The deep population history of northern East Asia from the Late Pleistocene to the Holocene.

Northern East Asia was inhabited by modern humans as early as 40 thousand years ago (ka), as demonstrated by the Tianyuan individual. Using genome-wide data obtained from 25 individuals dated to 33.6-3.4 ka from the Amur region, we show that Tianyuan-related ancestry was widespread in northern East Asia before the Last Glacial Maximum (LGM). At the close of the LGM stadial, the earliest northern East Asian appeared in the Amur region, and this population is basal to ancient northern East Asians. Human populations in the Amur region have maintained genetic continuity from 14 ka, and these early inhabitants represent the closest East Asian source known for Ancient Paleo-Siberians. We also observed that EDAR V370A was likely to have been elevated to high frequency after the LGM, suggesting the possible timing for its selection. This study provides a deep look into the population dynamics of northern East Asia.

Mild-Temperature Supercritical Water Confined in Hydrophobic Metal-Organic Frameworks.

Fluids under extreme confinement show characteristics significantly different from those of their bulk counterpart. This work focuses on water confined within the complex cavities of highly hydrophobic metal-organic frameworks (MOFs) at high pressures. A combination of high-pressure intrusion-extrusion experiments with molecular dynamic simulations and synchrotron data reveals that supercritical transition for MOF-confined water takes place at a much lower temperature than in bulk water, ∼250 K below the reference values. This large shifting of the critical temperature (Tc) is attributed to the very large density of confined water vapor in the peculiar geometry and chemistry of the cavities of Cu2tebpz (tebpz = 3,3',5,5'-tetraethyl-4,4'-bipyrazolate) hydrophobic MOF. This is the first time the shift of Tc is investigated for water confined within highly hydrophobic nanoporous materials, which explains why such a large reduction of the critical temperature was never reported before, neither experimentally nor computationally.

Intercalation of Metal into Transition Metal Dichalcogenides in Molten Salts.

Van der Waals (vdW)-layered materials have drawn tremendous interests due to their unique properties. Atom intercalation in the vdW gap of layered materials can tune their electronic structure and generate unexpected properties. Here a chemical-scissor-mediated method that enables metal intercalation into transition metal dichalcogenides (TMDCs) in molten salts is reported. By using this approach, various guest metal atoms (Mn, Fe, Co, Ni, Cu, and Ag) are intercalated into various TMDC hosts (such as TiS2 , NbS2 , TaS2 , TiSe2 , NbSe2 , TaSe2 , and Ti0.5 V0.5 S2 ). The structure of the intercalated compound and intercalation mechanism are investigated. The results indicate that the vdW gap and valence state of TMDCs can be modified through metal intercalation, and the intercalation behavior is dictated by the electron work function. The adjustable charge transfer and intercalation endow a channel for rapid mass transfer to enhance the electrochemical performances. Such a chemical-scissor-mediated intercalation provides an approach to tune the physical and chemical properties of TMDCs, which may open an avenue in functional application ranging from energy conversion to electronics.

Counterintuitive Trend of Intrusion Pressure with Temperature in the Hydrophobic Cu2(tebpz) MOF.

Liquid porosimetry experiments reveal a peculiar trend of the intrusion pressure of water in hydrophobic Cu2(3,3',5,5'-tetraethyl-4,4'-bipyrazolate) MOF. At lower temperature (T) range, the intrusion pressure (Pi) increases with T. For higher T values, Pi first reaches a maximum and then decreases. This is at odds with the Young-Laplace law, which for systems showing a continuous decrease of contact angle with T predicts a corresponding reduction of the intrusion pressure. Though the Young-Laplace law is not expected to provide quantitative predictions at the subnanoscale of Cu2(tebpz) pores, the physical intuition suggests that to a reduction of their hydrophobicity corresponds a reduction of the Pi. Molecular dynamics simulations and sychrothron experiments allowed to clarify the mechanism of the peculiar trend of Pi with T. At increasing temperatures the vapor density within the MOF' pores grows significantly, bringing the corresponding partial pressure to ≈5 MPa. This pressure, which is consistent with the shift of Pi observed in liquid porosimetry, represents a threshold to be overcame before intrusion takes place. Beyond some value of temperature, the phenomenon of reduction of hydrophobicity (and water surface tension) dominated over the opposite effect of increase of vapor pressure and Pi inverts its trend with T.

