The gene has remained a central organizing concept in biology for more than a century, yet its definition has become increasingly difficult to reconcile with contemporary molecular and genomic evidence. This article combines a historical review with a conceptual perspective to examine the evolution of the gene concept from Mendelian heredity to postgenomic biology. Early gene concepts assumed discreteness and stable relationships between genes and traits. These assumptions were highly productive but became inadequate as gene regulation, RNA processing, epigenetic modification, and long-range genomic interactions were discovered. Rather than converging on a refined definition, biological research progressively expanded the range of phenomena that gene concepts were required to accommodate. By synthesizing key developments across classical genetics, molecular biology, and genomics, this review explains why defining the gene has become empirically challenging while the gene itself remains indispensable in biological practice. On this basis, a pragmatic working definition of the gene is proposed that is grounded in DNA sequence and reproducible transcriptional output under regulatory control, while remaining compatible with contemporary genomic research.
Prostate cancer (PCa) is characterized by a unique metabolic dependency on the hyperactivated tricarboxylic acid (TCA) cycle, creating a distinct vulnerability to cuproptosis-a copper-dependent form of regulated cell death. However, metabolic plasticity allows tumor cells to evade single-pathway inhibition through compensatory glycolysis, limiting the efficacy of copper-based therapies. Therefore, there is an urgent need to develop integrated nanoplatforms capable of orchestrating a dual-pathway metabolic blockade to overcome this therapeutic resistance. Herein, we engineered a self-assembling copper-epigallocatechin gallate (EGCG) nanoreactor (Cu-EQ NP) designed to execute a synchronized dual-metabolic assault. The Cu-EQ NPs leverage the tumor microenvironment to release copper ions that trigger TCA-dependent cuproptosis, while the EGCG component simultaneously inhibits key glycolytic enzymes to prevent metabolic escape. Mechanistically, this lethality is self-amplified by EGCG-quinone-mediated depletion of glutathione (GSH) and the downregulation of the ATPase copper-transporting beta (ATP7B) efflux pump, leading to irreversible intracellular copper accumulation. Furthermore, we demonstrate that this metabolic collapse is highly immunogenic. In a syngeneic RM-1 mouse model, Cu-EQ NP-induced immunogenic cell death (ICD) released damage-associated molecular patterns (DAMPs) that successfully transformed the immunologically "cold" tumor microenvironment. This remodeling was characterized by enhanced dendritic cell maturation, M2-to-M1 macrophage repolarization, and robust infiltration of cytotoxic CD8 + T cells, resulting in potent tumor regression. The Cu-EQ nanoreactor represents a precision nanomedicine strategy that converts the specific metabolic vulnerabilities of PCa into a fatal weakness. By integrating dual-metabolic disruption with robust immune activation, this platform offers a promising therapeutic paradigm for overcoming resistance in advanced prostate cancer.
Menke-Hennekam syndrome (MKHK) is a rare autosomal dominant disorder caused by mutations in the CREBBP and EP300 genes. The absence of established diagnostic criteria and non-specific clinical manifestations complicate timely diagnosis and management. This report presents a case of MKHK in which early diagnosis and intervention were achieved through the application of rapid whole-genome sequencing (rWGS), a tool that offers superior speed and genomic coverage compared to whole-exome sequencing (WES). This case report describes a male Han Chinese neonate who presented at birth (0 days) with intrauterine growth restriction, respiratory distress, and feeding difficulties. During follow-up, he developed hearing loss and demonstrated global developmental delay. Clinical examination revealed craniofacial dysmorphism. Trio rWGS was performed in the neonatal period, with results returned within 72 h of sample submission at 23 days of age. Trio rWGS identified a de novo missense variant in the CREBBP gene (c.5570A > C, p.His1857Pro). Sanger sequencing confirmed its absence in both parents, and the variant was classified as likely pathogenic despite no prior documented cases. Based on integrated genetic and clinical findings, a neonatal diagnosis of MKHK-ID4 was established. Following this diagnosis, early targeted interventions were initiated, including hearing aid fitting, enrollment in a comprehensive rehabilitation program, and planning for necessary surgical corrections. Significant developmental improvement was observed at the 15-month follow-up assessment. In this case, rWGS facilitated a neonatal diagnosis of MKHK-ID4 and enabled early multidisciplinary intervention during a critical neurodevelopmental window. This experience suggests that such an approach may contribute to improved developmental outcomes in this rare disorder, though further studies are required to confirm its broader applicability and long-term benefits.
