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Metabolically Dysfunctional-Associated Steatotic Liver Disease (MASLD) affects both metabolically healthy obese (MHO) individuals and metabolically unhealthy lean (MUL) individuals. Key genes linked to liver dysfunction, such as Show less

This study aimed to collaboratively investigate the mechanism of variations in intramuscular fat (IMF) content in Wandong cattle using transcriptomics and metabolomics techniques. Longissimus dorsi (LD) muscle samples were collected from thirteen free-range Wandong cattle in Fengyang County, Anhui Province, China. From this initial cohort, eight animals closely matched in age and body weight were selected. Based on IMF content measured by Soxhlet extraction, these eight cattle were divided into two groups: the high-IMF (HF, n = 4) and low-IMF (LF, n = 4) groups. Subsequent analyses were performed on integrated datasets comprising the transcriptome, metabolome, and fatty acid profile. The results revealed a significant increase in IMF in the HF group compared to the LF group ( Show less

Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less

Anxiety is significantly correlated with levels of physical activity in university students. This research assessed the effects of anxiety on engagement in physical activity and explored the potential mediating function of psychological resilience. Additionally, latent profile analysis (LPA) was employed to identify distinct subtypes based on anxiety and resilience levels, and to explore their associations with physical activity. Utilizing a non-probability convenience sampling approach, this cross-sectional study recruited a total of 1,436 collegiate participants from multiple universities. Data collection was carried out with the Generalized Anxiety Disorder Scale (GAD-7), the abbreviated Connor-Davidson Resilience Scale (CD-RISC-10), and the Physical Activity Rating Scale (PARS-3). Data analysis included mediation effect analysis via Bootstrap methods (Model 4) and latent profile analysis (LPA). Anxiety demonstrated a significant negative association with physical activity ( Results demonstrated that anxiety affects physical activity both directly and indirectly, with the latter effect occurring through the channel of psychological resilience. Latent profile analysis identified three distinct profiles among college students based on anxiety and psychological resilience: High Anxiety-Low Psychological Resilience, Moderate Anxiety-Moderate Psychological Resilience, and Low Anxiety-High Psychological Resilience. Marked variations in physical activity levels were observed among these subgroups. The results underscore the complex relationships among mental health indicators and health behaviors within the collegiate population. The delineation of distinct profiles offers practical implications for designing tailored intervention strategies. Show less

Dyslipidemia and oxidative stress are key components in the pathophysiology of gestational diabetes mellitus (GDM), yet the contribution of genetic factors to these metabolic disturbances remains unclear. This study aimed to investigate the relationship between two lipid-related genetic polymorphisms, apolipoprotein C1 (apoC1) gene -317H1/H2 (rs1568822) and rs4420638, with GDM risk and lipid profiles and oxidative stress markers in Chinese populations. The apoC1 -317H1/H2 and rs4420638 polymorphisms were genotyped in 734 GDM patients and 1,102 control subjects. Genetic association with GDM risk and related traits were also analyzed. The distribution of genotype and allele in both polymorphisms were similar between the two groups. However, the combined H1H1/AG+GG genotype was significantly more frequent in women with GDM than in the control group. GDM patients who carried H1H1/AG+GG genotype were 1.97-fold increased risk to develop GDM (95% CI: 1.140-3.414, ApoC1 gene polymorphisms associate with GDM risk and affect the lipid profile. The combined H1H1/AG+GG genotype of the apoC1 gene polymorphisms appears to augment the propensity to develop GDM, while the rs4420638 polymorphism links to adverse lipid components in the patients. Further genetic studies to add information beyond the traditional risk factors in GDM and to identify risk genotypes will help in early prediction and identification of at-risk patients. Show less

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), has been implicated in promoting renal fibrogenesis. Nevertheless, its precise role and underlying mechanisms remain incompletely defined. To investigate the role of EZH2 in partial epithelial-mesenchymal transition (pEMT) and renal fibrosis, we utilized a mouse model with renal tubular cell-specific EZH2 deletion and administered gambogic acid (GA), a selective EZH2 degrader, following unilateral ureteral obstruction (UUO). In vitro, mouse renal epithelial cells were stimulated with TGF-β1 and treated with either EZH2-specific siRNA or GA to assess the effects on EMT and Notch1/3 signaling. In addition, chromatin immunoprecipitation (ChIP) assays were conducted to evaluate the binding of EZH2 and H3K27me3 to the promoters of Notch1 and Notch3. Compared with wild-type controls, mice with tubular cell-specific EZH2 deletion exhibited significantly reduced renal fibrosis, characterized by decreased expression of fibronectin, collagen III, vimentin, and Snail, while preserving E-cadherin levels in injured kidneys. Pharmacological degradation of EZH2 with GA produced comparable antifibrotic effects. UUO injury markedly upregulated Notch1, Notch3, the Notch intracellular domain, Hes1, Hey2, and Jagged-1; these increases were significantly suppressed by either EZH2 deletion or GA treatment. Similarly, in vitro, GA or EZH2-specific siRNA inhibited the expression of Notch signaling molecules in TGF-β1-treated renal epithelial cells. Chromatin immunoprecipitation analyses revealed direct binding of EZH2 and H3K27me3 to the Notch1 and Notch3 promoters. UUO injury enhanced EZH2 binding while reducing H3K27me3 enrichment at these sites, effects reversed by GA treatment. These findings demonstrate that epithelial EZH2 contributes to pEMT in renal tubular cells and promotes renal fibrosis, at least in part through activation of Notch signaling. Targeting EZH2 may hold potential as a therapeutic approach for chronic kidney disease. Show less