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.

Nanoarchitectonics of Methyl and Aldehyde Group-Decorated SOD-Type Metal-Azolate Framework for SF6 Capture and Recovery.

Sulfur hexafluoride (SF6) is widely used as an insulating gas, being an etchant and contrast agent in the electrical, semiconductor, and medical industries. However, due to its long lifetime and high global warming potential in the atmosphere, SF6 must be carefully handled to prevent leakage during production and usage. Herein, we report a sod-net metal-azolate framework (MAF) named MAF-stu-111, which decorates methyl and aldehyde groups in the porous windows, showing high adsorption affinity for SF6 at low pressure. Stability tests, gas adsorption, and breakthrough experiments demonstrated that MAF-stu-111 possesses excellent water and chemical stability, fully reversible SF6 uptake, high SF6/N2 separation selectivity (10:90, 285.2), good reusability, and high SF6 recovery purity (99.03%). Theoretical calculations revealed that hydrogen atoms of methyl and aldehyde groups can form multiple hydrogen bonds with SF6 molecules, which ensure that SF6 molecules are firmly held within the MAF-stu-111 framework, playing a key role in the selective separation of SF6/N2.

The Impact of Metal Ions on MXene Membranes: Critical Role of Titanium Vacancies.

Two-dimensional transition metal carbides and nitrides (MXenes) and MXene-based membranes hold promise for applications including water purification and seawater desalination; however, their environmental behavior and fate in these matrices remain unknown. In this study, we systematically assessed the reaction efficiencies of Ti3C2Tx at varying important environmental conditions. Our experiments revealed that copper and iron ions accelerated the oxidation rate of Ti3C2Tx 55.4 and 33.4 times, respectively. TiO2 and amorphous carbon were identified as the primary solid products. Based on in situ water-phase atomic force microscopy, atomic high-angle annular dark-field scanning transmission electron microscopy, and theoretical results, we postulate that metal ions enhance Ti3C2Tx oxidation by spontaneously migrating and anchoring at Ti vacancies, which then become active sites for this reaction. This process increases the adsorption of H2O and oxygen, making the Ti vacancy-rich surface convex area the most vulnerable site to attack. The findings in this study provide useful information for a comprehensive understanding of the interaction between MXene structural defects and metal ions as well as for the design and modification of MXene membranes resistant to metal ion impact.

Association between updated cardiovascular health construct and risks of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: The American Heart Association (AHA) updated the construct and algorithm of cardiovascular health (CVH) recently. We aimed to explore the relationship between the new CVH score and the development of non-alcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: 3266 adults free of NAFLD identified via ultrasound were recruited in this prospective study. A modified AHA "Life's Essential 8" (mLE8, i.e., physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) were collected to evaluate the CVH score. Then participants were categorized into low, moderate, and high CVH subgroups based on overall mLE8 CVH score. According to modified Life's Simple 7 (mLS7) CVH construct, participants were also subdivided into poor, intermediate, and ideal CVH subgroups. During a median 4.3 years follow-up, 623 incident cases of NAFLD were recorded. Compared to those with high CVH, participants with low CVH (adjusted OR = 2.56, 95% CI 1.55-4.24) and moderate CVH (adjusted OR = 1.83, 95% CI 1.17-2.85) had a significantly increased risk of incident NAFLD. Participants with poor CVH (mLS7) but without low CVH (mLE8) did not show a significant elevated risk of incident NAFLD (P = 0.1053). A significant trend was found between increased changes in mLE8 score and a lower risk of NAFLD occurrence. CONCLUSION: Our findings suggested high mLE8 CVH score was associated with a lower risk of NAFLD incidence. The new CVH construct showed a more reasonable classification of CVH status and was more robust in association with NAFLD risks compared with the original one.

Hypertriglyceridemic hyperapoB and the development and resolution of nonalcoholic fatty liver disease: a cohort study.

