👤 Yong Shi

While family resilience is a recognized determinant of adaptation following stroke, the distinct, empirically derived profiles of family resilience among Chinese stroke survivor-caregiver dyads have not been clearly delineated. Identifying these profiles and their determinants is crucial for developing targeted interventions. To identify latent profiles of family resilience and examine the socio-demographic and clinical factors associated with profile membership among stroke patient-caregiver dyads in China. In this cross-sectional study, a convenience sample of 773 stroke survivor-caregiver dyads was recruited from three hospitals in Zhejiang Province, China. Latent profile analysis (LPA) was conducted on the 20-item Family Resilience Questionnaire (FRQ). Multinomial logistic regression was used to determine factors associated with profile membership. LPA supported a four-profile solution: Profile 1 "Low-Functioning Families" (22%), Profile 2 "Moderately Resilient - Low Cohesive Families" (24%), Profile 3 "Highly Resilient - Well-Functioning Families" (31%), and Profile 4 "High-Functioning - Optimistically Resilient Families" (24%). Multinomial logistic regression revealed that lower caregiver competence (higher FCTI scores) was strongly associated with profile membership (standardized aORs ranged from 2.58 to 43.19), whereas higher perceived social support (PSSS) was a significant protective factor (standardized aORs ranged from 0.03 to 0.19). Caregiver relationship and payment source were also significantly associated with profile membership. Family resilience among Chinese stroke families manifests in four distinct profiles, which are differentiated predominantly by caregiver competence and perceived social support. Our findings advocate for a precision family support paradigm, shifting from one-size-fits-all approaches to interventions tailored to distinct resilience profiles. Given the strong association, intervention programs should prioritize enhancing core caregiver competencies as a primary leverage point for building family resilience. Show less

Illness perceptions have been associated with outcomes in patients with atrial fibrillation (AF). This study aimed to identify distinct illness perception profiles in patients with AF and examine their associations with psychological and physical responses. A total of 150 patients with AF were enrolled in this study. Illness perception profiles were identified using latent profile analysis (LPA). Model fit indices were evaluated to determine the optimal class solution. Logistic regression analyses were conducted to examine the associations between illness perception profiles and psychological and physical outcomes, including Generalized anxiety disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), 12-Item Short Form Health Survey (SF-12) and University of Toronto atrial fibrillation severity scale (AFSS). A two-class model was identified as optimal, comprising a "Reactive-Minimizing" profile (Class 1, 49%) and a "Symptom-Helplessness" profile (Class 2, 51%). Univariate logistic analysis revealed significant differences between classes in age, AF type, work status, PHQ-9, AFSS-symptoms, and AFSS-burden. In the multivariable logistic regression adjusted for age and sex (logistic outcome: Class 2 vs. Class 1), higher AFSS-burden scores were independently associated with the "Symptom-Helplessness" profile (OR = 1.26, 95% CI: 1.09-1.45, p = 0.001). Conversely, higher PHQ-9 scores were associated with the "Reactive-Minimizing" profile (OR for Symptom-Helplessness = 0.92, 95% CI: 0.86-0.99, p = 0.018). Person-centered illness perception profiling revealed two distinct cognitive-emotional patterns in patients with AF that were associated with depressive symptoms and symptom burden, highlighting their potential value for individualized psychological and clinical management. Show less

Peripheral artery disease (PAD) is a major manifestation of systemic atherosclerosis and affects vascular health in older adults. Dyslipidaemia contributes significantly to PAD, but the predictive value of composite lipid indices remains unclear. The non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) reflects the balance between atherogenic and protective lipoproteins. This study aimed to explore the association between the NHHR and PAD among vascular surgery inpatients aged ≥50 years in Kunshan, China. This retrospective cross-sectional study included 3,532 patients (aged ≥ 50 years) hospitalized at the Affiliated Kunshan Hospital of Jiangsu University, Suzhou, from December 2017 to August 2024. NHHR, calculated as (total cholesterol - HDL-C)/HDL-C, was the exposure variable; PAD, defined as PAD-like symptoms with an ankle brachial index < 0.9, was the outcome. Covariates included age, sex, lipoprotein(a) level [Lp(a)], apolipoprotein A1 level (Apo A1), alanine aminotransferase (ALT) level, neutrophil count (NEUT), hypertension status, diabetes status, smoking status, and alcohol consumption status. Multivariate logistic regression, smooth curve fitting, and threshold analyses were performed. After adjustment for confounders, the NHHR was nonlinearly associated with PAD (OR = 0.77; 95% CI: 0.65-0.93; The NHHR was associated with the presence of PAD, with the evidence suggesting a nonlinear relationship and potential sex-specific differences. Given the retrospective cross-sectional design, this association does not support causal inference or strong predictive claims. The NHHR may help identify individuals who could benefit from further clinical evaluation for PAD, but prospective studies are needed to confirm its clinical relevance before its routine application. Show less