Long-persistent luminescent (LPL) materials store photon energy as charges and emit light over extended periods via charge recombination. LPL decay typically follows a power law rather than an exponential decay, enabling confirmation of charge accumulation from emission decay characteristics. While charge generation in organic materials has been widely studied at donor-acceptor (D/A) interfaces, it remains underexplored in single-component luminescent materials. Here, we investigate charge generation in organic solids by dispersing a luminescent molecule in various hosts and performing slow transient emission analyses. This approach enables the evaluation of ionization through accumulated triplet excited states and the detection of weak charge accumulation, which are difficult to capture using conventional transient techniques. Our results show that ionization in single-component materials proceeds through resonance-enhanced multiphoton ionization, although it is less efficient than at D/A interfaces. This approach provides insight into long-term photophysical and photochemical processes such as photodegradation. Show less

Sarcopenic obesity (SO) is characterized by the presence of both obesity and sarcopenia and is related to disability and loss of independence in older adults. The extent to which time spent in light physical activity (LPA), or moderate-to-vigorous physical activity (MVPA) is associated with SO risk in older adults remains unclear. The aim of this study was (a) to examine the association between the level of adherence to recommended amounts of MVPA and the risk of SO in older adults and (b) to determine whether time spent in LPA is associated with SO risk independently of time spent in MVPA. This cross-sectional study involved 862 community-dwelling older adults (58% women; aged 65-79 years) from four European countries. Accelerometer-determined time in MVPA was categorized as follows: inactive (< 75 min/week), moderately active (75-149 min/week), active (150-299 min/week) and highly active (≥ 300 min/week). Time in LPA was expressed in tertiles. The outcome measure SO risk was determined based on appendicular lean mass, waist circumference, handgrip strength and the 5-times sit-to-stand test. Odds ratios (OR) with a 95% confidence interval (95% CI) of high SO risk across levels of MVPA and LPA were determined by binary logistic regression adjusted for the level of systemic inflammation (high-sensitivity C-reactive protein) and dietary protein intake. Compared to the inactive group, ORs of having a high SO risk were about 50%-80% lower, depending on the MVPA level, with the largest risk reduction in the highly active group (OR: 0.23, 95% CI: 0.13-0.39; p < 0.05). The likelihood of having a high SO risk was significantly lower among the highly active group compared to the active group (OR: 0.50; 95% CI: 0.33-0.77; p < 0.05). More time in LPA was associated with a significantly lower likelihood of having high SO risk (highest vs. lowest tertile: OR: 0.52, 95% CI: 0.30-0.89; p < 0.05) only in participants with low amounts of MVPA. In contrast, LPA was not associated with SO risk among participants meeting the MVPA recommendation. MVPA is strongly associated with a lower likelihood of having a high SO risk in older adults, independently of the level of systemic inflammation and intakes of dietary proteins. LPA is related to SO risk in sedentary older adults, which supports the promotion of physical activity regardless of intensity for mitigating SO. Show less

A meta-analysis was conducted to assess the effects of citric acid (CA) on silage fermentation, and then used whole-plant cassava silage as a model to explore the underlying microbiological mechanisms with metagenomic and metabolomic data. The meta-analysis revealed that CA supplementation increased the dry matter, crude protein, water-soluble carbohydrate, and lactic acid contents in silage, but decreased the pH, dry matter loss, and the contents of fiber, NH Show less

Background & objectives Central TB division facilitated development of a line probe assay (LPA) artificial intelligence (AI) tool. The tool was developed, trained, and validated for performance by collecting more than 18,000 LPA strips across culture and drug susceptibility Testing (C&DST) laboratories. The Indian Council of Medical Research (ICMR)-National Institute for Research in Tuberculosis (NIRT) evaluated the LPAAI tool independently. The objective was to establish and verify an AI-driven system for automatically interpreting LPA strips, which are employed in tuberculosis drug resistance screening, to improve accuracy, consistency, and scalability across diverse laboratory settings. Methods The AI system integrates faster regions convolutional neural network (FR-CNN) for strip detection, detection transformer (DETR) for band localisation, and a hierarchical neural network (HNN) for classification of bands, loci, and drug labels. Independent validation was conducted by ICMR-NIRT using 2810 first-line (FL)-LPA and 241 reflex second-line (SL-LPA) across ten intermediate reference laboratories (IRLs). Results AI comparative models demonstrated an accuracy range of 92-100 per cent, with sensitivity between 80-100 per cent and specificity from 86-100 per cent for the tub, rpoB, katG, InhA, gyrA/gyrB,rrs, and eisgenes. The overall F1 score varies from 0.81 to 1.00, indicating perfect precision and recall. Interpretation & conclusions This AI system offers a novel, modular architecture capable of expert-level interpretation of LPA strips. The AI tool performs at par with expert readers and offers a reliable, scalable solution for LPA interpretation.AI tool adoption can reduce interpretation time, enhance result uniformity, and improve treatment delivery across India's TB programme, supporting national goals for TB elimination. Show less