Hypertriglyceridemic hyperapoB is an adverse lipoprotein phenotype characterized by low high density lipoprotein (HDL) cholesterol, high triglycerides, high apolipoprotein B (ApoB), and low low density lipoprotein (LDL) cholesterol to ApoB ratio. We investigated whether and to what extent hypertriglyceridemic hyperapoB associates with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD). This prospective cohort study included 9,019 Chinese participants 40 years or older, from 2010 to 2015. Logistic regression models were used to examine the odds ratios (ORs) for the incidence and resolution of NAFLD associated with the hypertriglyceridemic hyperapoB lipoprotein phenotype and individual lipid and lipoprotein parameters. During a median 4.3 years of follow-up, compared with participants with optimal phenotype, the fully adjusted ORs (95% CIs) for participants with hypertriglyceridemic hyperapoB were 2.75 (1.91, 3.95) and 0.57 (0.33, 1.00) for incidence and resolution of NAFLD, respectively. These associations were consistent across subgroup participants with varied demographic, lifestyle, and metabolic status. Individually, each unit increase in HDL cholesterol (OR: 0.98; 95% CI: 0.97, 0.99), natural logarithm-transformed triglycerides (1.89; 1.52, 2.36), and ApoB (1.006; 1.002, 1.011) was independently associated with NAFLD incidence, and only triglycerides (0.77; 0.60, 0.99) was independently associated with NAFLD resolution. Our findings suggest that Chinese adults with hypertriglyceridemic hyperapoB have a higher risk of NAFLD incidence and a lower likelihood of NAFLD resolution. These associations were stable among adults with different demographic, lifestyle, and metabolic status, supporting hypertriglyceridemic hyperapoB as a valuable clinical marker for the prevention and control of NAFLD.

Outdoor light at night in relation to glucose homoeostasis and diabetes in Chinese adults: a national and cross-sectional study of 98,658 participants from 162 study sites.

AIMS/HYPOTHESIS: Exposure to artificial light at night (LAN) disrupts the circadian timing system and might be a risk factor for diabetes. Our aim was to estimate the associations of chronic exposure to outdoor LAN with glucose homoeostasis markers and diabetes prevalence based on a national and cross-sectional survey of the general population in China. METHODS: The China Noncommunicable Disease Surveillance Study was a nationally representative study of 98,658 participants aged ≥18 years who had been living in their current residence for at least 6 months recruited from 162 study sites across mainland China in 2010. Diabetes was defined according to ADA criteria. Outdoor LAN exposure in 2010 was estimated from satellite data and the participants attending each study site were assigned the same mean radiance of the outdoor LAN at the study site. The linear regression incorporating a restricted cubic spline function was used to explore the relationships between LAN exposure and markers of glucose homoeostasis. Cox regression with a constant for the time variable assigned to all individuals and with robust variance estimates was used to assess the associations between the levels of outdoor LAN exposure and the presence of diabetes by calculating the prevalence ratios (PRs) with adjustment for age, sex, education, smoking status, drinking status, physical activity, family history of diabetes, household income, urban/rural areas, taking antihypertensive medications, taking lipid-lowering medications, and BMI. RESULTS: The mean age of the study population was 42.7 years and 53,515 (weighted proportion 49.2%) participants were women. Outdoor LAN exposure levels were positively associated with HbA1c, fasting and 2 h glucose concentrations and HOMA-IR and negatively associated with HOMA-B. Diabetes prevalence was significantly associated with per-quintile LAN exposure (PR 1.07 [95% CI 1.02, 1.12]). The highest quintile of LAN exposure (median 69.1 nW cm-2 sr-1) was significantly associated with an increased prevalence of diabetes (PR 1.28 [95% CI 1.03, 1.60]) compared with the lowest quintile of exposure (median 1.0 nW cm-2 sr-1). CONCLUSIONS/INTERPRETATION: There were significant associations between chronic exposure to higher intensity of outdoor LAN with increased risk of impaired glucose homoeostasis and diabetes prevalence. Our findings contribute to the growing evidence that LAN is detrimental to health and point to outdoor LAN as a potential novel risk factor for diabetes.

Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study.