To investigate the dose-response relationship between e-health literacy and light physical activity (LPA) in older adults is to provide evidence for targeted interventions that enhance e-health literacy and promote LPA, thereby advancing healthy aging. This study used a convenience sampling method to select two residential neighborhoods. Subsequently, a random cluster sampling approach was employed, resulting in a total final sample of 105 community-dwelling older adults (aged 60 and above) from these neighborhoods. A three-axis accelerometer (ActiGraph wGT3X-BT) recorded the older adults' LPA, and the Electronic Health Literacy Scale assessed their e-health literacy. Multiple linear regression was used to explore the dose-response relationship between LPA and e-health literacy and sub-dimension scores. Multiple linear regression revealed that both the overall e-health literacy score and its components were positively associated with daily LPA (Tables 2 and 3). However, the empirical impact varied substantially across components. For each 1-point increase, LPA increased by 2.8 min for the overall score, 11 min for judgment ability, and 19.4 min for decision-making ability, whereas the effect of application ability was statistically significant but minimal. Notably, the effect sizes of all e-health literacy components were substantially smaller than that of educational attainment (β = 0.638-0.947), which was the strongest predictor in all models. This study provides empirical evidence that higher e-health literacy and its specific sub-dimensions are positively associated with light physical activity (LPA) among community-dwelling older adults, with educational attainment emerging as a key independent predictor. These findings suggest that public health interventions aimed at promoting LPA could be enhanced by incorporating strategies to improve e-health literacy, particularly targeting older adults with lower educational backgrounds. The development of tailored, theory-informed programs based on these insights holds promise for fostering healthy aging at the community level. Show less

Accumulating research has demonstrated a significant association between early-life inflammation and behavioral disorders later in life. However, the effects of early-life inflammation on aggressive behavior in adulthood remain poorly understood. Here, we show that early-life inflammation induced by lipopolysaccharide (LPS) upregulated neuronal dynamin-related protein 1 (DRP1) and impaired mitochondrial function in medial prefrontal cortex (mPFC) of adult mice, thereby increasing aggressive behavior in adulthood. We further identify that CCAAT/enhancer binding protein β (C/EBPβ) is the transcription factor of Dnm1l, which was activated by an increased release of lysophosphatidic acid (LPA) induced by early-life inflammation. Moreover, the overproduction of LPA was due to a specific increase in astrocyte-secreted autotaxin (ATX). Specific knockdown of astrocytic ATX reduced early-life inflammation-induced aggression in wild-type mice, but not in Thy1-C/EBPβ transgenic mice. Remarkably, coenzyme Q10 decreased early-life inflammation-induced aggressive behavior in adult mice. Altogether, these findings provide new insights into the molecular mechanisms by which early inflammation promotes aggressive behavior in adulthood. Show less

Intramuscular fat (IMF) is a key determinant of meat quality, influencing tenderness, juiciness, and flavor. Previous studies have reported that the deposition of IMF is controlled by various factors. However, there is a shortage of research exploring the variations in IMF deposition across age groups from a microbial perspective. This study evaluated the differences in IMF deposition between yearling (1-year-old) and mature (4-year-old) Longdong Cashmere goats and analyzed its association with gut microbiota. The results revealed that the IMF content in shoulder meat and blood lipid levels increased with age (p < 0.05). Conversely, the contents of lipoprotein lipase (LPL) in the liver and duodenum significantly decreased with age. Microbial diversity differed between the two age groups, with specific microbiota identified from the gut of goats involved in the lipid metabolism pathway. The concentrations of valeric and isovaleric acids in the rumen, as well as acetic, propionic and isovaleric acids in the colon, were higher in yearling goats than in mature goats (p < 0.05). Spearman correlation analysis of IMF deposition indicators with gut microbiota revealed that, within the rumen, the abundances of CAG-791 and Sodaliphilus were positively correlated with IMF content in shoulder meat and TG levels, while exhibiting a negative correlation with the contents of valeric acids. Furthermore, the abundance of Clostridium_R showed a positive association with IMF content in shoulder meat and with the abundances of CAG-791and Sodaliphilus. In contrast, the abundance of Bact₁₁ was negatively correlated with IMF content in shoulder meat, TG levels, and the abundances of CAG-791, Sodaliphilus and Clostridium_R. Within the abomasum, the abundances of UMGS and Hylemonella₅₈₂₃₀₈ were correlated with IMF content in the shoulder meat, as well as serum LDL and VLDL levels. This study provides significant insights into the age-dependent gut microbiota associated with intramuscular fat deposition in goats and identifies several potential gut microbiota for further research on their impacts on IMF deposition. Show less