As university libraries transform into "Learning Commons," peer collaborative learning has become increasingly common. However, the complexity of its effectiveness and its underlying mechanisms remain underexplored. This study systematically investigates the relationship between peer collaborative learning and academic engagement. Integrating both person-centered and variable-centered approaches, the study employs Latent Profile Analysis (LPA) to identify heterogeneous groups of students based on their collaboration patterns and engagement levels, challenging the conventional wisdom that "collaboration is always beneficial." Concurrently, based on Self-Determination Theory (SDT), a mediation model is constructed to test the bridging role of basic psychological needs (competence and relatedness). Using a questionnaire survey, data were collected from 820 university students to measure their quality of peer collaborative learning, basic psychological need satisfaction, and academic engagement. The SPSS PROCESS macro was used for mediation analysis, and Mplus was used for Latent Profile Analysis. (1) LPA identified four heterogeneous profiles: "High-Achieving All-Rounders" (26.1%), "Balanced Developers" (25.5%), "Inefficient Socializers" (27.6%), and "Indifferent and Unengaged" (20.9%). Notably, the largest group, "Inefficient Socializers," exhibited a distinct pattern of "high emotional support, low academic engagement." (2) Basic psychological needs played a significant partial mediating role in the relationship between the quality of peer collaborative learning and academic engagement, with the mediating effect accounting for 52.3% of the total effect. (3) The moderating effect of academic discipline was not significant. The study confirms that while high-quality peer collaboration can promote academic engagement by satisfying students' psychological needs, not all forms of collaboration are beneficial. The discovery of the "Inefficient Socializers"-the largest profile-is the core contribution of this research. It exposes the existence of a "pseudo-collaboration" trap, where social interaction detached from task-oriented goals may actually inhibit academic engagement. This finding offers crucial practical implications for the design of university learning spaces (shifting from "promoting co-presence" to "fostering effective interaction") and for academic advising (enabling the precise identification and intervention for different student types). Show less

To develop and evaluate a predictive model for myocardial injury in patients with advanced gastric cancer treated with fluorouracil plus platinum-based chemotherapy, incorporating baseline characteristics and inflammatory, nutritional, and atherosclerotic factors. A total of 268 patients with advanced gastric cancer who received this treatment between April 2020 and September 2024 were selected and divided into a training set ( In the training set, 56 patients (29.79%) developed myocardial injury, while 23 patients (28.75%) in the validation set developed myocardial injury, with no statistically significant difference in the incidence or clinical characteristics between the two sets ( This predictive model aids in the early identification of myocardial injury, guiding clinical decision-making and improving prognosis. Show less

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with challenges in diagnosis and treatment due to tumor heterogeneity. This study identifies palmitoylation-related signature genes as potential diagnostic and therapeutic targets. Integrating GEO datasets, six differentially expressed genes (DEGs) linked to palmitoylation were identified. Machine learning algorithms (LASSO, RF, SVM) selected three core genes: TRPM4, LAMB3, and APOE. A diagnostic model based on these genes achieved an AUC of 0.929, demonstrating robust accuracy in distinguishing PCa from normal tissues. Functional analysis revealed roles in lipid metabolism and immune modulation, with ssGSEA highlighting correlations between key genes and immune cell infiltration. Experimental validation showed that LAMB3 overexpression suppressed PCa cell proliferation, migration, and invasion, while knockdown enhanced these processes. Molecular docking identified diethylstilbestrol as a potential therapeutic agent targeting LAMB3 and APOE. These findings emphasize the clinical relevance of palmitoylation-related genes in PCa diagnosis and therapy, offering novel biomarkers and insights for personalized treatment strategies. Show less

