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Timosaponin AIII (Tim-AIII), a steroidal saponin derived from Anemarrhena asphodeloides, has emerged as a promising antitumor agent, yet its precise molecular targets and mechanisms in breast cancer remain poorly defined. Here, we identify fibroblast growth factor 2 (FGF2) as a direct binding target of Tim-AIII using a combination of network pharmacology, CETSA, and surface plasmon resonance assays. Mechanistically, Tim-AIII exhibits a dual therapeutic mode of action. First, it induces reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, activating the eIF2α-ATF4-CHOP axis and initiating apoptosis. Second, it dampens the FGF2-FGFR1-PI3K/AKT signaling cascade, thereby inhibiting epithelial-mesenchymal transition (EMT) and suppressing cell migration and invasion. RNA sequencing and enrichment analyses confirm that Tim-AIII regulates critical oncogenic pathways, including ER stress, calcium signaling, and PI3K/AKT. In vivo evaluations demonstrate that Tim-AIII significantly reduces tumor growth without detectable systemic toxicity in breast cancer-bearing mice. This study not only elucidates the molecular basis of Tim-AIII's antitumor efficacy but also positions it as a potential targeted therapeutic for breast cancer, with dual action on ERS-induced apoptosis and EMT suppression. Show less

Physical inactivity is a health concern for children and adolescents with neurodevelopmental disorders (NDDs) as it directly increases their risk of developing various health problems. Evidence on differences in accelerometer-assessed physical activity between children and adolescents with and without NDDs is inconclusive. And age- and body mass index (BMI)-related effects on physical activity remain unclear. The systematic literature searches were performed in 6 databases up to March 2025. Methodological quality was evaluated by the Newcastle-Ottawa Scales. Data were pooled using a random-effects model. Hedges' g was used to express the effect size index with 95 % confidence interval (CI). Meta-regression on age and BMI was also performed to investigate the potential moderating effects. Out of the 2167 studies initially identified, 28 were included in the analysis, which comprised total physical activity (TPA), moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA) included in the meta-analysis, respectively. These studies involved 1060 children and adolescents with NDDs and 1820 without, aged 6.6-16.9 years. A small-to-moderate effect size exists for the difference in TPA (g=-0.299) and MVPA (g=-0.479) between children and adolescents with and without NDD, particularly indicating a difference in 12.7 min of MVPA daily. The difference in LPA was not significant (g=0.450, p = 0.125). The decline in MVPA with age was more pronounced in those with NDDs, and the difference in MVPA was smaller for those with lower BMI. The variation in MVPA differences by age and BMI highlights the need to develop better physical activity habits and reduce these disparities for children and adolescents with NDDs. Show less

With a global annual cumulative incidence of depression at 4.5% in community-dwelling older adults, understanding non-pharmacological interventions is essential. This narrative review explores the neuroprotective mechanisms of physical activity (PA) on brain function and mental health in individuals aged 60 and older. We conducted a search across multiple databases (MEDLINE, PsycINFO, EMBASE) using keywords related to aging, cognition, and physical activity. Our analysis of relevant studies shows that PA benefits the brain through several pathways. Early findings focused on improved cerebral blood flow and glucose utilization. More recent evidence highlights that PA increases neurotrophic factors like BDNF and IGF-1, enhances mood-regulating neurotransmitters, and promotes structural adaptations in key brain regions. These findings suggest that PA is a cost-effective, multi-domain intervention. This review provides healthcare professionals with actionable evidence to incorporate PA into clinical practice for older adults. Show less

Skeletal muscle atrophy is a common complication of heart failure, with myocardial infarction (MI) being the primary cause. Yet, the mechanisms linking post-MI cardiac insufficiency to muscle atrophy have remained unclear. The molecular basis for the beneficial effects of exercise on exercise intolerance in MI patients also remains absent. Serum IL-27 levels were measured in 48 MI patients and correlated with cardiac injury markers. Along with this, a rat model of post-MI cardiac insufficiency was used to assess skeletal muscle mass, cross-sectional area (CSA) of muscle fibers, and the expression of atrophy-related (MAFbx, MuRF-1) and differentiation-related markers (MyoD, Myogenin). The impact of exercise on muscle atrophy, cardiac inflammation, and IL-27 expression was then evaluated, with a focus on macrophage polarization. Serum IL-27 level was significantly elevated in MI patients and that it was positively correlated with myocardial injury and cardiac insufficiency. In post-MI rats, skeletal muscle mass and CSA of muscle fibers were reduced. Meanwhile, the expression level of myogenic markers was downregulated, while that atrophy markers was upregulated. IL-27 treatment promoted catabolism in L6 myotubes, and of note, HIF-1α overexpression in macrophages enhanced IL-27 secretion, and increased MAFbx and MuRF-1 expression. IL-27 level was also elevated in the heart, serum, and gastrocnemius muscle of MI rats. Exercise counteracted these effects by promoting M2-like macrophage polarization and suppressing HIF-1α, thereby reducing IL-27 expression. Furthermore, exercise ameliorated IL-27-induced muscle atrophy via the WSX-1/gp130/pSTAT3 signaling axis. IL-27 contributes to muscle atrophy in post-MI cardiac insufficiency. Exercise attenuates IL-27-driven muscle wasting by modulating inflammation and promoting M2-like macrophage polarization. These findings provide insights into the mechanisms of MI-induced muscle atrophy and highlight the therapeutic potential of exercise in cardiac rehabilitation. [Image: see text] The online version contains supplementary material available at 10.1186/s12967-025-07527-7. Show less

