations and individual therapies to enhance reproductive outcomes. Furthermore, our findings emphasized that relying solely on anti-Müllerian hormone is not sufficient for accurately predicting the age at menopause, and a combination of other factors needs to be considered. Exploring new therapeutics aimed at delaying at the onset of menopause holds promise, particularly when targeting shared genes based on their shared genetic architecture.

Stromal mediated DNA damage promotes high grade serous ovarian cancer initiation.

The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, thus providing critical barriers to the development of prevention or early detection strategies for this deadly disease. Increasing evidence demonstrates most HGSOC starts in the fallopian tube epithelium (FTE). Current models propose HGSOC initiates when FTE cells acquire increasing numbers of mutations allowing cells to evolve into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer. Here we report that epigenetically altered mesenchymal stem cells (termed high risk MSC-hrMSCs) can be detected prior to the formation of ovarian cancer precursor lesions. These hrMSCs drive DNA damage in the form of DNA double strand breaks in FTE cells while also promoting the survival of FTE cells in the face of DNA damage. Indicating the hrMSC may actually drive cancer initiation, we find hrMSCs induce full malignant transformation of otherwise healthy, primary FTE resulting in metastatic cancer in vivo . Further supporting a role for hrMSCs in cancer initiation in humans, we demonstrate that hrMSCs are highly enriched in BRCA1/2 mutation carriers and increase with age. Combined these findings indicate that hrMSCs may incite ovarian cancer initiation. These findings have important implications for ovarian cancer detection and prevention.

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer's Disease in Human Prefrontal Cortex at Single-Nucleus Resolution.

Aging significantly elevates the risk for Alzheimer's disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-ß (Aß), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aß clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aß plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.