Low-density lipoprotein cholesterol (LDL-C) has traditionally been the primary biomarker used to assess cardiovascular risk. However, a substantial proportion of cardiovascular events occur in individuals with LDL-C levels within the normal range, highlighting the need for additional risk markers. Lipoprotein(a) [Lp(a)] has emerged as an independent and genetically determined cardiovascular risk factor that is not adequately captured by conventional lipid profiling. Elevated Lp(a) levels are associated with an increased risk of atherosclerotic cardiovascular disease, including coronary artery disease, ischemic stroke, and calcific aortic valve stenosis, and appear to be particularly relevant in the context of premature cardiovascular events. The pathogenicity of Lp(a) is driven by distinct mechanisms that extend beyond cholesterol transport. These include pro-atherogenic, pro-inflammatory, and pro-thrombotic effects mediated largely by oxidized phospholipids carried by the particle and by the structural properties of apolipoprotein(a), which interfere with fibrinolysis. Despite its strong and stable genetic determination, Lp(a) remains underrecognized and inconsistently measured in clinical practice, partly due to historical limitations in assay standardization and reporting. This minireview summarizes current knowledge on the pathophysiological mechanisms underlying elevated Lp(a), discusses its clinical implications for cardiovascular risk assessment, and highlights the importance of standardized Lp(a) measurement in routine practice, particularly in light of emerging Lp(a)-targeted therapies. Show less

Alzheimer disease neuropathologic change (ADNC) is the most common pathology underlying cognitive impairment and dementia in the aging population, but there is significant variation in outcome between affected individuals. Moreover, other common neurodegenerative processes are often concurrent and may significantly worsen cognition, but the degree to which these processes interact and affect the We performed a cross-sectional cohort study of 586 participants from the National Alzheimer’s Coordinating Center (NACC) database, who were ≥ 65 years of age and displayed high-level ADNC at autopsy, and who had available longitudinal cognitive data and Clinical Dementia Rating (CDR) performed within the final 24 months of life. This cohort was subdivided into “resilient” individuals/those with minimal progression of cognitive decline (MinP; Individuals with rapid progression were more likely to have at least one These data suggest that resilience and progression in ADNC are impacted by AD-relevant genetics and the severity of late-stage ADNC (even within the narrow range of values compatible with high-level ADNC), additional pathologic features, and potentially the clinical management of underlying systemic disorders. The online version contains supplementary material available at 10.1186/s13195-025-01904-6. Show less

This study aimed to identify profiles of autistic youths' sibling relations and examined if social-ecological variables (i.e., youth characteristics, family and caregiver functioning, peer relations, academic performance) were associated with these profiles. Caregivers (N = 2,142; 88.1% mothers) of autistic youths aged 6-17 years (M = 11.07 years; SD = 3.17; 80.1% male) completed electronic measures assessing social-ecological variables and youths' sibling relations. We used a latent profile analysis (LPA) to define sibling relation profiles based on the qualities (emotional support, companionship, conflict, and criticism) of relations between autistic youths and their closest-in-age siblings. We performed ANOVAs to compare sibling profiles on social-ecological variables. The LPA yielded a 3-profile solution: a positive group (18.2%), a negative group (17.2%), and a low engagement group (64.5%). ANOVAs and χ Most sibling relations among autistic youth fit a low engagement profile based on caregiver report. Positive sibling relations were linked with positive functioning in other social-ecological domains. The nature of these linkages warrants further investigation, particularly using longitudinal, multi-informant, and mixed-method designs. Show less

Although studies have suggested a potential link between the nervous system and prostate cancer, the underlying regulatory mechanisms remain unclear. Therefore, it is crucial to identify the genes involved in regulating prostate cancer within the nervous system. We utilized eQTL data from eight neural cell types as exposure factors and GWAS data for prostate cancer as outcome events. Mendelian randomization (MR) analyses were performed to identify causative genes associated with prostate, bladder, and renal cancers in Astrocytes, Endothelial cells, Excitatory neurons, Inhibitory neurons, Microglia, Oligodendrocytes, OPCs/COPs, and Pericytes. Bladder and renal cancers were used as controls. Sensitivity analyses (heterogeneity, pleiotropy, and leave-one-out tests) were conducted to ensure reliability. In astrocytes, seven positive genes were identified as being causally related to prostate cancer: KANSL1, AC005670.2, ARL17B, LRRC37A2, LRRC37A, MAPT, and LINC02210. In. Endothelial cells, Inhibitory neuron and Microglia, three genes (LRRC37A2, ARL17B, and KANSL1) were identified as risk genes that are associated with prostate cancer. Four protective genes were identified in excitatory neurons, including LRRC37A2, ARL17B, KANSL1 and LINC02210. In oligodendrocytes, eight genes were identified, with LRRC37A2, ARL17B, and KANSL1 acting as protective factors, while OR2L13, OR2L3, OR2L5, OR2L2, and OR2M4 were identified as risk factors. Additionally, sensitivity analyses showed no heterogeneity or horizontal pleiotropy in the MR results, confirming their reliability and stability. In addition, no positive genes were found in bladder cancer and renal cancer. Our study highlights the role of the nervous system, particularly astrocytes, in regulating prostate cancer. We identified three genes, with LRRC37A2, ARL17B, and KANSL1 emerging as key protective factors. These findings provide potential targets for prostate cancer diagnosis and treatment. The online version contains supplementary material available at 10.1007/s12672-025-03711-9. Show less