The paraventricular hypothalamus (PVH) controls behavioral and physiologic processes, including appetite, social behavior, autonomic outflow, and pituitary hormone secretion. However, molecular markers for centrally projecting PVH neuron populations remain largely undefined, and a complete census of PVH cell types has not been established. Therefore, we performed extensive single-cell/nucleus RNA sequencing to catalog PVH neuron subtypes and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to map them spatially. Our spatial transcriptomic atlas resolves 26 Sim1 Show less

17β-Hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency is a rare 46XY disorder of sex development (DSD) of androgen biosynthesis. We aimed to describe the complexities in diagnosis, gender assignment, and the timing of irreversible surgical interventions in 17β-HSD3 deficiency. We described three genetically confirmed cases of 46XY DSD due to 17β-HSD3 deficiency. All of them had female-appearing external genitalia, and the third case had well-developed breasts with clitoromegaly. The biochemical evaluation showed hCG-stimulated T/A ratios of 0.4 and 0.35 in Cases 1 and 2, respectively, and an unstimulated T/A ratio of 0.25 in Case 3. Molecular analysis revealed three different 17β-HSD3 deficiency remains a challenging 46 XY DSD due to its clinical heterogeneity and diverse molecular spectrum. This report adds to current molecular knowledge by reporting two novel variants in the Show less

Lobar intracerebral haemorrhage (ICH) is associated with cerebral amyloid angiopathy (CAA) pathology. Uncertainty remains about the mechanisms leading from CAA to ICH. We investigated the distribution and characteristics of CAA, and its clinical and neuropathological associations. Participants underwent research autopsy in the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study. Neuropathologists rated tissue for CAA using standardised consensus criteria, as well as non-amyloid small vessel disease, Thal phase, and Braak stage. We compared the presence, distribution, and severity of CAA among different brain regions, and in the lobe or hemisphere affected by lobar ICH to corresponding contralateral regions. We evaluated the diagnostic accuracy of Vonsattel CAA grade on a post-mortem cortical specimen (simulating surgical biopsy) versus the reference standard of moderate-to-severe parenchymal CAA at autopsy. Among 162 participants, parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy were diffusely distributed among all cerebral lobes irrespective of the ICH location, but capillary CAA showed an occipital predominance. In lobar ICH, all CAA measures did not differ between the ICH lobe or hemisphere and the contralateral unaffected region. CAA measures did not increase with age, but they were higher in carriers of APOE ε2 or ε4 alleles and in individuals with higher Thal phase or Braak stage. Using a rule-out category of Vonsattel grade ≥ 1 to diagnose CAA on a simulated cortical biopsy achieved 100% sensitivity (95%CI 93.4-100), and a rule-in category of Vonsattel grade ≥ 2 had 79.5% specificity (95%CI 63.5-90.7) versus the reference standard. The distribution and severity of parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy are diffuse regardless of ICH location, indicating the need to better understand the factors underlying bleeding in CAA-affected vessels. Show less

Hepatoid lung carcinomas, similar to hepatoid carcinomas of other sites, are defined as extrahepatic tumors exhibiting divergent hepatocellular differentiation. Uniquely, hepatoid carcinomas of lung origin are reported to commonly express only hepatocyte paraffin 1 (HepPar1)-a hepatocellular marker, which recognizes mitochondrial enzyme carbamoyl-phosphate synthetase-1 (CPS1). Recently, HepPar1/CPS1 was found to accumulate in lung adenocarcinomas (LUADs) harboring STK11mutations, presumably as a genotype-associated metabolic adaptation. The impact of these insights on the concept of hepatoid lung carcinoma has not been explored. Here, we performed a detailed clinicopathologic and genomic analysis of carcinomas prospectively regarded as hepatoid with isolated HepPar1 expression (n = 17). We found that although robustly positive for HepPar1, these tumors were entirely negative for an extended panel of other hepatocellular markers (alpha-fetoprotein, Arginase1, Glypican3, and albumin-in situ hybridization). Morphologically, tumors exhibited solid-trabecular architecture with expanded granular-vacuolated-clear cytoplasm, thus evoking hepatoid morphology; however, focal-to-moderate intracytoplasmic mucin was consistently present, and hepatoid resemblance was variable. Pneumocytic markers (TTF1 and Napsin A) were entirely negative (except for cytoplasmic TTF1), commonly leading to diagnostic challenges at metastatic sites. Remarkably, next-generation sequencing revealed invariable STK11 mutations/loss (P < .00001 vs unselected LUAD, n > 2.5K). Patient survival was dismal (median, 5.8 vs 25 months for stage-matched LUAD, P = .0002). Tumors harbored high mitochondrial content by electron microscopy and other methods. For comparison, we reviewed conventional, predominantly acinar LUAD with HepPar1 expression (n = 22) and found that they also lacked any other hepatocellular markers, had invariable STK11 mutations/loss, increased granular cytoplasm, lower TTF1, and poor prognosis. We conclude that isolated HepPar1 expression in LUAD reflects mitochondrial adaptation to STK11 mutations rather than bona fide hepatocellular differentiation, and that HepPar1-expressing solid and granular adenocarcinomas represent an undifferentiated (solid, TTF1 negative) variant in this spectrum of tumors. Recognition of these tumors is warranted due to their exceptionally aggressive behavior, distinct pathogenomic features, and common association with diagnostic challenges. Show less