The bulb of Fritillaria unibracteata is a valuable traditional Chinese medicinal material whose bioactive compound accumulation is closely linked to carbon metabolism. As a perennial herb, its bulbs undergo multi-year developmental cycles, with starch and sucrose serving as key storage and mobilizable carbohydrates, respectively. However, the age-dependent dynamics of starch-sucrose interconversion during bulb development and its expression patterns remain poorly understood, limiting our comprehension of the carbon allocation dynamics that support biomass accumulation and medicinal metabolite production. Starch content increased progressively from the first to fourth year, peaked in the fourth year, and then significantly declined in the fifth year. By contrast, sucrose levels exhibited an opposite trend, decreasing in the fourth year and rising sharply in the fifth year, indicating a marked shift in carbohydrate allocation during the late developmental stage. Transcriptome analysis identified 21,964 differentially expressed genes, among which the starch and sucrose metabolic pathway was significantly enriched. Notably, key genes involved in starch biosynthesis, including ADP-glucose pyrophosphorylase and soluble starch synthase/granule-bound starch synthase, showed their highest expression levels in the fourth year, coinciding with maximum starch accumulation. Conversely, the expression of genes associated with sucrose biosynthesis, particularly sucrose phosphate synthase, was significantly upregulated from the fourth to fifth year, corresponding to the observed sucrose increase. Enzyme activity assays mirrored these transcriptional patterns. Weighted gene co-expression network analysis further identified modules associated with starch-sucrose metabolic traits, providing evidence for coordinated transcriptional networks in carbon allocation. Collectively, these findings reveal a pronounced metabolic transition from starch accumulation to sucrose synthesis during bulb development. The transition from the fourth to fifth year represents a critical developmental stage, during which the carbon allocation pattern shifts from starch-dominated storage to enhanced sucrose accumulation and mobilization. This study provides evidence for an age-dependent starch-sucrose metabolic pattern during bulb development in F. unibracteata, offering a theoretical basis for understanding carbon allocation dynamics in Fritillaria bulbs.
Pain may be linked to neuropsychiatric symptoms in dementia but the nature of these associations is unclear. The aims of this study were to examine the concurrent validity of pain scales and to investigate the relationship between pain and neuropsychiatric symptoms in community-dwelling people with dementia. This study recruited dyads of people with dementia and their caregivers. Questionnaires measuring pain (Numeric Rating Scale, Brief Pain Inventory Short Form, EQ5D3L) and cognition (Mini- Addenbrookes Cognition Examination) were completed by people with dementia. Dyad partners completed the Neuropsychiatric Inventory Questionnaire (NPI-Q). We examined the degree of agreement between different measures of pain and compared the NPI-Q score and items between people with dementia with and without troublesome pain (NRS ≥ 4, NRS < 4), and between those with single and multisite pain. The study recruited 35 individuals with dementia (49% female, mean age 80 with a range of 65-91 years, mean Mini-ACE 13.6/30) and 35 dyad partners. 66% of people with dementia had troublesome pain and compared to those without troublesome pain they were not significantly different in terms of age, sex, frailty, or other demographic variables, but were more likely to take regular paracetamol. Agreement between the NRS and EQ5D3L pain score was good (Cohen's kappa 0.70, p<0.001), as was agreement between the NRS and BPI-SF with a close to 0 mean difference between the scores on a Bland-Altman plot. The total NPI-Q score was not significantly associated with the presence of troublesome pain. Of all NPI-Q symptoms, only disinhibition showed associations with both painseverity and multisite pain (44% vs 0% and 38% vs 0% respectively, both p<0.05). Community-dwelling people living with dementia can self-report pain using a range of pain scales. Certain neuropsychiatric symptoms may be more common in the presence of pain but requires further study with larger cohorts.