Aging and alcohol misuse independently alter monocyte (MO) and macrophage (MØ) function, leading to impaired antimicrobial responses. However, how alcohol misuse contributes to impaired MO/MØ function during aging remains unclear. We compared the transcriptomes of MOs and MØs from alcohol-modulated niches (liver, brain, and bone marrow [BM]) in young (3-month-old) and old (20-24-month-old) female C57BL/6N mice (n = 4-6 per group). Statistical significance was determined using two-way ANOVA. MO/MØ transcriptomes showed unique organ-specific responses to aging and alcohol. Aging elicited a common deregulation of pathogen-responsive pathways, while alcohol misuse commonly inhibited IFN signaling in the aged populations. Our studies on intercellular communication using ligand-receptor interactions revealed that BM MOs were the least communicative and liver MØs were the most communicative. Alcohol misuse specifically increased MO/MØ communication in aging. We also identified and validated specific pathways driving inter-organ MO/MØ crosstalk in alcohol misuse during aging, including APOE-TREM2 signaling from the liver to microglia and the NRXN2 and SPP1 pathways. Our results provide a unique insight into the heterogeneity of the MO/MØ transcriptome and define the inter-organ crosstalk between BM, liver, and brain during aging and alcohol misuse. Aging and alcohol misuse are linked to immune dysfunction, systemic inflammation, and altered innate immune responses. Here, we examined monocyte/macrophage responses in the liver, brain, and bone marrow of young and aged mice under alcohol exposure at the transcriptomic level. We observed that aging and alcohol predominantly elicited organ-specific changes in gene expression, with minimal overlap between the monocyte/macrophage populations across different tissues. However, aging commonly upregulated pathogen response pathways while alcohol misuse inhibited interferon signaling. We also assessed cell-cell communication by analyzing ligand-receptor expression in the different monocyte/macrophage populations and identified candidate molecules (APOE, TREM2, NRXN2, SPP1) from the top pathways guiding inter-organ signaling specifically in aging and alcohol misuse. Our findings have generated a unique repository and provide novel insights on how aging and alcohol impact tissue-specific monocytes/macrophages and their crosstalk. Show less

Lipoprotein lipase (LPL) is the rate-limiting enzyme responsible for hydrolyzing triglycerides in circulating lipoproteins. Reduced LPL activity contributes to hypertriglyceridemia, a major cardiovascular risk factor. LPL activity is thought to depend on the conformation of the lid domain, the lipid pore, N- and C-terminal domains (NTD, CTD), and stabilization of these domains by endogenous activators such as apolipoprotein C-II (ApoC-II). Despite major clinical significance, the structure-function relationship of LPL's functional domains and cofactors remain incompletely understood. To address this, we performed the longest known (1-μs) molecular dynamics simulations of LPL independently and in complex with an ApoC-II mimetic peptide (ApoC-II-P). For the first time, we show that LPL's flexible lid can adopt multiple orientations, transitioning between open and closed states that regulate lipid pore access and catalytic activity. We also observed 'flipping' of ~180° by the CTD, a unique characteristic that dictates LPL activity when not in a closed lid state. Furthermore, ApoC-II-P stabilizes LPL by bridging its NTD and CTD, while maintaining an optimal lid orientation. Biochemical and cellular assays corroborate these findings, demonstrating that ApoC-II-P enhances LPL hydrolysis and supports noncanonical LPL functions. Together, these insights reveal previously unrecognized mechanisms governing LPL regulation and activity dynamics. Show less

Familial hypercholesterolemia (FH) is characterized by lifelong elevated LDL-C levels and increased cardiovascular risk. PCSK9 inhibitors (PCSK9i) reduce LDL-C and Lp(a), however, the effect of dual lipid reduction on mechanical vascular function remains unclear. The aim of this study was to evaluate the efficacy of PCSK9i in reducing LDL-C and Lp(a) and to assess the relationship between the dual lipid reduction and the mechanical vascular profile improvement in FH subjects. This prospective observational study included 301 genetically confirmed FH subjects treated with PCSK9i added to high-intensity statins and ezetimibe. Biochemical and PWV measurements were performed at baseline and after six months. Subjects were stratified into four groups based on median values of ΔLDL-C and ΔLp(a). After six months of add-on PCSK9i, 44.9% of FH subjects achieved their LDL-C targets. Reductions were observed in LDL-C (− 49.8%, Dual lipid reduction with PCSK9i was associated with a pronounced mechanical vascular profile improvement in FH subjects; however, an intensive Lp(a) reduction may be needed to achieve a greater mechanical vascular benefit. Show less