Conversion of cholesterol into bile acids is a central pathway for cholesterol disposal, which was mainly controlled by cholesterol 7alpha-hydroxylase (Cyp7a1). In present study, we aimed to investigate the effect and the potential underlying mechanism of microRNA-96 (miR-96) on atherosclerosis development. The anti-atherosclerosis effects of a miR-96 inhibitor (miR-96i) were evaluated using ApoE KO mice fed a high-fat diet, which was treated with miR-96i for 8 weeks. The regulatory mechanism was revealed and validated by RNA-seq transcriptomics, quantitative PCR and western blotting analyses in hepatic cells. The authors identified that miR-96i significantly decreased serum cholesterol and bile acid levels and attenuated arterial plaque in mice. We further revealed that miR-96 regulated Cyp7a1 via a FOXO1-involved indirect pathway, in which miR-96 directly modulated FOXO1 in a posttranscriptional manner. A coordinated regulatory effect of miR-96 and miR-185 on FOXO1 was also observed. The full spectrum of mechanisms underlying the antiatherosclerotic activity beside miR-96-FOXO1-CYP7A1 axis remains to be elucidated. This study provides convincing evidence for the pivotal role of miR-96 in FOXO1 modulation and CYP7A1-involved cholesterol-bile acid metabolism, suggesting that miR-96 is a novel therapeutic target for the discovery and development of drugs against ACVD. Show less

Three-dimensional (3D) spheroid models are increasingly used to emulate the tumour microenvironment for preclinical drug screening. This study aimed to optimise and assess spheroid formation from MDA-MB-468 triple-negative breast cancer (TNBC) cells using hanging drop, liquid overlay, and rigid scaffold methods under normal oxygen (NOC) and low oxygen (LOC) culture conditions. Spheroids were generated and characterised using bright-field microscopy with AnaSP morphometrics (sphericity, solidity, and perimeter). Gene expression of Epithelial-Mesenchymal Transition (EMT), stemness, and hypoxia/angiogenesis markers (CD44, HIF1A, VEGFA, TWIST1, SNAI1, and NES) was quantified using qPCR. The optimised model was further evaluated using field-emission scanning electron microscopy (FE-SEM) and Hoechst fluorescence. A workflow combining hanging-drop pre-aggregation with ultra-low attachment (ULA) or agarose-coated plates under NOC produced consistent, compact spheroids. Scaffold cultures formed rapidly but showed size variability under NOC and LOC. Across methods, spheroids were less compact, and gene expression patterns deviated from expected hypoxic responses. Spheroids cultivated under normoxic conditions demonstrated enhanced structural integrity and transcriptional fidelity. Nonetheless, the study identified that the most compact and resilient spheroids were achieved through the use of hanging-drop pre-aggregation combined with ULA-plates under NOC. The enhanced structural integrity and transcriptional fidelity observed in these spheroids make them valuable models for studying cancer biology and drug responses. The online version contains supplementary material available at 10.1007/s11033-026-11451-4. Show less