Emergency care is essential for the management of the growing burden of disease and traffic injuries in low- and middle-income countries (LMICs). In Nepal, nearly one in ten deaths in 2017 were attributed to injury. The Primary Emergency Care (PEC) training package of 6 days duration was developed to equip the various health care cadres with knowledge and skills to deliver emergency response. The study evaluates the effectiveness of the training, skill utilization, and the significance of an enabling work environment on application of acquired knowledge and skills. A mixed-methods evaluation was conducted using the four-level Kirkpatrick Model (KM) to assess the PEC training. Participant details and training scores were obtained from training records of 295 training graduates for level one results. Pre/post-knowledge tests were compared using paired t-tests. Eleven health facilities were purposively selected for follow up, assessing 48 PEC graduates via knowledge assessments, structured clinical skills assessments, and simulations. Qualitative data were collected via 19 in-depth interviews, 10 key informant interviews with hospital leadership, and 11 focus group discussions (FGDs) with non-PEC-trained staff. These qualitative data were thematically analyzed using Ms-excel. There was a significant 35.9% ± 17.3% increase in knowledge after the PEC training (p = 0.001), with a significant 7.2% ± 12.9% decline at study follow up (p = 0.001), although there was no significant difference by length of time since the training (p = 0.652). Paramedics showed the greatest loss in knowledge compared to other health cadres (p = 0.005). Trainees reported increased confidence, and workplace observations indicated a positive "ripple effect" of peer-to-peer knowledge sharing among PEC and non-PEC staff. The PEC training significantly improved knowledge and skills with evidence of sustained knowledge retention although a modest but significant decline was observed over time along with evidence of workplace application of skills. Limitations existed in measuring patient level outcomes as per the KM, positive spillover effects along with an enabling environment were reported in emergency departments as result of the training. The training is a feasible, low-cost approach to strengthening emergency care in resource-limited settings like Nepal.
Rapid urbanization has heightened the need for evidence-based healthy city planning. To resolve the methodological limitations of parallel biometric data stacking, this study developed a synchronized cross-modal framework to evaluate the restorative potential of a 9-typology urban-to-natural landscape continuum. A laboratory experiment was conducted with 42 healthy undergraduate students (21 males, 21 females; mean age = 21.4 ± 1.8 years). Brain activity (EEG), visual attention (eye-tracking), and peripheral autonomic signals (EDA, HRV, respiration) were synchronously recorded alongside the Profile of Mood States (POMS) scale. To integrate these multi-scale data streams, we formulated the Cross-Modal Restorative Index (CMRI). The empirical findings reveal a distinct, non-linear hierarchy of environmental restoration. Pristine natural environments, especially Mountainous and Field landscapes, elicited complete "Integrated Restoration," characterized by significant systemic convergence: central cognitive relaxation via posterior α power activation (Field: 7.35; Water: 7.03), robust parasympathetic upregulation (Field HF: 12518.77), and profound down-regulations in subjective tension (Mountainous: 18.6 → 12.3) and fatigue. Conversely, built landscapes demonstrated "Fragmented Restoration." Notably, Road scenes exhibited a localized dissociation where physiological calming (sharp increase in posterior α wave SD from 15.11 to 20.54) was decoupled from visual and psychological domains, with over 74% of visual dwell time remaining locked on artificial elements and subjective fatigue rising (15.3 → 16.2). These findings provide quantitative, systems-level evidence for integrating ecologically authentic blue-green infrastructure into resilient urban design.
Surgical management of spinal metastases aims to palliate symptoms but poses significant perioperative risks. Traditional tools like survival scores and comorbidity indices inadequately capture the multidimensional frailty in cancer patients, prompting interest in frailty indices for risk stratification. This meta-analysis evaluates the predictive value of frailty indices for postoperative outcomes in spinal metastasis surgery. Adhering to PRISMA guidelines, PubMed, Embase, Cochrane Library, and other databases were systematically searched until May 2025. Observational clinical studies reporting frailty indices and postoperative outcomes (complications, LOS, nonroutine discharge, and survival rate) in spinal metastasis surgery were included. Study quality was assessed via Newcastle-Ottawa Scale. Pooled odds ratios (ORs) were calculated using fixed-effect model. A total of 12 studies involving 17,446 patients were included. The predictive value of several frailty indices, such as the 5-item/ 11-item modified frailty index (mFI-5/mFI-11), Metastatic Spinal Tumor Frailty Index (MSTFI), and Johns Hopkins Adjusted Clinical Groups (JHACG), were assessed. Some of the frailty indices predicted adverse outcomes: prolonged LOS (mFI-5 OR = 1.67, p = 0.014; JHACG OR = 2.65, p < 0.001), nonroutine discharge (MSTFI OR = 1.59, JHACG OR = 1.79; all p < 0.001), and complications (mFI-11 OR = 2.94, p = 0.003; MSTFI OR = 1.42, p < 0.001; JHACG OR = 1.54, p < 0.001). Survival prediction was inconsistent; only MSTFI correlated with 30-day mortality in one study (p < 0.05). Synthesized evidence from observational studies suggests that frailty indices were potential prognostic factors to predict post-operative morbidity, LOS, and discharge complexity. However, survival prognostication remains limited by tumor biology variability and methodological heterogeneity. Future efforts should integrate frailty assessments with tumor-specific factors to enhance prognostic precision and guide personalized perioperative optimization.