Obesity is a multifactorial disease caused by an interaction between genetic, environmental and behavioral factors. Polymorphisms of the two genes Circadian Locomotor Output Cycles Kaput (CLOCK) rs1801260 and Melanocortin-4-receptor (MC4R) rs17782313, are associated with obesity. Knowledge is limited on the interaction between CLOCK, MC4R and obesity. The aim was to explore the interactions between the CLOCK and MC4R gene variants on markers related to obesity. There were 423 subjects with information on two genetic variants of two genes (CLOCK and MC4R). Their interaction was evaluated with: chronotype, sleeping duration, emotional eating, food timing, stress, dietary intake, appetite, physical activity (assessed by questionnaires), anthropometric measures of obesity (assessed by physical measurements), and also hormonal factors (assessed by ELISA). Generalized Linear Models were applied. Our results revealed that significant differences were observed between the genotypes of CLOCK rs1801260 for weight, Body Mass Index (BMI), Glucagon-like peptide-1 (GLP-1), cortisol, energy, fat, sleep duration, chronotype, appetite, depression, stress, emotional eating, physical activity, breakfast, lunch, and dinner time (p˂0.05). Also, significant differences were observed between the genotypes of MC4R rs17782313 for weight, BMI, Waist Circumference (WC), Waist to Hip Ratio (WHR), ghrelin, energy, carbohydrate, fat, appetite, depression, stress, breakfast time, and emotional eating (p˂0.05). Our findings also showed significant interactions between the CLOCK (CC)∗MC4R (CT) genotypes for higher appetite, stress and CLOCK (CT)∗ MC4R (CC) genotypes for higher fat and energy intake and CLOCK (CC)∗MC4R (CC) genotypes for higher weight, BMI, energy and fat intake, appetite, emotional eating, stress, ghrelin, cortisol and lower sleep duration and GLP-1 (p˂ 0.05). Due to the non-significance of the interaction in CLOCK (CT)∗ MC4R (CT) genotypes, it seems that the presence of a healthy arm in the CLOCK and MC4R polymorphism is necessary for the proper function of the genes. Thus, these results highlight that gene variants and their interaction should be considered in obesity assessment. Show less

Apolipoprotein C-III (apoC-III) is transported on chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein(a) [Lp(a)]. Olezarsen, a hepatic-targeted antisense oligonucleotide targeting APOC3 mRNA, lowers apoC-III and triglycerides and reduces pancreatitis events. This study evaluated the reduction of apoC-III in specific lipoprotein pools after treatment with olezarsen. Participants with familial chylomicronemia syndrome (FCS) in the Balance study received olezarsen 80 mg (n = 22), 50 mg (n = 21), or placebo (n = 23). Triglycerides, apoC-III, and lipoprotein-associated apoC-III was measured at baseline and days 85, 169, 253, and 365 using chemiluminescent ELISAs. Lipoprotein-associated apoC-III levels were measured in 4 lipoprotein pools, apoC-III-total apoB (apoB-48+apoB-100), apoC-III-apoA-I (HDL), apoC-III-apoB-100 (VLDL + LDL), and apoC-III-apo(a) (Lp(a)). The placebo-adjusted average percent changes from baseline to day 365 were calculated. The average percent changes from baseline to day 365 in apoC-III were -61.9 % and -74.7 % and for triglycerides -37.8 % and -55.7 % with olezarsen 50 mg and olezarsen 80 mg, respectively. The corresponding olezarsen-placebo average differences (95 % CI) in apoC-III-total apoB levels were -47.1 % (-64.1, -32.6) and -65.8 % (-81.5, -49.8), respectively and apoC-III-apoA-I by -53.6 % (-79.3, -29.4) and -76.1 % (-104.1, -55.4), respectively (p<0.001 for all). ApoC-III-apoB-100 was reduced by -12.5 % (-28.1, 2.1) (p = 0.0768) and -29.9 % (-46.1, -16.0) (p = 0.0006) and apoC-III-apo(a) by -15.7 % (-47.5, 10.6) (p = 0.18) and -39.1 % (-70.2, -16.1) (p = 0.0024), with olezarsen 50 mg and olezarsen 80 mg respectively. In adults with FCS, olezarsen significantly lowers apoC-III in all major lipoprotein pools, particularly in total apoB and apoA-I. Tracking changes in apoC-III among various lipoprotein pools elucidates the action of olezarsen on apoC-III and may inform future studies of pancreatitis and cardiovascular risk with apoC-III-targeted therapies. Show less

Hepatocellular carcinoma (HCC) arises from various etiologies, including viral hepatitis and non-viral liver diseases. Although comprehensive genomic profiling (CGP) is increasingly applied in oncology, the influence of disease etiology on the genomic landscape of HCC and biomarker applicability remains insufficiently characterized. CGP data from 551 patients with HCC, registered in the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, were analyzed after excluding cases with undefined etiology. We characterized the mutational landscape, compared mutation frequencies among HBV-, HCV-, and non-viral, non-cholestatic (nBnC)-related HCC, assessed the association between homologous recombination repair (HRR)-related gene alterations and tumor mutation burden (TMB), and evaluated the detection rates of actionable mutations in tissue- versus liquid-based CGP. Telomerase reverse transcriptase splice site mutations were the most common genomic alteration and were consistently observed across all etiologic groups. Although mutations in AXIN1 and DDR2 genes showed modest enrichment in HCV- and HBV-related HCC, respectively, the overall mutational profiles remained largely conserved across etiologies. TMB was significantly lower in nBnC-HCC compared to HCV-related HCC but showed no association with HRR-related mutations. The detection rates of targetable mutations were similar between tissue and liquid biopsies; however, only a small proportion of patients received matched therapies. Real-world data indicate a conserved genomic architecture in HCC regardless of etiology, supporting unified therapeutic approaches. The absence of a relationship between HRR alterations and TMB suggests distinct biological mechanisms. Liquid biopsy remains a reliable option when tissues are unavailable in managing patients with HCC. Show less

