Tert-expressing cells contribute to salivary gland homeostasis and tissue regeneration after radiation therapy.

Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (TertHigh) cell population located in the ductal region of the adult SMG. These TertHigh cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. TertHigh cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in TertHigh cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of TertHigh cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.

Clara cell 10 (CC10) protein attenuates allergic airway inflammation by modulating lung dendritic cell functions.

Allergic asthma is a complex inflammatory disorder predominantly orchestrated by T helper 2 (Th2) lymphocytes. The anti-inflammatory protein Clara Cell 10-kDa (CC10), also known as secretoglobin family 1A member 1 (SCGB1A1), shows promise in modulating respiratory diseases. However, its precise role in asthma remains unclear. This study examines the potential of CC10 to suppress allergic asthma inflammation, specifically assessing its regulatory effects on Th2 cell responses and dendritic cells (DCs). Lower CC10 levels in asthma were observed and correlated with increased IgE and lymphocytes. Cc10-/- mice exhibited exacerbated allergic airway inflammation marked by increased inflammatory cell infiltration, Th2 cytokines, serum antigen-specific IgE levels, and airway hyperresponsiveness (AHR) in house dust mite (HDM)-induced models. Conversely, recombinant CC10 significantly attenuated these inflammatory responses. Intriguingly, CC10 did not directly inhibit Th cell activation but significantly downregulated the population of CD11b+CD103- DCs subsets in lungs of asthmatic mice and modulated the immune activation functions of DCs through NF-κB signaling pathway. The mixed lymphocyte response assay revealed that DCs mediated the suppressive effect of CC10 on Th2 cell responses. Collectively, CC10 profoundly mitigates Th2-type allergic inflammation in asthma by modulating lung DC phenotype and functions, highlighting its therapeutic potential for inflammatory airway conditions and other related immunological disorders.

Pulmonary Epithelium Cell Fate Determination: COPD, Lung Cancer, or Both.

The concurrence of chronic obstructive pulmonary disease (COPD) and lung cancer has been widely reported and extensively addressed by pulmonologists and oncologists. However, most studies have focused on shared risk factors, DNA damage pathways, immune microenvironments, inflammation, and imbalanced proteases/antiproteases. In the present review, we explored the association between COPD and lung cancer in terms of airway pluripotent cell fate determination and discussed the various cell types and signaling pathways involved in the maintenance of lung epithelium homeostasis, and their involvement in the pathogenesis of co-occurrence of COPD and lung cancer.

Extension and Fusion of Cyclic Polyantimony Units.

The synthesis and characterization of a series of polyantimony anionic clusters are reported. The products [(NbCp)2Sb10]2-, [MSb13]3- (M = Ru/Fe), and [MSb15]3- (M = Ru/Fe) were isolated as either K(18-crown-6) or K([2.2.2]-crypt) salts. The Sb10 ring contained in the [(NbCp)2Sb10]2- cluster can be viewed as an extension of two envelope-like cyclo-Sb5 units and represents by far the largest monocyclic all-antimony species. The clusters [MSb13]3- and [MSb15]3- (M = Ru/Fe) illustrate the variability of crown-like Sb8 ring motifs and reveal the fusion of different antimony fragments featuring unique Sb-Sb chain-like units. The reported synthetic approaches involve the fabrication of a variety of distinctive polyantimony anionic clusters, enhancing our understanding of the coordination chemistry of heavier group 15 elements.

Electron Divergence of Cuδ- and Pdδ+ in Cu3Pd Alloy-Based Heterojunctions Boosts Concerted C≡C Bond Binding and the Volmer Step for Alkynol Semihydrogenation.