Sotagliflozin is a dual SGLT-1 and SGLT-2 inhibitor approved by the FDA in 2023 which has emerged as a novel therapeutic agent for the management of type 2 diabetes mellitus. In this study robust and sensitive LC-MS/MS method was developed and validated for quantification of sotagliflozin in rabbit plasma as rabbit is commonly used non-rodent model for preclinical research. Sample preparation involved protein precipitation for efficient analyte extraction from rabbit plasma. Chromatographic separation was performed utilizing on BDS Hypersil C18 column (100 mm x 4.6 mm, 5 μm) using mobile phase composed of methanol (85%) and 5 mM ammonium acetate in milli-Q water (15%) and rolipram as internal standard. The method employed flow rate of 0.7 mL/min with a total runtime of 4 min and an injection volume of 10 µL. Method validation was carried out in accordance with ICH M10 guidelines, covering precision, accuracy, selectivity, recovery, and stability at different storage conditions. The method was found to be linear over the concentration range of 10-1280 ng/mL with sensitivity of 10.20 ng/mL (LLOQ) in rabbit plasma. Recovery of analyte from the rabbit plasma was found to be > 92% with stability > 99% at different storage conditions (viz., room temperature, autosampler, freeze-thaw and frozen). Overall, the developed LC-MS/MS method offers a simple, precise and reproducible approach for the quantification of sotagliflozin in rabbit plasma and is well-suited for application in pharmacokinetic and other preclinical studies.
Breast cancer (BC) has become the most common malignancy worldwide. Our aim was to assess the global diversity of disability due to breast cancer in 204 countries and territories. Using data from the Global Burden of Disease (GBD) 2021 study the diversity of disability due to breast cancer was estimated for 204 countries and territories, and breast cancer incidence, prevalence, mortality, and Years Lived with Disability (YLDs) were further assessed. Absolute number, rate, and age standardized rate with 95% uncertainty intervals (UIs) were used to compare the difference. Data analysis was further stratified by the socio-demographic index (SDI) of the regions, average annual percentage changes (AAPC) and trends were analyzed by the Joinpoint regression procedure. From 1990 to 2021, the global disability-adjusted life years (DALYs) caused by breast cancer showed a trend of first decrease and then increase in 204 countries, especially during the epidemic period of Corona Virus Disease 2019 (COVID-19) from 2019 to 2021, with 63% of countries experiencing an increase in DALYs for three consecutive years, mainly in Africa. During this period, there was a significant increase trend in DALYs caused by breast cancer in low - and middle-income countries, with Turkey having the highest growth rate. High-income countries showed declines, with Denmark, Luxembourg and the United Kingdom experiencing declines of more than 50%. For males, the highest incidence, prevalence, mortality, and DALYs are mainly concentrated in the Eastern Sub-Saharan Africa region. For females, high incidence and prevalence are found in economically developed regions such as Europe and North America, while the highest mortality and DALYs are primarily concentrated in the Oceania region. The DALYs of breast cancer patients in the 15-49 years age group are highest in low-middle SDI countries, approximately 180.86 per 100,000 (95% UI:161.08, 201.32). For the 50-74 years age group, the highest DALYs are found in low SDI countries, about 754.47 per 100,000 (95% UI: ). In the ≥ 75 years age group, the highest DALYs are observed in high SDI countries, approximately 1166.46 per 100,000 (95% UI:952.49, 1296.24). Overall, DALYs showed a slight global increase from 2012 to 2021 but a decrease over the 30-year span from 1990 to 2021. From 1990 to 2021, DALYs due to breast cancer worldwide decreased first and then increased, especially during the COVID-19 pandemic. There is a significant increase in breast cancer DALYs in low - and middle-income countries, while there is a downward trend in high-income countries. In addition, there is a complex relationship between breast cancer indicators and socio-demographic index (SDI) in different countries and regions, indicating the importance of considering multiple factors when analyzing cancer epidemiology and the need to tailor cancer prevention and treatment approaches based on local context and social characteristics.