Obesity, a pandemic, worldwide afflicts almost one billion people. Obesity and ageing share several pathological pathways leading to neurological disorders. However, due to a lack of suitable animal models, the long-term effects of obesity on age-related disorders- cognitive impairment and dementia have not yet been thoroughly investigated. Therefore, the current investigation focuses on developing a suitable model to explore the effects of obese-ageing. It also aims to determine whether obesity affects cognitive abilities in an age-dependent manner, and to identify a potential biomarker(s) for cognitive decline. Cognitive tests were carried out on 6-months and 1-year-old melanocortin-4 receptor (Mc4r)-deficient-obese and lean (wildtype) mice. Additionally, brains and sera were harvested for molecular, histological and serological analyses from 6, 12, and 24-months-old mice. Finally, RT-PCR was carried out after hippocampal mRNA sequencing. The cognitive tests revealed that 1-year-old obese mice have cognitive impairment along with underlying neurodegenerative changes, such as enlarged lateral ventricles. Serum neurofilament light chain (sNfL) levels were also elevated. Lipid accumulation and neuroinflammation were apparent besides, a compromised blood-brain barrier (BBB) indicated by altered junction protein gene expression. Differentially-expressed genes associated with cognitive decline were identified by mRNA sequencing of hippocampi. One such gene, Secreted Phosphoprotein 1 (Spp1) had markedly increased expression in cognitively-impaired obese mice. Our findings present an obese-aged mouse model of cognitive decline with neuroinflammation, reduced BBB-integrity and predisposing neurodegenerative changes. Obese-ageing accelerates the progression of cognitive impairment. Furthermore, Spp1 appears to be a potential biomarker for early diagnosis of neuropathological disorders. Show less

Cancer cells fulfil their energy requirements by acquiring fatty acids (FAs) through both de novo synthesis and exogenous uptake. Although studies have focused on de novo FAs synthesis in papillary thyroid cancer (PTC), research on exogenous FAs uptake is scarce. Lipoprotein lipase (LPL), which enhances cellular FAs uptake, serves as the focal point of this study, which explored the role of LPL-mediated exogenous FAs uptake and FAs synthase (FASN)-mediated endogenous FAs synthesis in PTC cell proliferation. The expression of LPL was analyzed using databases including GTEx, GEO, and TCGA. Furthermore, its expression in PTC tissue samples and cell lines was confirmed. To observe the impact of the lipoprotein-deficient medium on PTC cells, EdU and TUNEL staining assays were conducted. CCK-8, colony formation, and TUNEL assays were performed to assess the effect of down-regulating LPL and/or FASN expression in PTC cells. Bioinformatics analysis revealed the upregulation of LPL mRNA in thyroid cancer. LPL expression was significantly elevated in PTC tissues and cell lines. Lipoprotein-deficient medium inhibited PTC cell proliferation and induced apoptosis. Similarly, silencing either LPL or FASN led to comparable outcomes. The combined inhibition of both LPL and FASN had a synergistic effect, enhancing the inhibition of PTC cell proliferation and the increase in apoptosis. Both the de novo synthesis and exogenous uptake of FAs are important for PTC cell proliferation. The combined inhibition of LPL and FASN inhibitors shows promise for PTC treatment. Show less

Obesity and its associated intestinal inflammatory responses represent a significant global challenge. (IF) is a dietary intervention demonstrating various health benefits, including weight loss, enhanced metabolic health, and increased longevity. However, its effect on the intestinal inflammation induced by high-fat diet (HFD) is still not fully comprehended. Thirty-four male Sprague-Dawley rats were randomized into three groups: Control (fed standard chow diet for 24 weeks); the HFD group (fed HFD for 24 weeks); and the HFD + IF group (fed HFD for 12 weeks, followed by an alternate day regimen of fasting and HFD for 12 weeks). The results revealed that IF significantly reduced body weight, food intake, and blood glucose levels compared to the HFD group. Furthermore, rats undergoing the intermittent fasting regimen exhibited a significant reduction in resting time, along with increased durations of grooming and exploration when compared to those on HFD. IF significantly reduced HFD-induced intestinal oxidative stress by lowering malondialdehyde levels and substantially increasing intestinal total antioxidant capacity, consistent with histopathological findings of gastric and intestinal tissues. The investigation of the underlying mechanisms revealed that IF significantly increased the intestinal expression of Farnesoid X receptor (FXR), glucagon-like peptide 1 (GLP-1), and melanocortin-4 receptors (MC4R), with a significant decrease in gastrointestinal peroxisome proliferator-activated receptor-γ (PPAR-γ) compared to the HFD group. The findings indicate that IF can mitigate HFD-induced intestinal inflammation via the FXR/GLP-1/MC4R/ PPAR-γ pathway. This highlights the need for further research to elucidate these mechanisms. Show less