Diabetic lower extremity arterial disease (LEAD) is a manifestation of diabetic lower extremity vascular complications. This study aimed to screen the key single nucleotide polymorphism (SNP) gene signature in patients with type 2 diabetes mellitus (T2DM) and LEAD. A total of 147 patients with T2DM complicated by LEAD and 144 patients with T2DM without LEAD were enrolled for transcriptome sequencing. The Plink software was used to preprocess the data. Five machine learning methods were adopted to build the SNP diagnosis models. The receiver operating characteristic (ROC) curve was used to quantify the predicted probabilities of the model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the cluster Profiler package. Finally, regression statistical analysis was used to correlate the key SNPs with clinical information and biochemical indicators. A total of 24 SNPs were retained and 10 SNPs were risk allele genes. Nine SNPs (rs7412, rs1800629, rs699947, rs3918242, rs668, rs1800470, rs1800449, rs1800469, and rs1024611) were identified as the key SNPs sites. GO and KEGG pathway analyses revealed that these genes are mainly enriched in fluid shear stress and atherosclerosis. Finally, rs1800449 was associated with low-density lipoprotein cholesterol (LDL-C). With high density lipoprotein cholesterol (HDL-C), related site was rs1024611. The sites associated with total cholesterol (CHOL) were rs1800449 and rs7412.The site associated with apolipoprotein B (APOB) and apolipoprotein A1 (APOA1) were rs1800470 and rs1800469. This study authenticated nine SNPs for the diagnosis of T2DM patients with LEAD, which will be of great significance in the development of diagnostic molecular biomarkers for T2DM patients. Show less

Hypertension is a global target for noncommunicable diseases, and meditation-based interventions (MBIs) benefit patients with hypertension (HTN). The primary objective of this scoping review is to map the globally published MBI studies on patients with HTN. The secondary goal is to identify the role of brain-derived neurotrophic factor (BDNF) in HTN. Based on the Arksey and O'Malley protocol of the Joanna Briggs Institute framework for scoping review, 5 electronic databases were searched with search terms related to HTN and meditation. The open-access articles in the English language published between 1985 and 2024 were selected. The selected articles involved MBIs. All the studies were uploaded to the Rayyan software. Two reviewers worked independently and in duplicate to screen the studies first for title and abstract, and then for full text. Data were extracted based on the template for the intervention description and replication checklist. The data were summarized and reported as a narrative summary. In total, 966 studies were identified. After removing 429 duplicates, 537 studies were screened for their titles and abstracts. 467 studies were excluded based on the inclusion and exclusion criteria, 18 were not retrieved, and 20 were excluded with reasons. Finally, the full texts of 70 studies were read. 32 eligible studies were included in this review. The studies were divided into 3 categories based on meditation and into 7 categories based on outcome. Moreover, no study involving human subjects has analyzed the level of BDNF in HTN patients receiving MBIs. MBIs have shown promising results among HTN patients. There is a research gap in studies related to BDNF and meditation among hypertensive patients. The limitation of the review is the inclusion of open-access articles published only in the English language. Hypertension, Meditation, Mindfulness, Brain-Derived Neurotrophic Factor. Show less

Hepatoid adenocarcinoma (HAD) and adenocarcinoma with enteroblastic differentiation (ACED) are rare gastric cancer types that produce alpha-fetoprotein (AFP) that morphologically resembles the liver or fetal organ. This study investigated the molecular profiling of HAD and ACED compared with common-type gastric adenocarcinoma (CGA). This study enrolled 496 patients with gastric adenocarcinoma who underwent radical gastrectomy. Whole-exome sequencing and gene expression profiling were conducted to compare HAD/ACED and CGA. Immunohistochemistry was performed in 39 patients with HAD/ACED, including 10 who underwent genomic analysis. TP53 (100 %), CSMD3 (30 %), LRP1B, FAT3, TG, APOB, CREBBP, PASK, DROSHA, and STK40 (20 %) were mutated genes with high frequency (>20 %) in HAD/ACED. Gene expression analysis revealed 15 overexpressed genes in HAD/ACED, many of which were associated with hepatocytes and fetal organs. Furthermore, cancer stemness gene overexpression, including LIN28B, IGF2BP1, and HMGA2, which are related to TP53, was observed. Immunohistochemistry revealed positive staining for LIN28B (82 %), IGF2BP1 (94 %), and HMGA2 (72 %), as well as staining for AFP (69 %), GPC3 (75 %), and SALL4 (94 %). Additionally, positive cancer stemness gene staining was observed in CGA mucosa coexisting with HAD/ACED. HAD/ACED demonstrated higher TP53 mutation accumulation and TP53-related cancer stemness gene overexpression, including LIN28B, IGF2BP1, and HMGA2. Therefore, TP53 and these cancer stemness genes might be involved in the occurrence of HAD/ACED. Show less