Cancer-associated fibroblasts (CAFs) are important contributors to malignant progression in bladder cancer (BLCA), yet the mechanisms by which they promote tumor progression remain incompletely understood. In this study, we integrated patient-derived CAFs with bulk and single-cell transcriptomics, spatial transcriptomics, and multi-cohort clinical datasets to systematically define the molecular mechanisms underlying CAF-driven BLCA progression. Integrated analyses of bulk RNA sequencing, single-cell transcriptomics, spatial transcriptomics, immunohistochemistry, and multiplex immunofluorescence of paraffin-embedded tissues, together with PCR, immunoblotting, and immunofluorescence in patient-derived normal fibroblasts and CAFs, consistently demonstrated marked enrichment of NOTCH3 in CAFs in bladder cancer. Silencing of NOTCH3 attenuated extracellular matrix deposition, contractile capacity, intracellular ROS accumulation, and the ability of CAFs to support tumor growth. Mechanistically, TGF-β induced NOTCH3 transcription through SMAD2 binding to the NOTCH3 promoter. In turn, NOTCH3 recruited HSPA8 to promote K48-linked ubiquitination and proteasomal degradation of P62, thereby suppressing the P62-NRF2 antioxidant pathway and sustaining intracellular ROS accumulation. Restoration of P62 expression or pharmacological scavenging of ROS effectively reversed NOTCH3-driven myofibroblastic differentiation and stromal support of tumor growth. In vivo, CAF-specific deletion of NOTCH3 significantly inhibited tumor growth, reduced collagen deposition, and attenuated stromal remodeling in both subcutaneous and orthotopic bladder cancer models. Collectively, these findings identify CAF-intrinsic NOTCH3 as important regulator of myofibroblastic differentiation through integration of upstream TGF-β signaling with redox and proteostatic control, highlighting stromal NOTCH3 as a potential therapeutic target to limit malignant progression in BLCA.
Anatomic liver resection traditionally relies on intraoperative ultrasound to identify hepatic veins as landmarks for parenchymal transection.1-3 Recently, portal territory staining with indocyanine green (ICG) has emerged as a key research focus in precision liver surgery, offering direct visualization of segmentation boundaries.4,5 However, a standardized technique for staining complex, multi-segmental tumors is lacking. This study evaluated a novel multi-subsegmental positive staining technique to achieve precise resection in such cases. The study enrolled a 59-year-old man with a 7.5-cm hepatocellular carcinoma (HCC) occupying segments Ⅷ and Ⅳa. Preoperative three-dimensional reconstruction mandated resection of both segments for adequate margins. Informed consent was obtained from the patient and his family. Intraoperatively, under ultrasound guidance, the portal veins supplying segments Ⅷ and Ⅳa were selectively punctured. A 1:1000 diluted ICG solution was injected into each, generating a composite positive staining map to delineate the combined resection territory. This approach was termed the "jigsaw-patterned staining technique." The total operative time was 240 min, with the staining procedure requiring 30 min. Intraoperative blood loss was 50 mL. The fluorescent boundaries closely correlated with the subsequent ischemic planes after targeted pedicle division. Histopathology confirmed HCC with microvascular invasion and satisfied margins. At this writing, the patient has recovered without complications and has maintained a disease-free survival for more than 20 months. The "jigsaw-patterned" multi-subsegmental portal vein ICG staining technique is technically feasible and safe. It enables precise anatomic resection for complex HCC spanning multiple segments, optimizing oncologic margin control while sparing functional parenchyma.