With less than two years remaining from 2027-the year which the government has targeted to achieve zero Indigenous cases, we map the malaria indicators across the 700 + districts for five years between 2019 and 2023 using spatiotemporal maps and also assess the potential drivers of malaria transmission in different regions. We used the annual district-wise malaria data from the National Center for Vector Borne Disease Control Programme (NCVBDC) and the cross-sectional socio-economic data from the National Family Health Survey. We also collated the meteorological and land-use land-cover data from the MERRA-2 and Sentinel-LPA satellites, respectively. We then developed region-specific ensembles of spatiotemporal models that allowed us to identify the associated covariates while the regions were identified using the Getis-Ord Gi* statistics. With 0.33 million malaria cases in 2019, the COVID-19 pandemic led to a significant reduction in reported cases. The P. falciparum affected regions are widespread in North-eastern and Central India. However, after the pandemic, an emerging geographical expansion into the north-eastern parts is observed for the P. vivax, which is evident from the clusters and the spatiotemporal ensemble models. Population belonging to scheduled castes and scheduled tribes and those economically marginalised are among the most vulnerable, but lifestyle habits such as drinking water practices, maternal education, and healthcare accessibility are associated with malaria transmission. We also developed a digital dashboard that allows the general public and the stakeholders to track the malaria indicators for each district and the corresponding year. Show less

Sex is a key piece of patient information but is often not actively considered in drug use. This is partly due to the lack of molecular evidence at the gene expression level beyond sex chromosomes and sex hormones. We aim to investigate how sex differences in tissue-specific gene expression relate to FDA-approved drugs using the latest database of The Genotype-Tissue Expression (GTEx) V10. Our analysis reveals that 91.4% of FDA-approved drug target genes exhibit sex-differential expression in at least one tissue. The tissues with the most pronounced sex differences include subcutaneous adipose tissue, skeletal muscle, and the pituitary gland, while sex differences are less pronounced in the liver, other brain regions, and the spleen. Sex-differential disease-related genes include those associated with obesity (PPARG, INSR), cancer (FGFR1, CD22), and immunity (IL6R, IL3RA). Based on our findings, we advocate for a policy shift that integrates sex-based molecular data into preclinical studies, drug development, and clinical practices. This paradigm aligns biomedical research with precision medicine, mitigates drug-related risks, and promotes equitable healthcare outcomes. Show less

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Lipoprotein (a) [Lp(a)] has emerged as an independent risk factor for CAD, but its role in predicting coronary severity in Vietnamese populations remains unclear. To evaluate the value of Lp(a) in predicting the severity of coronary artery stenosis in chronic CAD. This cross-sectional study was conducted at Tam Anh General Hospital from June 2024 to June 2025, including 138 patients diagnosed with chronic CAD. Demographic, clinical, laboratory, and coronary angiographic data were collected. CAD severity was assessed using the Gensini score. Logistic regression and ROC analysis were employed to evaluate the predicting value of Lp(a). Severe CAD (Gensini score >40) was present in 31.9% of the cohort. Patients with Lp(a) ≥30 mg/dL exhibited a significantly higher prevalence of severe CAD (72.5% vs. 8.0%). Lp(a) levels correlated strongly with the Gensini score. The optimal cut-off for predicting severe CAD was 30.6 mg/dL (AUC = 0.869). Multivariate analysis confirmed Lp(a) as an independent predictor. Lp(a) ≥30 mg/dL is strongly associated with severe coronary artery stenosis. Lp(a) is a valuable independent predictor of CAD severity and may serve as an essential tool for risk stratification in clinical practice. Show less

Intramuscular fat (IMF) critically governs beef sensory attributes (juiciness, tenderness, flavor). Previous studies have predominantly focused on genomics and transcriptomics, with limited proteomic data available. To gain a more comprehensive understanding of the mechanisms regulating IMF deposition, we integrated proteomic and metabolomic profiling of the Longissimus dorsi across three genetically distinct cattle breeds. A comprehensive analysis of 633 differentially abundant proteins (DAPs) and 1456 differential metabolites (DAMs) identified 20 potential protein regulators (e.g., ACAA1, ACACA, ADIPOQ, and HSD17B12) and 19 candidate metabolites (e.g., hexadecanoic acid, icosadienoic acid, oleic acid, and oxaloacetate) as key molecular markers. Furthermore, HSD17B12 was found to inhibit IMF cell proliferation while promoting differentiation and lipid accumulation. This integrated approach highlights HSD17B12 as a critical regulator in enhancing IMF content, providing a theoretical foundation for improving beef quality. Show less