Genetic risk accentuates dietary effects on hepatic steatosis, inflammation and fibrosis in a population-based cohort.

BACKGROUND & AIMS: Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has a differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank. METHODS: We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3-rs738409-G, TM6SF2-rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a measure of liver inflammation and fibrosis) and liver-related events/mortality. RESULTS: A total of 21,619 participants met inclusion criteria. In non-interaction models, Mediterranean diet and intake of fruit/vegetables/legumes and fish associated with lower LFC, while higher red/processed meat intake and all genetic predictors associated with higher LFC. In interaction models, all genetic predictors interacted with Mediterranean diet and fruit/vegetable/legume intake, while the steatosis PRS interacted with fish intake and the TM6SF2 genotype interacted with red/processed meat intake, to affect LFC. Dietary effects on LFC were up to 3.8-fold higher in PNPLA3-rs738409-GG vs. -CC individuals, and 1.4-3.0-fold higher in the top vs. bottom quartile of the steatosis PRS. Gene-diet interactions were stronger in participants with vs. without overweight. The steatosis PRS interacted with Mediterranean diet and fruit/vegetable/legume intake to affect cT1 and most dietary and genetic predictors associated with risk of liver-related events or mortality by age 70. CONCLUSIONS: Effects of diet on LFC and cT1 were markedly accentuated in patients at increased genetic risk for SLD, implying dietary interventions may be more impactful in these populations. IMPACT AND IMPLICATIONS: Genetic variants and diet both influence risk of hepatic steatosis, inflammation/fibrosis, and hepatic decompensation; however, how gene-diet interactions influence these outcomes has previously not been comprehensively characterized. We investigated this topic in the community-based UK Biobank and found that genetic risk and dietary quality interacted to influence hepatic steatosis and inflammation/fibrosis on liver MRI, so that the effects of diet were greater in people at elevated genetic risk. These results are relevant for patients and medical providers because they show that genetic risk is not fixed (i.e. modifiable factors can mitigate or exacerbate this risk) and realistic dietary changes may result in meaningful improvement in liver steatosis and inflammation/fibrosis. As genotyping becomes more routinely used in clinical practice, patients identified to be at high baseline genetic risk may benefit even more from intensive dietary counseling than those at lower risk, though future prospective studies are required.

PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

Differences in intracranial atherosclerosis plaque between posterior circulation and anterior circulation on high-resolution magnetic resonance imaging: A systematic review and meta-analysis.

OBJECTIVE: The clinical characteristics and mechanisms of stroke caused by anterior circulation atherosclerotic plaques (ACAPs) and posterior circulation atherosclerotic plaques (PCAPs) are distinct. We aimed to compare the differences in vulnerability, morphology, and distribution between ACAPs and PCAPs based on hign-resolution magnetic resonance imaging (HR-MRI). MATERIALS AND METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang database were retrieved from inception through May 2023. Meta-analysis was performed by R 4.2.1 software. The quality of the literature was assessed by the Agency for Healthcare Research and Quality (AHRQ). Subgroup analysis was conducted to explore the heterogeneity of the pooled results. RESULTS: There were a total of 13 articles, including 1194 ACAPs and 1037 PCAPs. The pooled estimates demonstrated that the incidence of intraplaque hemorrhage in the PCAPs was higher (OR 1.72, 95%CI 1.35-2.18). The plaque length (SMD 0.23, 95%CI 0.06-0.39) and remodeling index (SMD 0.29, 95%CI 0.14-0.44) of PCAPs were larger than those in ACAPs. However, there were no evident differences in significant enhancement or stenosis degree between the two groups. CONCLUSION: There were more unstable features in PCAPs, highlighting an elevated risk of recurrent ischemic stroke in the posterior circulation. Furthermore, PCAPs were prone to developing penetrating artery disease due to their wider distribution. Nevertheless, posterior circulation arteries exhibited a greater propensity for outward remodeling, which may lead treatment team to miss the optimal intervention stage by being overlooked on angiographic detection.

Enhancing Plasmonic Hot Electron Energy on Ag Surface by Amine Coordination.