Organic and organic-inorganic hybrid materials exhibiting room-temperature phosphorescence (RTP) and long persistent luminescence (LPL) materials have attracted growing attention for various time-resolved optoelectronic applications. To date, realizing intrinsically distinct RTP and LPL emissions within a single material system remains elusive, yet it is crucial for unlocking multifunctional applications such as multilevel optical encryption. Here, a Mn Show less

This study induced diabetic nephropathy (DN) in rats, analyzing perirenal adipose tissue (PRAT) via whole transcriptome sequencing to identify key mRNAs in DN pathogenesis. Type-2 diabetes was induced in SD rats, evaluating metabolic and renal indicators. Whole transcriptome sequencing identified differentially expressed RNAs in PRAT. CeRNA networks, PPI networks, and ingenuity pathway analysis (IPA) revealed key mRNAs linked to physiological indicators in DN. This study explores correlations between mRNAs and health parameters, shedding light on the complex interplay in type-2-diabetes mellitus (T2DM)-induced nephropathy. SD rats with type-2 diabetes exhibited insulin resistance, elevated blood glucose, disrupted lipid metabolism, and renal dysfunction. PRAT weight was higher in T2DM rats, and immunohistochemistry revealed distinct renal injury. Transcriptome sequencing identified 476 DE-mRNAs, 79 DE-miRNAs, 200 DE-lncRNAs, and 10 DE-circRNAs. The lncRNA-miRNA-mRNA network comprised 159 lncRNAs, 62 miRNAs, and 138 mRNAs, whereas the circRNA-miRNA-mRNA network included 76 mRNAs, 27 miRNAs, and 10 circRNAs. Key mRNAs (Lpl, Elovl6, Dgat2, Acaca, and Acly) were associated with 10 classical pathways according to IPA. Notably, all key mRNAs showed a negative correlation with blood urea nitrogen (BUN), serum creatinine, proteinuria, LDL-C, triglycerides (TG), and total cholesterol (TC), and a positive correlation with urine creatinine and HDL-C. Our study successfully established a T2DM model in SD rats and identified five key mRNAs, elucidating the role of PRAT in DN. These findings lay a scientific foundation for future investigations into DN. Show less

We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations. In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants. Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1. Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA. Show less

The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis. Show less

Inhibitors of the menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged leukemias. We evaluated menin inhibition in patient-derived xenografts of KMT2A-rearranged leukemias with high-risk features. Three acute myeloid leukemias with high-risk fusion partners (mixed-lineage leukemia-10 [MLLT10] and mixed-lineage leukemia-4 [MLLT4]) and two infant acute lymphocytic leukemia (ALL) samples were sensitive to menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A::AFF1 ALL samples were much less sensitive compared with cells obtained earlier in the same patients' disease course. Because none of the patients had been treated with a menin inhibitor, resistance in these highly pretreated samples was acquired in the absence of menin-inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy toward the canonical targets of the menin inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple comutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patient; inactivation of KMT2C/D has been reported to result in menin-inhibitor resistance, and KMT2C-edited cells from this patient were selected for in menin-inhibitor-containing growth conditions. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data support using menin inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred. Show less

Renal tubulointerstitial fibrosis (TIF) is a hallmark pathological feature of diabetic kidney disease (DKD). This study investigates the role and molecular mechanisms of retinol saturase (RetSat) in DKD-associated TIF. RetSat expression was assessed in renal tissues from DKD patients and mice and correlated with the severity of TIF. Functional experiments were conducted RetSat expression was significantly up regulated in the renal tissues of both DKD patients and mice, correlating with the deterioration of TIF. These findings indicate that RetSat promotes TIF in DKD by disrupting the Smurf2-ChREBP ubiquitination axis, highlighting RetSat as a promising therapeutic target for DKD. Show less