Electrocatalytic semihydrogenation of alkynols presents a sustainable alternative to conventional thermal methodologies for the high-value production of alkenols. The design of efficient catalysts with superior catalytic and energy efficiency for semihydrogenation poses a significant challenge. Here, we present the application of an electron-divergent Cu3Pd alloy-based heterojunction in promoting the electrocatalytic semihydrogenation of alkynols to alkenols using water as the proton source. The tunable electron divergence of Cuδ- and Pdδ+, modulated by rectifying contact with nitrogen-rich carbons, enables the concerted binding of active H species from the Volmer step of water dissociation and the C≡C bond of alkynols on Pdδ+ sites. Simultaneously, the pronounced electron divergence of Cu3Pd facilitates the universal adsorption of OH species from the Volmer step and alkynols on the Cuδ- sites. The electron-divergent dual-center substantially boosts water dissociation and inhibition of completing hydrogen evolution to give a turnover frequency of 2412 h-1, outperforming the reported electrocatalysts' value of 7.3. Moreover, the continuous production of alkenols at industrial-related current density (-200 mA cm-2) over the efficient and durable Cu3Pd-based electrolyzer could achieve a cathodic energy efficiency of 45 mol kW·h-1, 1.7 times the bench-marked reactors, promising great potential for sustainable industrial synthesis.

Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

Association of sleep fragmentation with general and abdominal obesity: a population-based longitudinal study.

OBJECTIVE: To evaluate the causal relationship between sleep fragmentation (SF) parameters with general and abdominal obesity in free-living conditions. METHODS: SF parameters were assessed by ActiGraph accelerometers for 7 consecutive days. Obesity was measured at baseline and 1-year follow-up with InBody S10 body composition analyzer. RESULTS: At baseline, the mean age of the study population was 18.7 years old (SD = 0.9) and 139 (35.7%) were male. Each 1-unit increase of baseline sleep fragmentation index (SFI) was associated with 0.08 kg/m2-increase of body mass index (BMI) (95% CI: 0.03, 0.14), 0.20%-increase of percentage of body fat (PBF) (95% CI: 0.07, 0.32), 0.15 kg-increase of fat mass (FM) (95% CI: 0.03, 0.27), 0.15 cm-increase of waist circumference (WC) (95% CI: 0.03, 0.26) and 0.91 cm2-increase of visceral fat area (VFA) (95% CI: 0.36, 1.46) at the 1-year follow-up. In addition, each 1-unit increase of baseline SFI was associated with 15% increased risk of general obesity (OR = 1.15, 95% CI = 1.04-1.28; p = 0.006) and 7% increased risk of abdominal obesity (OR = 1.07, 95% CI = 1.01-1.13; p = 0.021) in the following year. CONCLUSIONS: Fragmented sleep is independently associated with an increased risk of both general and abdominal obesity. The result highlights SF as a modifiable risk factor for the prevention and treatment of obesity.

Prognostic and predictive value of super-enhancer-derived signatures for survival and lung metastasis in osteosarcoma.

BACKGROUND: Risk stratification and personalized care are crucial in managing osteosarcoma due to its complexity and heterogeneity. However, current prognostic prediction using clinical variables has limited accuracy. Thus, this study aimed to explore potential molecular biomarkers to improve prognostic assessment. METHODS: High-throughput inhibitor screening of 150 compounds with broad targeting properties was performed and indicated a direction towards super-enhancers (SEs). Bulk RNA-seq, scRNA-seq, and immunohistochemistry (IHC) were used to investigate SE-associated gene expression profiles in osteosarcoma cells and patient tissue specimens. Data of 212 osteosarcoma patients who received standard treatment were collected and randomized into training and validation groups for retrospective analysis. Prognostic signatures and nomograms for overall survival (OS) and lung metastasis-free survival (LMFS) were developed using Cox regression analyses. The discriminatory power, calibration, and clinical value of nomograms were evaluated. RESULTS: High-throughput inhibitor screening showed that SEs significantly contribute to the oncogenic transcriptional output in osteosarcoma. Based on this finding, focus was given to 10 SE-associated genes with distinct characteristics and potential oncogenic function. With multi-omics approaches, the hyperexpression of these genes was observed in tumor cell subclusters of patient specimens, which were consistently correlated with poor outcomes and rapid metastasis, and the majority of these identified SE-associated genes were confirmed as independent risk factors for poor outcomes. Two molecular signatures were then developed to predict survival and occurrence of lung metastasis: the SE-derived OS-signature (comprising LACTB, CEP55, SRSF3, TCF7L2, and FOXP1) and the SE-derived LMFS-signature (comprising SRSF3, TCF7L2, FOXP1, and APOLD1). Both signatures significantly improved prognostic accuracy beyond conventional clinical factors. CONCLUSIONS: Oncogenic transcription driven by SEs exhibit strong associations with osteosarcoma outcomes. The SE-derived signatures developed in this study hold promise as prognostic biomarkers for predicting OS and LMFS in patients undergoing standard treatments. Integrative prognostic models that combine conventional clinical factors with these SE-derived signatures demonstrate substantially improved accuracy, and have the potential to facilitate patient counseling and individualized management.