Prior studies suggest that TikTok users vary in their engagement behaviors, including passive viewing, participatory interaction, and content creation, and exhibit varying levels of problematic-use risk. Yet it remains unclear which combinations of these engagement behaviors correspond to higher versus lower risk, and which psychological vulnerabilities contribute to high-risk patterns. In a two-wave study of 715 Chinese young adults, we applied latent profile analysis (LPA) to problematic TikTok use and the frequency of passive viewing, participatory, and contributory behaviors at Time 2. We then used multinomial logistic regression with the three-step method to prospectively examine how Time 1 measures of psychopathology and related affective/cognitive vulnerabilities, including depression, social anxiety, life satisfaction, emotion dysregulation, and boredom proneness, predicted TikTok profile membership. Four profiles emerged: Minimal Users (6.7%), Passive Watchers with High Problematic Use Tendencies (38.0%), Moderate Users with Mild Problematic Use Tendencies (42.4%), and Active Users with Low Problematic Use Tendencies (12.9%). Greater life satisfaction, lower social anxiety, and lower boredom proneness at baseline predicted membership in the Active rather than Passive, Moderate, or Minimal profiles. Greater emotion dysregulation predicted membership in the Passive rather than Moderate profile. These findings highlight substantial heterogeneity in TikTok use and suggest that higher baseline psychological wellbeing may increase the likelihood of more active and less problematic patterns of engagement. The current study extends prior LPA research by specifying how risk manifests in everyday use, identifying contributors to high-risk profiles, and extending empirical support for the I-PACE theoretical framework of Internet use disorders. Show less

Physical activity (PA) is an important non-pharmacological intervention that can slow the progression of Chronic Obstructive Pulmonary Disease (COPD). Unfortunately, PA levels in older adults with COPD remain low, and there is substantial heterogeneity within this population. Therefore, identifying potential subgroups is essential for developing targeted interventions. The purpose of this study is to identify latent profiles of PA, and explore the associated factors to inform personalized interventions for this population. This multicenter cross-sectional study was conducted from November 2024 to March 2025 at a tertiary hospital and four community health service centers in the Changning District of Shanghai. The revised International Physical Activity Questionnaire-Long (IPAQ-L) was utilized to assess PA and sedentary behavior. Latent profile analysis (LPA) was employed to classify the subgroups, followed by multinomial logistic regression to explore influencing factors. A total of 423 older adults with COPD (male N = 383; aged 60-89) were included in this study. LPA identified three distinct PA profiles, named the "moderate activity-moderate sedentary-low barrier (C1) group", the "low activity-high sedentary-high barrier (C2) group", and the "high activity-low sedentary-moderate barrier (C3) group". The factors were significantly associated with PA, including Body Mass Index (BMI), disease duration, number of hospitalizations, GOLD stage, COPD Assessment Test (CAT) score, exercise self-efficacy, and exercise social support (p < 0.05). LPA identified three subgroups of PA in older adults with COPD. The results of this research will facilitate targeted interventions for each of the identified subgroups with distinct characteristics, thereby enhancing the management of COPD and reducing healthcare burdens. Show less

Diabetes-related neuropathy is a prevalent microvascular complication among elderly individuals with type 2 diabetes mellitus (T2DM). Apolipoprotein A1 (ApoA1) and Apolipoprotein B (ApoB) play opposing roles in lipid metabolism, and the ApoB/ApoA1 ratio has emerged as a sensitive marker of cardiometabolic risk. This study aimed to examine the association between ApoA1, ApoB and the ApoB/A1 ratio with the presence of diabetes-related neuropathy as indicated by MNSI scores. A cross-sectional study was conducted on 63 T2DM patients aged ≥60 years. Neuropathy was assessed using the Michigan Neuropathy Screening Instrument (MNSI), while ApoA1 and ApoB levels were measured via turbidimetry. Comparative and correlational analyses were performed to explore relationships between apolipoproteins, neuropathy status, HbA1c and lipid profiles. Diabetes-related neuropathy was identified in 55.6% of participants. ApoB and the ApoB/A1 ratio were significantly elevated in subjects with neuropathy (p = 0.015 and p = 0.014, respectively), while ApoA1 levels did not differ significantly (p = 0.172). MNSI scores were positively correlated with ApoB (r = 0.426; p < 0.001) and ApoB/A1 ratio (r = 0.431; p < 0.001), but not with ApoA1. HbA1c showed positive correlations with ApoB and the ratio and a negative correlation with ApoA1. Elevated ApoB and ApoB/A1 ratio are significantly associated with diabetes-related neuropathy in elderly T2DM patients. The ApoB/A1 ratio may serve as a valuable biomarker for identifying individuals at higher risk of neuropathic complications. Show less

Heart function depends on cardiomyocyte contractile apparatus and proper sarcomere protein expression. Variants in sarcomere genes cause inherited forms of cardiomyopathy and arrhythmias, including atrial fibrillation. Recently, a sarcomere component, myosin-binding protein-H like (MyBP-HL), was identified. MyBP-HL is mainly expressed in cardiac atria and is homologous to the last three C-terminal domains of cardiac myosin-binding protein-C (cMyBP-C). The MYBPHL R255X nonsense variant has been linked to atrial enlargement, dilated cardiomyopathy, and arrhythmias. Similar nonsense mutations in MYBPC3 are linked to hypertrophic cardiomyopathy, with these mutations preventing myofilament incorporation and the degradation of the truncated protein. However, the allele frequency of the MYBPHL R255X variant is too high in the human population to be pathogenic. We sought to determine whether MYBPHL nonsense variants impact on MyBP-HL sarcomere integration and degradation of the truncated protein, and whether the MyBPHL nonsense variants lead to changes in cardiomyocyte calcium dynamics and contractility. We mimicked human MYBPHL nonsense variants in the mouse Mybphl cDNA sequence and tested their sarcomere incorporation. We demonstrated that full-length MyBP-HL overexpression showed the expected C-zone sarcomere incorporation. Nonsense variants showed defective sarcomere incorporation. We demonstrated that full-length MyBP-HL and MyBP-HL nonsense variants were degraded by both proteasome and calpain mechanisms. We did not observe changes in calcium transients. In addition, we observed changes in contraction kinetics, including sarcomere shortening. Together, these data support the hypothesis that MYBPHL nonsense variants are functionally similar. Show less