Plasmonic catalysis has emerged as a promising approach to solar-chemical energy conversion. Notably, hot carriers play a decisive role in plasmonic catalysis since only when their energy matches with the LUMO or HOMO energy of the reactant molecule, can the reaction be activated. However, the hot carrier energy depends on the intrinsic physicochemical properties of the plasmonic metal substrate and the interaction with incident light. Tuning the hot carrier energy is of great significance for plasmonic catalysis but remains challenging. Here, we demonstrate that the energy of hot electrons can be significantly elevated to an unprecedented level through the coordination of amines on Ag surface. The bonding of amines and Ag reduces the work function of nanoparticles, leading to the increase of hot electron energy by 0.4 eV. This enhancement of energy promotes the cleavage of C-X (X=Cl, F) bonds upon excitation by visible light. This study provides new insights for promoting plasmonic charge transfer and enhancing the photocatalytic performance of plasmon-mediated systems.

Efficient C(sp3)-H bond oxidation on perovskite quantum dots based on Ce-oxygen affinity.

Perovskite quantum dots (QDs) have shown attractive prospects in the field of visible photocatalysis, especially in the synthesis of high value-added chemicals. However, under aerobic conditions, the stable operation of QD catalysts has been limited by the reactive oxygen species (ROS) generated by photoexcitation, especially superoxide species. Here, we propose a strategy of Ce3+ doping in perovskite QDs to guide superoxide species for photocatalytic oxidation reactions. In C(sp3)-H bond oxidation of hydrocarbons, superoxide species were rapidly generated and efficiently utilized on the surface of perovskite QDs, which achieves the stable operation of the catalytic system and obtains a high product conversion rate (15.3 mmol/g/h for benzaldehydes). The mechanism studies show that the strong Ce-oxygen affinity accelerates the relaxation process of photoinduced exciton transfer to superoxide species and inhibits the radiative recombination pathway. This work provides a new idea of utilizing oxygen species on perovskite surface and broadens the design strategy of high-performance QD photocatalysts.

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.

A common variant that alters SUN1 degradation associates with hepatic steatosis and metabolic traits in multiple cohorts.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD. METHODS: Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope-related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture. RESULTS: A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation. CONCLUSIONS: Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of nearly 30%, is a growing cause of morbidity and mortality for which there is no approved pharmacologic therapy. Our data provide a rationale for broadening current concepts of NAFLD genetics and pathophysiology to include the nuclear envelope, and particularly Sad1 and UNC84 domain containing 1 (SUN1), as novel contributors to this common liver disease. Furthermore, if future studies confirm causality of the common SUN1 H118Y variant, it has the potential to become a broadly relevant therapeutic target in NAFLD and metabolic disease.

Polygenic Risk Prediction in Diverticulitis.

OBJECTIVE: To derive and validate a polygenic risk score (PRS) to predict the occurrence and severity of diverticulitis and to understand the potential for incorporation of a PRS in current decision-making. BACKGROUND: PRS quantifies genetic variation into a continuous measure of risk. There is a need for improved risk stratification to guide surgical decision-making that could be fulfilled by PRS. It is unknown how surgeons might integrate PRS in decision-making. METHODS: We derived a PRS with 44 single-nucleotide polymorphisms associated with diverticular disease in the UK Biobank and validated this score in the Michigan Genomics Initiative (MGI). We performed a discrete choice experiment of practicing colorectal surgeons. Surgeons rated the influence of clinical factors and a hypothetical polygenic risk prediction tool. RESULTS: Among 2812 MGI participants with diverticular disease, 1964 were asymptomatic, 574 had mild disease, and 274 had severe disease. PRS was associated with occurrence and severity. Patients in the highest PRS decile were more likely to have diverticulitis [odds ratio (OR)=1.84; 95% confidence interval (CI), 1.42-2.38)] and more likely to have severe diverticulitis (OR=1.61; 95% CI, 1.04-2.51) than the bottom 50%. Among 213 surveyed surgeons, extreme disease-specific factors had the largest utility (3 episodes in the last year, +74.4; percutaneous drain, + 69.4). Factors with strongest influence against surgery included 1 lifetime episode (-63.3), outpatient management (-54.9), and patient preference (-39.6). PRS was predicted to have high utility (+71). CONCLUSIONS: A PRS derived from a large national biobank was externally validated, and found to be associated with the incidence and severity of diverticulitis. Surgeons have clear guidance at clinical extremes, but demonstrate equipoise in intermediate scenarios. Surgeons are receptive to PRS, which may be most useful in marginal clinical situations. Given the current lack of accurate prognostication in recurrent diverticulitis, PRS may provide a novel approach for improving patient counseling and decision-making.

Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network.

Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30-1.73), p = 2.1 × 10-8 ) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16-1.36), p = 4.3 × 10-8 ). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13-1.43), p = 5 × 10-5 ) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97-1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

Deep-Penetrating Triple-Responsive Prodrug Nanosensitizer Actuates Efficient Chemoradiotherapy in Pancreatic Ductal Adenocarcinoma Models.

Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long-term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose-limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ-glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple-responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple-responsiveness, deep tumor penetration, GSH/hypoxia-responsive drug release/activation, and hypoxia-induced chemoradio-sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.

Perturbation of TM6SF2 Expression Alters Lipid Metabolism in a Human Liver Cell Line.

Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong association of NAFLD with non-synonymous E167K amino acid mutation in the transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation reduces TM6SF2 stability, and its carriers display increased hepatic lipids and lower serum triglycerides. However, the effects of TM6SF2 on hepatic lipid metabolism are not completely understood. We overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used untargeted lipidomic analysis, RNAseq transcriptome analysis, and fluorescent imaging to determine changes in hepatic lipid metabolism. Both TM6SF2 knockdown and E167K overexpression increased hepatic lipid accumulation, while wild-type overexpression decreased acylglyceride levels. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown, leading to a relative increase in species with shorter, more saturated side chains. RNA-sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown. Taken together, our data show that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Additionally, our data further confirms a loss-of-function effect for the E167K variant.

17-Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single-nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13), to identify associations with histological features of NAFLD and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis but decreased inflammation, ballooning, Mallory-Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy-proven NAFLD and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice-site SNP in high linkage with rs6834314 (r2 = 0.94) generates splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6-skipping and G-nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation), is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9-fold higher (P = 0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved amino acid 22-28 sequence and amino acid 71-106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. Conclusion: We demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology and identify the enzyme as a lipid droplet-associated RDH; our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits.

BACKGROUND AND AIMS: Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS: We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS: Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS: We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.

Metal-organic framework-based fluorescent sensing of tetracycline-type antibiotics applicable to environmental and food analysis.

Antibiotics have been noted as an important class of emerging contaminants in the environment. Metal-organic frameworks (MOFs), which have been intensely investigated as a novel kind of sensing material, have been tentatively applied to the detection of antibiotics in recent years. In this work, a nanoscale MOF (In-sbdc) with a strong (quantum yield = 13%) and stable emission in water was synthesized. With its effective spectral overlap with tetracyclines, adsorption preconcentration and the usage of a masking agent, In-sbdc gave sensitive responses to a series of tetracycline antibiotics (tetracycline, chlorotetracycline and oxytetracycline) with detection limits of 0.28-0.30 µM, but another eight tested kinds of antibiotics did not cause a remarkable change in its emission (<10% of the response caused by an equal amount of tetracyclines). This MOF-based sensing system was successfully applied to tetracyclines detection in a series of actual water and food samples.

Enhanced bone regeneration by osteoinductive and angiogenic zein/whitlockite composite scaffolds loaded with levofloxacin.

Promoting angiogenesis following biomaterial implantation is essential to bone tissue regeneration. Herein, the composite scaffolds composed of zein, whitlockite (WH), and levofloxacin (LEVO) were fabricated to augment bone repair by facilitating osteogenesis and angiogenesis. First, three-dimensional composite scaffolds containing zein and WH were prepared using the salt-leaching method. Then, as a model antibiotic drug, the LEVO was loaded into zein/WH scaffolds. Moreover, the addition of WH enhanced the adhesion, differentiation, and mineralization of osteoblasts. The zein/WH/LEVO composite scaffolds not only had significant osteoinductivity but also showed excellent antibacterial properties. The prepared composite scaffolds were then implanted into a calvarial defect model to evaluate their osteogenic induction effects in vivo. Micro-CT observation and histological analysis indicate that the scaffolds can accelerate bone regeneration with the contribution of endogenous cytokines. Based on amounts of data in vitro and in vivo, the scaffolds present profound effects on improving bone regeneration, especially for the favorable osteogenic, intensive angiogenic, and alleviated inflammation abilities. The results showed that the synthesized scaffolds could be a potential material for bone tissue engineering.

Biomimetic wafer-scale alignment of tellurium nanowires for high-mobility flexible and stretchable electronics.