Optical transmission of microwave control signal towards large-scale superconducting quantum computing.

With the rapid development of superconducting quantum computing and the implementation of surface code, large-scale quantum computing is emerging as an urgent demand. In a superconducting computing system, the qubit is maintained in a cryogenic environment to avoid thermal excitation. Thus, the transmission of control signals, which are generated at room temperature, is needed. Typically, the transmission of these signals to the qubit relies on a coaxial cable wiring approach. However, in a large-scale computing system with hundreds or even thousands of qubits, the coaxial cables will pose great space and heat load to the dilution refrigerator. Here, to tackle this problem, we propose and demonstrate a direct-modulation-based optical transmission line. In our experiment, the average single-qubit XEB error and control error are measured as 0.139% and 0.014% separately, demonstrating the feasibility of the optical wiring approach and paving the way for large-scale superconducting quantum computing.

A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

Updated epithelial barrier dysfunction in chronic rhinosinusitis: Targeting pathophysiology and treatment response of tight junctions.

Tight junction (TJ) proteins establish a physical barrier between epithelial cells, playing a crucial role in maintaining tissue homeostasis by safeguarding host tissues against pathogens, allergens, antigens, irritants, etc. Recently, an increasing number of studies have demonstrated that abnormal expression of TJs plays an essential role in the development and progression of inflammatory airway diseases, including chronic obstructive pulmonary disease, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS) with or without nasal polyps. Among them, CRS with nasal polyps is a prevalent chronic inflammatory disease that affects the nasal cavity and paranasal sinuses, leading to a poor prognosis and significantly impacting patients' quality of life. Its pathogenesis primarily involves dysfunction of the nasal epithelial barrier, impaired mucociliary clearance, disordered immune response, and excessive tissue remodeling. Numerous studies have elucidated the pivotal role of TJs in both the pathogenesis and response to traditional therapies in CRS. We therefore to review and discuss potential factors contributing to impair and repair of TJs in the nasal epithelium based on their structure, function, and formation process.

Computer-Aided Synthesis Planning (CASP) and Machine Learning: Optimizing Chemical Reaction Conditions.

Computer-aided synthesis planning (CASP) has garnered increasing attention in light of recent advancements in machine learning models. While the focus is on reverse synthesis or forward outcome prediction, optimizing reaction conditions remains a significant challenge. For datasets with multiple variables, the choice of descriptors and models is pivotal. This selection dictates the effective extraction of conditional features and the achievement of higher prediction accuracy. This review delineates the origins of data in conditional optimization, the criteria for descriptor selection, the response models, and the metrics for outcome evaluation, aiming to acquaint readers with the latest research trends and facilitate more informed research in this domain.

The vasculogenic mimicry related signature predicts the prognosis and immunotherapy response in renal clear cell carcinoma.