N-carbamylglutamate (NCG) is an activator of arginine biosynthesis, but its specific role in crustaceans remains poorly understood. This study aimed to investigate the effects of NCG on arginine biosynthesis capacity, metabolism, digestion, and the gene expression of the mTOR signaling pathway in Eriocheir sinensis. In Experiment 1, hepatopancreas was cultured in vitro with NCG medium (0, 65, 75, and 85 mg/L NCG). In Experiment 2, crabs were fed either regular feed or NCG feed (content: 302.96 ± 4.07 mg/kg) for 14 days. In Experiment 1, NCG significantly upregulated pyrroline-5-carboxylate synthase (p5cs) gene expression (P < 0.05), an enzyme that is related to arginine biosynthesis. Similarly, dietary NCG upregulated p5cs expression and significantly increased the activities of carbamoyl-phosphate synthase-1 (CPS-1) and P5CS in the hepatopancreas and intestine (P < 0.05). Metabolomics analysis indicated that NCG altered the metabolic profile of the hepatopancreas, promoting cholesterol metabolism, and arginine and proline metabolism. In the intestine, trypsin and α-amylase activities were significantly elevated (P < 0.05). NCG also altered the composition of intestinal microflora, with an increase in Proteobacteria and in the ratio of Firmicutes to Bacteroidota. Additionally, NCG increased the content of signaling molecule nitric oxide (NO) and upregulated the expression of genes in the mTOR signaling pathway (P < 0.05). In conclusion, NCG supplementation enhanced arginine biosynthesis capacity, stimulated intestinal enzymatic activities, and upregulated mTOR signaling pathway gene expression in Eriocheir sinensis, indicating the potential for improved metabolism and digestion. Show less

To date, despite the new lipid-lowering drugs, some subjects do not reach LDL-cholesterol and/or lipoprotein(a) [Lp(a)] goals and lipoprotein apheresis (LA) plays a role in atherosclerosis prevention. The aim of this study is to paint a portrait of the current LA activity in Italy, collecting data via an electronic survey. Forty-seven centers were contacted, data from 142 patients (male 67%) were obtained from 15 sites. Two sites had discontinued LA treatment. In the active sites, a median of 17 [14-26] LA treatment/patient per year was performed; 7/13 sites used more than one LA system, with venous vascular access used in 87% of cases. High Lp(a) plasma concentrations (> 60 mg/dL or ≥ 145 nmol/L) were recorded in 73/142 patients; 14/36 homozygous familial hypercholesterolemia patients were on lomitapide or evinacumab therapy. The PORTRAIT survey would like to promote a network to better manage the patients on chronic LA. Show less

In this work, we conducted a study on the analysis of monosodium glutamate (MSG) in broths by the induced fluorescence derivatization (IFD) method. The method was based on the derivatization of naturally non-fluorescent MSG to form a fluorescent structure when reacting with orthophthalaldehyde (OPA). The chemical reaction parameters were optimized in an aqueous medium. The calibration curve was subsequently established under optimal conditions, and its linearity was assessed using variance analysis, which indicated a significant regression. The low LOD (0.006 ng mL Show less

Dietary bile acids (BAs) have been shown to affect food intake in chicks; however, the underlying central mechanisms remain unclear. This study investigated the effects of taurochenodeoxycholic acid (TCDCA), sodium taurocholate (STC), chenodeoxycholic acid (CDCA), taurocholic acid (TCA), hyodeoxycholic acid (HDCA), allocholic acid (ACA), and a mixed BA (MBA; 4.6% hyodicolate, 72.6% hyodeoxycholate, and 18.3% chenodeoxycholate) on feed intake and hypothalamic mRNA expression of appetite-related neuropeptides in chicks. To determine the effects, intracerebroventricular (ICV) injections of three doses (0.25, 0.5, and 1 μg) of each BA were administered to 5-day-old layer-type chicks, and feed intake was recorded at 30, 60, and 120 minutes post-injection. Quantitative PCR was used to determine the hypothalamic mRNA expression of neuropeptide Y (NPY) and its receptors, agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), and melanocortin receptors. Results showed that feed intake decreased after ICV administration of CDCA, CA, HDCA, MBA, and STC, whereas ACA and TCDCA increased intake (P < 0.05). TCDCA upregulated NPY5R, while CDCA downregulated NPY4R (P < 0.05). STC and CA increased POMC and MC4R expression and reduced AgRP (P < 0.05), whereas HDCA decreased AgRP (P < 0.05). ACA reduced MC4R expression, and MBA downregulated both NPY4R and NPY5R (P < 0.05). The result suggests that both orexigenic and anorexigenic neuropeptide genes are involved in the effects of BAs. The effect of BAs acts in a dose-dependent manner in the hypothalamus to influence feed intake. Show less