BACKGROUND: Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. METHODS: Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. RESULTS: Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45-0.59), and decreased HOMA-IR (ß = - 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06-1.15), and decreased HOMA-B (ß = - 0.04, SE = 0.01, P = 4.52 × 10-5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. CONCLUSIONS: This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

Roles of gut microbiota in atrial fibrillation: insights from Mendelian randomization analysis and genetic data from over 430,000 cohort study participants.

BACKGROUND: Gut microbiota imbalances have been suggested as a contributing factor to atrial fibrillation (AF), but the causal relationship is not fully understood. OBJECTIVES: To explore the causal relationships between the gut microbiota and AF using Mendelian randomization (MR) analysis. METHODS: Summary statistics were from genome-wide association studies (GWAS) of 207 gut microbial taxa (5 phyla, 10 classes, 13 orders, 26 families, 48 genera, and 105 species) (the Dutch Microbiome Project) and two large meta-GWASs of AF. The significant results were validated in FinnGen cohort and over 430,000 UK Biobank participants. Mediation MR analyses were conducted for AF risk factors, including type 2 diabetes, coronary artery disease (CAD), body mass index (BMI), blood lipids, blood pressure, and obstructive sleep apnea, to explore the potential mediation effect of these risk factors in between the gut microbiota and AF. RESULTS: Two microbial taxa causally associated with AF: species Eubacterium ramulus (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.04-1.12, P = 0.0001, false discovery rate (FDR) adjusted p-value = 0.023) and genus Holdemania (OR 1.15, 95% CI 1.07-1.25, P = 0.0004, FDR adjusted p-value = 0.042). Genus Holdemania was associated with incident AF risk in the UK Biobank. The proportion of mediation effect of species Eubacterium ramulus via CAD was 8.05% (95% CI 1.73% - 14.95%, P = 0.008), while the proportion of genus Holdemania on AF via BMI was 12.01% (95% CI 5.17% - 19.39%, P = 0.0005). CONCLUSIONS: This study provided genetic evidence to support a potential causal mechanism between gut microbiota and AF and suggested the mediation role of AF risk factors.

Opposite causal effects of birthweight on myocardial infarction and atrial fibrillation and the distinct mediating pathways: a Mendelian randomization study.

BACKGROUND: Previous observational studies have documented an inverse association of birthweight with myocardial infarction (MI) but a positive association with atrial fibrillation (AF). However, the causality of these associations and the underlying mediating pathways remain unclear. We aimed to investigate the causal effects of birthweight, incorporating both fetal and maternal genetic effects, on MI and AF, and identify potential mediators in their respective pathways. METHODS: We performed Mendelian randomization (MR) analyses using genome-wide association study summary statistics for birthweight (N = 297,356 for own birthweight and 210,248 for offspring birthweight), MI (Ncase=61,000, Ncontrol=577,000), AF (Ncase=60,620, Ncontrol=970,216), and 52 candidate mediators (N = 13,848-1,295,946). Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the associations of birthweight with MI and AF, respectively. As a complement, we replicated analyses for fetal-specific birthweight and maternal-specific birthweight. RESULTS: Genetically determined each 1-SD lower birthweight was associated with a 40% (95% CI: 1.22-1.60) higher risk of MI, whereas each 1-SD higher birthweight was causally associated with a 29% (95% CI: 1.16-1.44) higher risk of AF. Cardiometabolic factors, including lipids and lipoproteins, glucose and insulin, blood pressure, and fatty acids, each mediated 4.09-23.71% of the total effect of birthweight on MI, followed by body composition and strength traits (i.e., appendicular lean mass, height, and grip strength) and socioeconomic indicators (i.e., education and household income), with the mediation proportion for each factor ranging from 8.08 to 16.80%. By contrast, appendicular lean mass, height, waist circumference, childhood obesity, and body mass index each mediated 15.03-45.12% of the total effect of birthweight on AF. Both fetal-specific birthweight and maternal-specific birthweight were inversely associated with MI, while only fetal-specific birthweight was positively associated with AF. Psychological well-being and lifestyle factors conferred no mediating effect in either association. CONCLUSIONS: Cardiometabolic factors mainly mediated the association between lower birthweight and MI, while body composition and strength traits mediated the association between higher birthweight and AF. These findings provide novel evidence for the distinct pathogenesis of MI and AF and advocate adopting a life-course approach to improving fetal development and subsequent causal mediators to mitigate the prevalence and burden of cardiovascular diseases.