BACKGROUND: Clear cell carcinoma of the kidney is a common urological malignancy characterized by poor patient prognosis and treatment outcomes. Modulation of vasculogenic mimicry in tumor cells alters the tumor microenvironment and the influx of tumor-infiltrating lymphocytes, and the combination of its inducers and immune checkpoint inhibitors plays a synergistic role in enhancing antitumor effects. METHODS: We downloaded the data from renal clear cell carcinoma samples and vasculogenic mimicry-related genes to establish a new vasculogenic mimicry-related index (VMRI) using a machine learning approach. Based on VMRI, patients with renal clear cell carcinoma were divided into high VMRI and low VMRI groups, and patients' prognosis, clinical features, tumor immune microenvironment, chemotherapeutic response, and immunotherapeutic response were systematically analyzed. Finally, the function of CDH5 was explored in renal clear cell carcinoma cells. RESULTS: VMRI can be used for prognostic and immunotherapy efficacy prediction in a variety of cancers, which consists of four vasculogenic mimicry-related genes (CDH5, MMP9, MAPK1, and MMP13), is a reliable predictor of survival and grade in patients with clear cell carcinoma of the kidney and has been validated in multiple external datasets. We found that the high VMRI group presented higher levels of immune cell infiltration, which was validated by pathological sections. We performed molecular docking prediction of vasculogenic mimicry core target proteins and identified natural small molecule drugs with the highest affinity for the target protein. Knockdown of CDH5 inhibited the proliferation and migration of renal clear cell carcinoma. CONCLUSIONS: The VMRI identified in this study allows for accurate prognosis assessment of patients with renal clear cell carcinoma and identification of patient populations that will benefit from immunotherapy, providing valuable insights for future precision treatment of patients with renal clear cell carcinoma.

Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.

Taxonomic identification, phenol biodegradation and soil remediation of the strain Rhodococcus sacchari sp. nov. Z13T.

Phenols are highly toxic chemicals that are extensively used in industry and produce large amounts of emissions. Notably, phenols released into the soil are highly persistent, causing long-term harm to human health and the environment. In this study, a gram-positive, aerobic, and rod-shaped bacterial strain, Z13T, with efficient phenol degradation ability, was isolated from the soil of sugarcane fields. Based on the physiological properties and genomic features, strain Z13T is considered as a novel species of the genus Rhodococcus, for which the name Rhodococcus sacchari sp. nov. is proposed. The type strain is Z13T (= CCTCC AB 2022327T = JCM 35797T). This strain can use phenol as its sole carbon source. Z13T was able to completely degrade 1200 mg/L phenol within 20 h; the maximum specific growth rate was µmax = 0.93174 h-1, and the maximum specific degradation rate was qmax = 0.47405 h-1. Based on whole-genome sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, strain Z13T contains a series of phenol degradation genes, including dmpP, CatA, dmpB, pcaG, and pcaH, and can metabolize aromatic compounds. Moreover, the potential of strain Z13T for soil remediation was investigated by introducing Z13T into simulated phenol-contaminated soil, and the soil microbial diversity was analyzed. The results showed that 100% of the phenol in the soil was removed within 7.5 d. Furthermore, microbial diversity analysis revealed an increase in the relative species richness of Oceanobacillus, Chungangia, and Bacillus.

Deep Eutectic Solvent-Assisted Corrosion Boosting Bulk FeCoNiCrMo High-Entropy Alloys as Highly Efficient Oxygen Evolution Reaction Catalyst.

The key to enhancing water electrolysis efficiency lies in selecting highly efficient catalysts. Currently, high-entropy alloys (HEAs) are utilized in electrocatalysis applications owing to their diverse elemental composition, disordered elemental distribution, and the high solubility of each element, endowing them with excellent catalytic performance. The experiments were conducted using isoatomic FeNiCrMo HEA as a precursor, with a high-activity three-dimensional nanoporous structure rapidly synthesized via electrochemical one-step dealloying in a choline chloride-thiourea (ChCl-TU) deep eutectic solvent (DES). The results indicate that the dealloyed Fe20Co20Ni20Cr20Mo20 HEA mainly consists of two phases: face-centered cubic and σ phases. The imbalance in the distribution of elements in these two phases leads to quite different corrosion speeds with the FCC phase being preferentially corroded. Furthermore, synergistic electron coupling between surface atoms in the three-dimensional nanoporous structure strengthens the behavior of the oxygen evolution reaction (OER). At a current density of 40 mA cm-2, the overpotential after dealloying decreased to 370 mV, demonstrating excellent stability. The technique demonstrated in this work provides a novel approach to improve the catalytic activity of OER.