Equitable access to anticancer drugs is a central concern in oncology care. China initiated National Drug Price Negotiation (NDPN) in 2016, which has been associated with improved accessibility and equity in anticancer drugs. This study aims to evaluate the current regional equity in the provision of negotiated anticancer drugs in China. The study collected data on the availability of anticancer drugs negotiated by public platforms across 31 provinces. We collected province-level data on the availability of negotiated anticancer drugs in hospitals and pharmacies across 31 provinces and calculated GDP-related concentration indices (CIs). A decomposition analysis of CIs was conducted to identify determinants of inequity, and CIs were further computed within the breast cancer subgroup. The CIs were 0.125 for hospitals and 0.139 for pharmacies, indicating pro-rich inequality in the regional provision of negotiated anticancer drugs, with higher-income eastern regions offering more hospitals and pharmacies with anticancer drugs. Medical insurance expenditures (56.209%) and inpatient costs (46.745%) exacerbated hospital supply inequality. The number of pharmacists in pharmacies (63.845%) was the primary positive contributor to pharmacy access inequality. Among breast cancer drugs, Abemaciclib and Nalatinib Maleate exhibited higher CIs of 0.244 and 0.223. The regional distribution of negotiated anticancer drugs reveals substantial disparities, with affluent regions more likely to access these medications through well-resourced hospitals and pharmacies. Health expenditure and financing mechanisms further amplify these inequalities. Even within similar indications, disparities persist in the availability of different drugs. Future initiatives should prioritize measures to ensure drug access in impoverished and remote areas.
Frailty has become a public health concern among older adults. Nutrition is closely associated with health. This study aimed to evaluate the relationships between nutrition literacy (NL) and dietary diversity and frailty. A cross-sectional analysis included 1,187 participants. NL was evaluated using the short-form nutrition literacy self-assessment questionnaire. Frailty was assessed via a modified Fried phenotype. Generalized estimating equations were used to examine the association between NL and frailty by considering odds ratios (OR) and 95% confidence intervals (CI); and generalized linear models were performed to calculate regression coefficients (ꞵ) and 95% CI for the association between NL and dietary diversity. The prevalence of frailty was approximately 13.7% in the study sample. Higher NL was associated with lower prevalence of frailty (OR = 0.98, 95% CI: 0.96-0.99), and was correlated with higher dietary diversity (ꞵ= 0.06, 95% CI: 0.05-0.07). Further exploratory statistical analysis indicated that the relationship between NL and frailty was related to dietary diversity, with an associative coefficient of - 0.0028 (95% CI: -0.0044 to - 0.0013) observed in the results. These findings showed that NL and dietary diversity were significantly associated with frailty in older adults, and dietary diversity may form an exploratory statistical association between NL with frailty. Our results underscore the potential value of strategies aimed at greater NL and dietary diversity for the management of frailty.
The diagnosis of rare diseases increasingly relies on the interpretation of high-throughput next-generation sequencing (NGS) data. As sequencing volume expands, the analytical burden grows substantially, and manual workflows become increasingly difficult to scale and prone to inconsistency. To address these challenges, we developed G.AI, an interpretable and traceable artificial intelligence (AI)-assisted genomic analysis platform that integrates automated phenotype standardization, variant pathogenicity ranking, and structured clinical reporting. The platform uses a modular architecture comprising data parsing, AI-driven inference, and structured report generation. Performance was assessed using 39,156 multicenter whole-exome sequencing (WES)/ parent-child trio sequencing (WES Trio) cases from China, including 7,097 confirmed pathogenic/likely pathogenic (P/LP) single-nucleotide variants (SNVs) positive cases. Key evaluation metrics included phenotype-model concordance, Top-1, Top-3 and Top-20 variant pathogenicity ranking accuracy and workflow efficiency. The AI-Human Phenotype Ontology (HPO) phenotype standardization model achieved 94% concordance with manual review. The pathogenicity-ranking model reached Top-1 95%, Top-3 98%, and Top-20 99.6% accuracy among positive cases, with metabolic disorders achieving 100% Top-3 accuracy. Additional analysis on non-diagnostic cases demonstrated low false prioritization rates and good model specificity. Total analysis time decreased from 4 to 6 h to 48 ± 12 min, demonstrating a significant improvement in efficiency. By integrating automated phenotype processing, variant annotation, and AI-driven pathogenicity evaluation, G.AI substantially enhances the accuracy, consistency, and scalability of rare disease variant interpretation. Its transparent and traceable workflow provides a robust foundation for large-scale clinical genomic applications.