Causal impacts of educational attainment on chronic liver diseases and the mediating pathways: Mendelian randomization study.

BACKGROUND AND AIMS: Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways. METHODS: We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association. RESULTS: Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%). CONCLUSIONS: Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education.

Causal effect of lower birthweight on non-alcoholic fatty liver disease and mediating roles of insulin resistance and metabolites.

BACKGROUND & AIMS: The causal association of lower birthweight with non-alcoholic fatty liver disease (NAFLD) and the mediating pathways remain unclear. We aimed to investigate the causal, independent association of lower birthweight with NAFLD and identify potential metabolic mediators and their mediation effects in this association. METHODS: We performed two-step, two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics for birthweight from the Early Growth Genetics Consortium of 298 142 Europeans, NAFLD from a GWAS meta-analysis of 8434 NAFLD cases and 770 180 controls of Europeans, and 25 candidate mediators from corresponding reliable GWASs. RESULTS: Genetically determined each 1-SD lower birthweight was associated with a 45% (95% CI: 1.25-1.69) increased risk of NAFLD, and this causal association persisted after adjusting for childhood obesity or adult adiposity traits in multivariable MR. Two-step MR identified 6 of 25 candidate mediators partially mediate the effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.05%), leucine (17.29%), isoleucine (13.55%), valine (11.37%), alanine (10.01%) and monounsaturated fatty acids (MUFA; 7.23%). Bidirectional MR suggested a unidirectional effect of insulin resistance on isoleucine, leucine and valine and a unidirectional effect of alanine on insulin resistance. CONCLUSIONS: This MR study elucidated the causal impact of lower birthweight on subsequent risk of NAFLD, independently of later-life adiposity and identified mediators including insulin resistance, branched-chain amino acids, alanine and MUFA in this association pathway. Our findings shed light on the pathogenesis of NAFLD and imply additional targets for prevention and intervention of NAFLD attributed to low birthweight.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

Multielemental single-atom-thick A layers in nanolaminated V2(Sn, A) C (A = Fe, Co, Ni, Mn) for tailoring magnetic properties.

Tailoring of individual single-atom-thick layers in nanolaminated materials offers atomic-level control over material properties. Nonetheless, multielement alloying in individual atomic layers in nanolaminates is largely unexplored. Here, we report 15 inherently nanolaminated V2(A xSn1-x)C (A = Fe, Co, Ni, Mn, and combinations thereof, with x ∼ 1/3) MAX phases synthesized by an alloy-guided reaction. The simultaneous occupancy of the 4 magnetic elements and Sn in the individual single-atom-thick A layers constitutes high-entropy MAX phase in which multielemental alloying exclusively occurs in the 2-dimensional (2D) A layers. V2(A xSn1-x)C exhibit distinct ferromagnetic behavior that can be compositionally tailored from the multielement A-layer alloying. Density functional theory and phase diagram calculations are performed to understand the structure stability of these MAX phases. This 2D multielemental alloying approach provides a structural design route to discover nanolaminated materials and expand their chemical and physical properties. In fact, the magnetic behavior of these multielemental MAX phases shows strong dependency on the combination of various elements.

Icosidodecahedral Coordination-Saturated Cuprofullerene.

The first coordination-saturated buckyball with a C60 molecule totally encased in an icosidodecahedral Cu30 in a (µ30 -(η2 )30 )-fashion, namely C60 @Cu30 @Cl36 N12 , has been successfully realized by a C60 -templated assembly. The 48 outmost coordinating atoms (36Cl+12N) comprise a new simple polyhedron that is described by a ccf topology. Charge transfer from (CuI , Cl) to C60 explains the expansion of the light absorption up to 700 nm, and accounts for an ultrafast photophysical process that underpins its high photothermal conversion efficiency. This work makes a giant step forward in exohedral metallofullerene (ExMF) chemistry.