The effects of ovomucoid (OVM), a by-product of egg white, and its hydrolysates on adipocyte differentiation and lipid accumulation were investigated. The OVM hydrolyzed using Alcalase® and pepsin was named AH and PH, respectively. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis revealed significant changes in molecular weight of both hydrolysates, with AH showing a higher degree of hydrolysis. AH exhibited a more pronounced inhibitory effect on fat accumulation than PH. In in vitro experiments, AH and PH suppressed lipid accumulation during 3T3-L1 adipocyte differentiation, with AH inhibiting lipid accumulation most effectively. Oil red O staining and triglyceride measurements revealed lipid reduction in AH-treated cells, indicating that AH plays a major role in preventing lipid accumulation in adipocytes. In addition, AH inhibited the expression of lipid transcription factors (CCAAT/enhancer-binding protein alpha (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), and sterol regulatory element-binding proteins (SREBP-1c)), adipogenesis-related factors (fatty acid synthase (FAS) and ACC1), insulin-related factors (insulin receptor substrate (IRS2) and protein kinase B (AKT2)), and lipolysis-related factors (glycerol-3-phosphate acyltransferase (GPAT), CD36, and lipoprotein lipase (LPL)) in a concentration-dependent manner. Specifically, the effect of AH was most pronounced in the early stages of adipocyte differentiation, where it activated AMPK early to associate energy homeostasis and downregulate genes important for cell cycle and lipid formation. This study suggests that OVM hydrolysates prepared using Alcalase® may contribute to the development of new strategies for the obesity treatment market. Show less

Sex hormones, particularly testosterone, modulate immune function during critical illness, and patients with septic shock frequently exhibit hypotestosteronemia. However, the causal relationship between testosterone and outcomes remains unclear owing to the confounding effects of illness-related changes in hormone levels during acute illness. We investigated 469 patients with septic shock in multicenter ICUs using a testosterone polygenic score (PGS) derived from genome-wide association studies combined with two-sample Mendelian randomization to establish causal relationships independent of confounding factors. Cox proportional hazards regression was performed to assess the association with 28-day mortality. Additionally, we evaluated whether apolipoprotein C3 (ApoC3) levels modified the protective effects of testosterone using interaction models and the likelihood ratio test. Higher genetically predicted testosterone levels were significantly associated with improved 28-day survival (adjusted hazard ratio [HR] 0.72 per 1-standard deviation increase in PGS; Genetically determined higher testosterone levels are causally associated with improved survival in patients with septic shock, particularly in men and in those with lipid dysmetabolism. These findings identify testosterone as a potential therapeutic target and highlight lipid metabolism as a key modifier of the protective effects of testosterone against septic shock, warranting the investigation of testosterone-based interventions in future clinical trials. The online version contains supplementary material available at 10.1186/s13054-026-05860-x. Show less

Anger is prevalent in chronic pain (CP), often co-occurring with heightened distress and disability. The complexity of the anger construct manifests in heterogeneity of how anger is experienced, expressed, and regulated. Nevertheless, most work does not consider the inter-relationships between multiple dimensions of anger, limiting understanding of how anger might differentially contribute to pain outcomes. Here, various anger metrics and latent profile analysis (LPA) were utilized to identify disparate anger profiles in people with CP. Whether these profiles associated cross-sectionally and longitudinally with pain outcomes was subsequently examined. Data was collected from 735 treatment-seeking adult patients with CP of varied etiologies, of which 242 also completed follow-up assessments about 5 months after baseline. Anger measures included state and trait anger, anger expression (anger-in, anger-out), anger control (control-in, control-out), and perceived injustice. Pain outcomes included pain- intensity, distribution, interference, and behavior, and physical function. LPA identified four distinct anger profiles characterized by the combination of varying levels (low, medium, high) of anger and of perceived injustice. These profiles significantly associated with pain outcomes at both baseline and follow-up, above and beyond anxiety and depression. Profiles with medium-to-high levels of both anger (state, trait, and expression) and perceived injustice predicted the worst pain outcomes, suggesting that injustice-based profiling should be prioritized for anger-related stratification of risk in CP. The mechanistic and prognostic value of these anger profiles suggests that early assessment could enhance long-term treatment planning and advance personalized pain care, further emphasizing the need for tailored, anger-focused, patient-specific interventions. PERSPECTIVES: This study demonstrates that multidimensional anger profiles, particularly those marked by higher perceived injustice, are linked to more severe and persistent high impact chronic pain. Identifying these profiles may facilitate early clinical screening for at-risk patients, personalized emotion-focused interventions, and potentially prevent progression to high-impact chronic pain and long-term disability. Show less