Cardiovascular-kidney-metabolic (CKM) syndrome represents a composite disease state driven by glucose and lipid metabolic dysregulation. The Cholesterol, High-density lipoprotein, and Glucose (CHG) index reflects the composite burden of these metabolic factors. However, its impact on the onset, stage-wise progression, and prognosis of CKM syndrome remains unclear. This study utilized data from two large-scale prospective cohorts. In the UK Biobank (UKB) cohort, Fine-Gray proportional subdistribution hazards models were employed to investigate associations between CHG levels and the risk of incident cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM), as well as the risk of progression from CKM Stage 0-1 to 2-3 and Stage 1-3 to 4. In the Beijing Anzhen Hospital cohort, Cox regression models assessed the impact of CHG on major adverse cardiovascular and cerebrovascular events (MACCE) in patients with CKM Stage 4 (established coronary artery disease). A causal forest algorithm was used to identify high-value subpopulations, and restricted cubic splines (RCS) characterized dose-response relationships. Sensitivity analyses were conducted to verify result robustness. The study included 370,916 participants free of CKM diseases from UKB (median follow-up: 16.5 years) and 8,494 patients with CKM Stage 4 from Beijing Anzhen Hospital (median follow-up: 645 days). In the general population, each 1-SD increase in the CHG index was significantly associated with an increased risk of incident T2DM (HR: 1.47; 95% CI: 1.40-1.53), CVD (HR: 1.07; 1.06-1.09), and CKD (HR: 1.07; 1.04-1.10). Furthermore, elevated CHG significantly accelerated CKM progression from Stage 0-1 to 2-3 (HR: 1.16; 1.11-1.23) and from Stage 1-3 to 4 (HR: 1.06; 1.05-1.08) per 1-SD increase. In patients with established CAD (Stage 4), a 1-SD increase in CHG was associated with a higher risk of MACCE (HR: 1.12; 1.05-1.19). Machine learning analysis revealed that this prognostic impact was particularly pronounced in patients with low systemic inflammation and elevated HbA1c. The CHG index demonstrates significant predictive value for the onset of component diseases, stage-wise progression, and adverse prognosis across the entire CKM syndrome continuum.
The incremental value of myocardial perfusion imaging (MPI) before coronary angiography (CAG) for suspected or known stable coronary artery disease (SCAD) has not been validated in China. This study investigated the necessity of MPI for these patients regarding improvements in cardiac outcomes and cost-effectiveness in China. The initial cohort comprised 7,437 patients with suspected or known SCAD between 2018 and 2019. After excluding patients with acute coronary syndrome, previous myocardial infarction (MI) and revascularization, enrolled patients were divided into the CAG group and the MPI group according to the initial strategy (CAG or MPI). Then, two groups were matched by propensity score. The cost, revascularization, MI, and all-cause mortality of patients were followed. The MPI and CAG groups each included 130 patients after matching, with similar basic characteristics (P > 0.05). Significantly decreased cardiac events were observed in the MPI group compared to the CAG group (6 vs. 16, P < 0.05). Furthermore, the number of revascularization (5 vs. 12), MI (1 vs. 3), and all-cause mortality (0 vs. 1) in the MPI group was also lower. The Cox model showed that fewer patients in the MPI group had cardiac events (HR 0.27, 95% CI 0.10-0.71). Moreover, patients in the MPI group had fewer first-visit costs ($718 vs. $1389) and fewer downstream costs ($120 vs. $344) than those in the CAG group (P < 0.001). Our findings suggest that an MPI-first strategy is associated with fewer cardiac events and lower costs compared with an initial CAG strategy. Not applicable. This study is a retrospective analysis.