Neuropathic pain (NP), a chronic disorder caused by somatosensory nervous system lesions, severely impairs the quality of life. Microglial metabolic reprogramming and neuroinflammation drive NP progression. Although ChREBP (key metabolic regulator) protects against NP, its specific mechanisms remain unclear. NP rat model was established via spared nerve injury (SNI) surgery, and mechanical allodynia was evaluated using Von Frey tests. ChREBP expression in microglia was detected through immunofluorescence, RT-qPCR, and western blot. Functional studies involved ChREBP knockdown/overexpression to assess effects on microglial polarization, neuroinflammation, neuronal excitability, pain behaviors, and fatty acid metabolism. Mechanisms were explored via dual-luciferase reporter and chromatin immunoprecipitation assays. Mechanical pain thresholds were significantly decreased on the ipsilateral side after SNI. ChREBP was upregulated in SDH microglia after SNI and in LPS-stimulated microglia in vitro. ChREBP knockdown inhibited anti-inflammatory microglial polarization, exacerbated neuroinflammation, and aggravated pain. Conversely, ChREBP overexpression promoted the anti-inflammatory phenotype, suppressed neuroinflammation, and alleviated pain. ChREBP enhanced microglial fatty acid oxidation and energy metabolism. Mechanistically, ChREBP bound to the TFBS1 site on the PGC-1α promoter to activate its transcription. PGC-1α overexpression rescued the impairments caused by ChREBP knockdown, including reduced fatty acid oxidation, suppressed anti-inflammatory polarization, elevated inflammatory factors, and increased neuronal excitability. The protective effects of ChREBP were attenuated by the fatty acid oxidation inhibitor Etomoxir. ChREBP alleviates NP by enhancing microglial fatty acid oxidation and anti-inflammatory phenotype via PGC-1α transcriptional activation, revealing a novel metabolic-immune axis for potential NP therapy. Show less

Sevoflurane, a widely used volatile anesthetic, has raised concerns regarding its potential developmental toxicity, particularly due to its extensive application in non-obstetric surgeries and fetal intervention procedures during pregnancy. However, its effects on heart development and function remain unclear. Using zebrafish larvae as a model, we investigated the effects of prolonged sevoflurane exposure (0.04-0.08%) from 10 to 72 h post-fertilization (hpf). Under these conditions, treated larvae exhibited dose-dependent developmental abnormalities, including reduced body length, pericardial edema, and impaired heart tube looping. Cardiac function analysis revealed significant decreases in ejection fraction, stroke volume, heart rate, and cardiac output, indicating impaired cardiac contractility and pumping efficiency. These functional impairments were accompanied by structural changes including ventricular wall thinning and chamber dilation, along with upregulation of cardiac stress markers (nppa, nppb) - characteristic features of dilated cardiomyopathy (DCM). Molecular analysis demonstrated downregulation of sarcomeric (tnnt2a, mybpc3) and calcium-handling (atp2a2a, slc8a1a) genes, suggesting disruption of sarcomere integrity and calcium homeostasis. Additionally, sevoflurane exposure elevated inflammatory cytokines (il-6, tnf-α, il-1β) and promoted leukocyte infiltration into cardiac tissue. RNA sequencing analysis implicated dysregulation of Apelin signaling pathway, with reduced prkaa2 (AMPKα2) expression and phosphorylation observed in both zebrafish and H9C2 cardiomyocytes. Critically, pharmacological activation of AMPK using A-769662 effectively mitigated sevoflurane-induced cardiotoxicity, identifying AMPKα2 as a potential therapeutic target. Collectively, these findings delineate the molecular mechanisms underlying sevoflurane-induced developmental cardiotoxicity following prolonged exposure in zebrafish and suggest that targeting AMPKα2 signaling merits investigation as a potential strategy to mitigate anesthetic-related cardiac developmental risks. Show less

Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge this gap, yet its immune system has not been comprehensively characterised at single-cell resolution. Here, we present a single-cell transcriptomic atlas of the tree shrew immune system, profiling 39 cell types across 12 tissues. We uncover human-like tonsillar structures and two transcriptionally distinct splenic macrophage subsets: an NR1H3 Show less