The effect of metformin on urate metabolism: Findings from observational and Mendelian randomization analyses.

AIM: To evaluate the effect of metformin on urate metabolism. MATERIALS AND METHODS: Using the UK Biobank, we first performed association analyses of metformin use with urate levels, risk of hyperuricaemia and incident gout in patients with diabetes. To explore the causal effect of metformin on urate and gout, we identified genetic variants proxying the glycated haemoglobin (HbA1c)-lowering effect of metformin targets and conducted a two-sample Mendelian randomization (MR) utilizing the urate and gout genetic summary-level data from the CKDGen (n = 288 649) and the FinnGen cohort. We conducted two-step MR to explore the mediation effect of body mass index and systolic blood pressure. We also performed non-linear MR in the UK Biobank (n = 414 055) to show the results across HbA1c levels. RESULTS: In 18 776 patients with type 2 diabetes in UK Biobank, metformin use was associated with decreased urate [ß = -4.3 µmol/L, 95% confidence interval (CI) -7.0, -1.7, p = .001] and reduced hyperuricaemia risk (odds ratio = 0.87, 95% CI 0.79, 0.96, p = .004), but not gout. Genetically proxied averaged HbA1c-lowering effects of metformin targets, equivalent to a 0.62% reduction in HbA1c, was associated with reduced urate (ß = -12.5 µmol/L, 95% CI -21.4, -4.2, p = .004). Body mass index significantly mediated this association (proportion mediated = 33.0%, p = .002). Non-linear MR results suggest a linear trend of the effect of metformin on urate reduction across various HbA1c levels. CONCLUSIONS: The effect of metformin may reduce urate levels but not incident gout in the general population.

Sex-specific causality of MRI-derived body compositions on glycaemic traits: Mendelian randomization and observational study.

AIM: To investigate the sex-specific causality of body compositions in type 2 diabetes and related glycaemic traits using Mendelian randomization (MR). MATERIALS AND METHODS: We leveraged sex-specific summary-level statistics from genome-wide association studies for three adipose deposits adjusted for body mass index and height, including abdominal subcutaneous adipose tissue, visceral adipose tissue (VATadj) and gluteofemoral adipose tissue (GFATadj), measured by MRI (20 038 women; 19 038 men), and fat mass-adjusted appendicular lean mass (ALMadj) (244 730 women; 205 513 men) in the UK Biobank. Sex-specific statistics of type 2 diabetes were from the Diabetes Genetics Replication and Meta-analysis Consortium and those for fasting glucose and insulin were from the Meta-analyses of Glucose and Insulin-related Traits Consortium. Univariable and multivariable MR (MVMR) were performed. We also performed MR analyses of anthropometric traits and genetic association analyses using individual-level data of body composition as validation. RESULTS: Univariable MR analysis showed that, in women, higher GFATadj and ALMadj exerted a causally protective effect on type 2 diabetes (GFATadj: odds ratio [OR] 0.59, 95% confidence interval [CI; 0.50, 0.69]; ALMadj: OR 0.84, 95% CI [0.77, 0.91]) and VATadj to be riskier in glycaemic traits. MVMR showed that GFATadj retained a robust effect on type 2 diabetes (OR 0.57, 95% CI [0.42, 0.77]; P = 2.6 × 10-4 ) in women, while it was nominally significant in men (OR 0.58, 95% CI [0.35, 0.96]; P = 3.3 × 10-2 ), after adjustment for ASATadj and VATadj. MR analyses of anthropometric measures and genetic association analyses of glycaemic traits confirmed the results. CONCLUSIONS: Body composition has a sex-specific effect on type 2 diabetes, and higher GFATadj has an independent protective effect on type 2 diabetes in both sexes.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.