Atherosclerosis, a chronic inflammatory disease of the arterial wall, is a leading cause of cardiovascular diseases worldwide. The complex pathogenesis of atherosclerosis involves genetic predisposition, environmental factors, and immune responses. N-Methyl-d-aspartate receptors (NMDARs), a subclass of glutamate receptors, are critical for synaptic plasticity, learning, and memory in the central nervous system (CNS). Non-neuronal NMDARs are poorly understood compared to neuronal receptors, but there is a developing consensus that they have distinct structural and functional properties when activated by glutamate and NMDARs co-agonists. Emerging evidence indicates that non-neuronal NMDARs may participate in an array of physiological and pathophysiological processes, including but not limited to driving macrophage polarization, lipid dysregulation in macrophages, inflammation response, vascular smooth muscle cells phenotype switching and endothelial dysfunction, thereby fueling atherogenesis. This review discusses the association between NMDARs genes and atherosclerosis risk, molecular mechanisms underlying NMDARs-mediated regulation of atherosclerosis-related cells, and potential therapeutic implications. Besides, we introduce some pharmacological tools that can be used for studying NMDARs outside the CNS, which reflect modern subunit-selective agents to provide more precise insight into NMDARs mediate the various effects. Overall, the study of NMDARs may provide insights into the pathogenesis of atherosclerosis and lead to the development of more effective therapeutic strategies.
The human microbiome, comprising trillions of microorganisms in distinct anatomical locations such as the gut, oral cavity, skin, and vagina, has emerged as a source of bioactive natural products with diverse scaffolds. Through co-evolution with the host, the human microbiome produces small molecules tailored to physicochemical environments that contribute to immune regulation, epithelial barrier maintenance, pathogen defense, and neurochemical signaling. Recent advances in metagenomics, single-cell genomics, synthetic biology, and integrated omics approaches have enabled rapid discovery and structural elucidation of biosynthetic gene clusters (BGCs) and metabolites. Cultivation-driven and genome mining strategies combined with omics analyses have improved the efficiency of discovering microbiome-derived drug leads. These metabolites mediate competitive and cooperative interactions within microbial ecosystems and hold high promise for therapeutic applications such as immunomodulators, anti-infectives, and neuroactive agents. This review outlines the structural features, biosynthetic pathways, and bioactivities of key metabolites across major microbial niches, together with strategies for their discovery, highlighting their potential in advancing drug development and human health.
Although poly (ADP-ribose) polymerase inhibitors (PARPi) have been established to enhance ovarian cancer outcomes, the emergence of drug resistance poses considerable clinical challenges. In this study, we constructed a Hi-C atlas to systematically characterize the effect of olaparib on chromatin organization at multiple hierarchical scales, namely, chromosomes, A/B compartments, topologically associating domains, and chromatin loops. To investigate the effects of PARPi on expression of the cohesion subunit RAD21, we established olaparib-resistant ovarian cancer cell line. Furthermore, we examined the effects of RAD21 on the functions of ovarian cancer cells and spheroids based on cell proliferation, apoptosis, and comet assays. In addition, by performing integrated analyses using ChIP-seq datasets, ChIP-qPCR, and chromosome conformation capture assays, we assessed the influence of RAD21 on the enhancer-promoter interactions of a homologous recombination repair gene. Moreover, on the basis of our findings in previous studies using clinical samples, we further evaluated the clinical value of RAD21 in multiple databases. Genome-wide Hi-C heatmap analysis revealed that olaparib led to a reduction in the genome-wide contact frequency for long distance interactions, altered the degree of chromatin compartmentalization, and promoted compartment switching in ovarian cancer. Differences between the olaparib-treated and control cells with respect to topologically associating domain boundaries and chromatin loops were found to be associated with key cellular functions, such as DNA repair and transcriptional mis-regulation in cancer. Furthermore, PARPi treatment was observed to induce the expression of RAD21, whereas an upregulation of RAD21 promoted proliferation and inhibited apoptosis in ovarian cancer spheroids. Mechanistically, we obtained evidence to indicate that by maintaining enhancer-promoter interactions within chromatin conformation, RAD21 regulates the transcription of RAD51, thereby mediating olaparib resistance in ovarian cancer. The high expression of RAD21 was found to show a significant association with poor overall and progression-free survival in patients with ovarian cancer. Our findings in this study indicate that RAD21 could serve as a potential therapeutic target for overcoming olaparib resistance in ovarian cancer, and provide new insights into the mechanisms underlying the resistance to PARPi from the perspective of chromatin organization.