Complex PTSD (CPTSD) is often associated with prolonged or repeated trauma exposure and the experience of intimate partner and childhood abuse. CPTSD includes the criteria for PTSD (re-experiencing, avoidance, and sense of threat) in addition to three criteria for self-organization disturbances (affective dysregulation, negative self-concept, and relational disturbance). This study aimed to assess profiles of CPTSD symptoms and their association with psychiatric distress among people with co-occurring Serious Mental Illness (SMI; schizophrenia/schizoaffective, bipolar, and treatment-refractory major depression). Treatment-seeking participants ( A model with three classes best fit the data with the most parsimonious interpretation: 26.7% ( The results demonstrate the heterogeneity in symptom presentation across the PTSD classes and that, despite similar diagnoses, individuals may present with varying symptom patterns. This emphasizes the importance of studying CPTSD in subpopulations of persons with SMI. Show less

To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the whole-exome sequencing data from 280 CHH probands, we identified 15 potential splice-site variants in CHD7, ANOS1 and FGFR1 by using in silico software. The functional consequences of these variants were analyzed by the minigene assay or RT-PCR analyses of RNA taken from the peripheral lymphocytes. Detailed phenotyping was performed in the CHH patients harboring deleterious variants and their available family members. 11 out of 15 potential splice-site variants were demonstrated to cause mis-splicing, resulting in loss of function through deletion, insertion or frameshift of amino acids in the proteins. Most patients with deleterious splice-site variants in CHD7, ANOS1, FGFR1 presented with gene-specific non-reproductive phenotypes, confirming the pathogenic contribution of these variants to CHH. Our study indicated that splice-site variants in CHD7, ANOS1, FGFR1 underlie the genetic basis of ~3.9% of CHH patients, warranting the inclusion of potential splice-site variants for genetic diagnosis and counseling of CHH. Show less

Suicidal behavior is a multifactorial and highly heritable phenotype; however, data concerning its genetic determinants in disparate ethnic groups remain limited. Genes implicated in serotonergic neurotransmission and stress response regulation are regarded as primary candidates for elucidating biological vulnerability to suicide. The objective of this study is to investigate the relationship between suicide attempts and candidate gene polymorphisms in an ethnically homogeneous Kazakh population from Astana, Kazakhstan. The study's sample population comprised 126 patients with a documented history of suicide attempts and 120 age- and gender-matched controls without a history of suicidal behavior. A comprehensive genotyping analysis was conducted, encompassing polymorphisms in genes associated with serotonergic signaling, stress response, and neuroplasticity ( Show less

Anoikis resistance and epithelial-mesenchymal transition (EMT) are crucial factors in tumor invasiveness and metastasis in lung adenocarcinoma (LUAD). Identifying anoikis-EMT-related genes could be beneficial for predicting prognosis and immunotherapeutic efficacy in patients with LUAD. This study aims to establish and validate a novel prognostic signature based on anoikis-EMT-related genes for LUAD and to identify the potential biomarkers encapsulated within it. Anoikis-related genes and EMT-related genes were retrieved from the GeneCards and dbEMT 2.0 databases. Univariate Cox regression analysis and principal component analysis (PCA) were conducted to define anoikis and EMT levels. Gene expression and clinical information of patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Univariate Cox regression and multivariate Cox regression analyses were conducted to construct a risk score model. Immune correlation and drug sensitivity analyses were performed to investigate the association of the risk score with the immune profile and antitumor treatment. Three essential genes in the model were examined for messenger RNA (mRNA) expression by reverse transcription-polymerase chain reaction (RT-PCR) and for protein levels via the Human Protein Atlas (HPA) database. LUAD patients demonstrating low Anoikis Potential Index (API) combined with high EMT Potential Index (EPI) exhibited the poorest overall survival (OS). We further constructed a nine-gene prognostic risk model that combines anoikis and EMT. High-risk patients demonstrated significantly shorter survival duration. The clinical-prognostic nomogram accurately predicted outcomes at 1, 3, and 5 years. In addition, patients in low-risk group demonstrated superior immune responses to treatment and were more sensitive to commonly used chemotherapy drugs. Our validation studies confirmed upregulated expression of ANGPTL4, SLC2A1, and BIRC5 in LUAD, observed at both transcriptional and translational levels. The anoikis-EMT-based risk model effectively forecasts both OS and immunotherapy response in LUAD patients, accelerating the identification of groundbreaking molecular biomarkers and prospective molecular targets. Show less