Hepatic intercellular communication is the driving force for the progression of chronic Hepatitis B virus (CHB)-associated hepatopathologies, with the dynamic molecular mechanisms largely unknown. Combining scRNA-seq and spatial transcriptomic analysis, the kinetic landscape of the liver microenvironment across time and space in AAV-HBV mice, which develop from inflammation to ultimately hepatocellular carcinoma is generated. Kupffer cells (KCs), originally resided within the peri-portal area, are persistently recruited to the HBV-enriched peri-central region via increased CXCL9 produced by endothelial cells, facilitating the interaction between KCs and HBV Show less

Primary Sjögren's disease (pSjD) is a chronic autoimmune disease. Clinically, sialography and lip gland biopsy in patients with pSjD show characteristic ductal dilations. However, the roles of the immune responses in ductal dilation remain unknown. We show that Th2 cells and their core cytokine IL-4 promote salivary duct dilatation in human and experimental SjD. Specifically, striated duct dilation is accompanied by periductal lymphocyte infiltration, which is correlated with increased IL-4 levels. In vivo, IL-4 neutralization reduced ductal dilation. Mechanistically, IL-4 induces the formation of cyst-like structures in cultured embryonic submandibular glands of mice. At the molecular level, IL-4 activates SHH signaling pathway in striated duct epithelial cells, upregulating SNAI1 and suppressing Cadherin 1 expression. This process disrupts interepithelial adhesion, leading to ductal dilation. Thus, IL-4 drives salivary gland ductal dilation that interferes with salivary gland function in SjD. Our findings should have implications for a potential therapeutic target in clinical pSjD. Show less

Cellular senescence, characterized by permanent cell cycle arrest, significantly influences cancer development, immune regulation, and progression. However, the precise mechanisms by which senescence contributes to colorectal cancer prognosis remain to be fully elucidated. By integrating expression profiles of senescence-related and prognostic genes in colon adenocarcinoma (COAD) patients, we formulated and confirmed a nine-gene cellular senescence-related signature (CSRS) that integrates senescence-associated and prognosis-predictive genes using data from the CellAge, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A cell senescence-related prognostic formula was developed as follows: CSRS = (CASP2 × 0.2098) + (CDKN2A × 0.1196) + (FOXD1 × 0.1472) + (ING5 × 0.3723) + (OXTR × 0.0786) + (PHGDH × 0.1408) + (SERPINE1 × 0.1127) + (SNAI1 × 0.1034) + (LIMK1 × 0.0747). In a multivariate Cox proportional hazards model, the CSRS score, age and TNM stage were all identified as significant independent indicators for overall survival, affirming their prognostic value in colorectal cancer. The CSRS-high group exhibited significantly up-regulated senescence-associated secretory phenotype (SASP) and immune cell infiltration, whereas the CSRS-low group showed an apparent better response to immune-checkpoint inhibitor therapy. Our findings suggest CSRS score and its constituent genes represent potential biomarkers for prognosis and immunotherapeutic benefit in COAD patients. Extending this nine-gene set into a broader senescence-associated panel should be a next step toward delivering truly individualized treatment plans. Show less

Although large-scale studies and potential pathways of genes on intramuscular fat (IMF) in livestock have been reported, research on circRNAs in yaks-a unique, low-IMF-content animal species that is native to the Qinghai-Tibetan Plateau-is still lacking. Based on previous high-throughput sequencing results on Show less

Convergent evolution offers a unique lens through which to explore the molecular underpinnings of significant phenotypic transformations. Similar selective pressures likely drove the evolution of analogous milk traits in sheep and goats. Consequently, the current study aimed to identify common selection signals for milk traits across dairy and non-dairy breeds of sheep and goats worldwide. In this study, a total of 308 whole-genome sequences from diverse sheep (n = 108) and goat (n = 200) breeds, including both dairy and non-dairy types, across the world were utilized. The population structure and genetic diversity of dairy and non-dairy sheep and goat breeds were characterized. Species-specific genes associated with milk traits, such as POU2F1, ABCD2, TRNAC-GCA in sheep and PRPF6, VPS13C, TPD52L2, NFX1 and B4GALT1 in goats, were identified. Further gene annotation and bioinformatics analyses indicated that different biological pathways are important for milk traits in each species: fatty acid oxidation and AMP metabolic process in sheep, the U2-type spliceosomal complex and propanoate metabolism in goats. Additionally, common signatures of selection such as CLASP1, PDS5B, ZNF831, CCDC73 were found in sheep and goats. Haplotype and transcriptional analyses further confirmed the role of these genes in milk production and provided evidence for their analogous evolution in sheep and goats. The CLASP1 gene was identified as a target of convergent selection, representing a promising candidate for genetic improvement programs in dairy species. These results provide insights into the genetic basis of convergent dairy traits, offering valuable targets for improving milk production and advancing dairy sheep and goat breeding programs. Show less

Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY-cAMP-PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY-PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes. Show less

Burnout, as a significant factor influencing the career development of military personnel, has garnered increasing attention from military decision-makers. Military personnel stationed in plateau areas exhibit unique occupational characteristics due to prolonged exposure to specific environmental conditions. This study aimed to investigate the characteristics of burnout and serum markers among military personnel in both plateau and plain regions, thereby elucidating the relationship between burnout and serum markers while considering the impact of environmental factors. This study conducted a cross-sectional survey involving 384 military personnel (Average age 23.14 ± 5.13) from both plateau and plain regions in China between June and December 2024, utilizing random stratified cluster sampling methods. The Maslach Burnout Scale was employed to evaluate burnout among the military personnel, while serum levels of brain-derived neurotrophic factor(BDNF), neuropeptide Y(NPY), and serotonin (5-HT) were quantified using commercial ELISA kits. One-way analysis of variance and independent sample t-tests were employed to examine the differences in burnout across various variables, while regression analysis was performed to identify the factors influencing burnout. The findings indicate that the overall level of burnout among military personnel is significantly elevated. Notably, the prevalence of burnout in military personnel stationed in plateau areas (100%) surpasses that observed in plain areas (96.6%). There were significant differences in the concentrations of burnout, BDNF, NPY and 5-HT among different environmental groups ( This study combines objective serological indicators with subjective questionnaire evaluations to provide a more accurate assessment of burnout. This method can more accurately reflect an individual's level of burnout and provide valuable experience and insights for improving the professional efficiency of military personnel in plateau environments and formulating targeted career development strategies. Show less

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less

G protein-coupled receptors (GPCRs) are transmembrane receptors that regulate intracellular signaling by interacting with G proteins and other effectors, influencing various physiological processes. The Glucose-dependent Insulinotropic Polypeptide Receptor (GIPR), a class B1 GPCR family member activated by GIP, regulates postprandial glycaemia by augmenting glucose-dependent insulin secretion, delaying gastric emptying, and suppressing appetite. Recent studies highlight the transmembrane domain (TMD) as the primary interface for dimerization, allowing GPCR to form homodimers or heterodimers with distinct physiological roles. However, the transient nature of these dimers challenges structural analysis, hindering experimental exploration and drug development. Computational methods now offer powerful tools for predicting such interactions. This study employs a hybrid approach, combining multiple protein docking software and dynamic structural optimization, to generate potential homodimeric models of GIPR-TMD. In addition, Next, validated models will provide insights into dimer activation mechanisms and support novel therapeutic discoveries. Show less

In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor-promoting tumor growth, cell survival, angiogenesis and metastasis-as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Show less

Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non-coding regions. However, the role of non-coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome-wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib-lenalidomide-dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd-resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9-mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi-omics analysis (H3K27ac ChIP-seq, scRNA-seq, scATAC-seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence-specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. Show less

Cholesterol synthesis and gallstone formation are promoted by trimethylamine-N-oxide (TMAO), a derivative of trimethylamine, which is a metabolite of gut microbiota. However, the underlying mechanisms of TMAO-induced lithogenesis remain incompletely understood. This study aimed to explore the specific molecular mechanisms through which TMAO promotes gallstone formation. Enzyme-linked immunosorbent assays were used to compare serum concentrations of TMAO, apolipoprotein A4 (APOA4), and proprotein convertase subtilisin/kexin type 9 (PCSK9) between patients with cholelithiasis and normal controls. A murine model of TMAO-induced cholelithiasis was employed, incorporating assays of gallstone weight and bile cholesterol content, along with RNA sequencing of murine hepatic tissue. A TMAO-induced AML12 hepatocyte line was constructed and transfected with targeted small interfering RNAs and overexpression plasmids. Serum TMAO and PCSK9 levels were elevated, whereas APOA4 levels were reduced in patients with cholelithiasis. Furthermore, our murine model demonstrated that TMAO upregulated hepatic expression of PCSK9, 3-hydroxy-3-methylglutaryl-CoA reductase, and ATP-binding cassette sub-family G member 5/8, while reducing APOA4 expression, thereby modulating cholesterol metabolism and promoting lithogenesis. TMAO upregulated hepatic Show less