Flexible and stretchable thin-film transistors (TFTs) are crucial in skin-like electronics for wearable and implantable applications. Such electronics are usually constrained in performance owing to a lack of high-mobility and stretchable semiconducting channels. Tellurium, a rising semiconductor with superior charge carrier mobilities, has been limited by its intrinsic brittleness and anisotropy. Here, we achieve highly oriented arrays of tellurium nanowires (TeNWs) on various substrates with wafer-scale scalability by a facile lock-and-shear strategy. Such an assembly approach mimics the alignment process of the trailing tentacles of a swimming jellyfish. We further apply these TeNW arrays in high-mobility TFTs and logic gates with improved flexibility and stretchability. More specifically, mobilities over 100 square centimeters per volt per second and on/off ratios of ~104 are achieved in TeNW-TFTs. The TeNW-TFTs on polyethylene terephthalate can sustain an omnidirectional bending strain of 1.3% for more than 1000 cycles. Furthermore, TeNW-TFTs on an elastomeric substrate can withstand a unidirectional strain of 40% with no performance degradation.

Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.

Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.

[Study of the radiotherapy modality for patients with stage IIb-IIIb cervical stump cancer].

OBJECTIVE: To investigate the radiotherapy modality progress of stageIIb-IIIb cervical stump cancer. METHODS: The clinical data of 13 patients with stageIIb-IIIb cervical stump cancer undergoing radiotherapy from January 2000 to April 2012 was reviewed. Before 2006, 8 patients received conventional external beam radiotherapy and brachytherapy.Since 2006, 5 patients received intensity-modulated radiotherapy (IMRT) and brachytherapy. RESULTS: The median survival was 12-139 months. The median overall survivals and disease free survivals in the conventional radiotherapy (CRT) group were 57 months and 50 months, 3 cases of them recurred during 8-19 months and died of tumor progression.While, the median overall survivals and disease free survival in the IMRT group both were 21 months and nobody recurred. In the CRT group, 7 patients suffered toxicities, including 5 patients grade I-II acute rectum reaction, 2 patients grade I bladder reaction; and 3 had grade I-III, late rectum reaction, 2 patients for grade II bladder late reaction.In the IMRT group, toxicities including 1 case grade I acute or late rectum reaction, and no bladder reaction. CONCLUSION: In our experience, the recommended IMRT and interstitial brachytherapy for the selected patients with advanced cervical stump carcinoma may be obtain better tumor dose distribution and more sparing of the organ at risk.

Risk Variants in or Near ZBTB40 AND NFATC1 Increase the Risk of Both IBD and Adverse Bone Health Outcomes Highlighting Common Genetic Underpinnings Across Both Diseases.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased risk of osteoporosis and bone fracture. The aims of this study were to (1) confirm the association between IBD and low bone density and (2) test for shared risk variants across diseases. METHODS: The study cohort included patients from the Michigan Genomics Initiative. Student's t tests (continuous) and chi-square tests (categorical) were used for univariate analyses. Multivariable logistic regression was performed to test the effect of IBD on osteoporosis or osteopenia. Publicly available genome-wide association summary statistics were used to identify variants that alter the risk of IBD and bone density, and Mendelian randomization (MR) was used to identify causal effects of genetically predicted IBD on bone density. RESULTS: There were 51 405 individuals in the Michigan Genomics Initiative cohort including 10 378 (20.2%) cases of osteoporosis or osteopenia and 1404 (2.7%) cases of IBD. Patients with osteoporosis or osteopenia were more likely to be older (64 years of age vs 56 years of age; P < .001), female (67% vs 49%; P < .001), and have a lower body mass index (29 kg/m2 vs 30 kg/m2; P < .001). IBD patients with (odds ratio, 4.60; 95% confidence interval, 3.93-5.37) and without (odds ratio, 1.77; 95% confidence interval, 1.42-2.21) steroid use had a significantly higher risk of osteoporosis or osteopenia. Twenty-one IBD variants associated with reduced bone mineral density at P ≤ .05 and 3 IBD risk variants associated with reduced bone mineral density at P ≤ 5 × 10-8. Of the 3 genome-wide significant variants, 2 increased risk of IBD (rs12568930-T: MIR4418;ZBTB40; rs7236492-C: NFATC1). MR did not reveal a causal effect of genetically predicted IBD on bone density (MR Egger, P = .30; inverse variance weighted, P = .63). CONCLUSIONS: Patients with IBD are at increased risk for low bone density, independent of steroid use. Variants in or near ZBTB40 and NFATC1 are associated with an increased risk of IBD and low bone density.

Patients with inflammatory bowel disease (IBD) are at an increased risk of osteopenia, osteoporosis, and bone fracture. Herein, we identify risk variants in or near ZBTB40 and NFATC1 which associate with risk of both IBD and low bone density. Therefore, a subset of patients with IBD may be at risk for osteopenia and osteoporosis regardless of steroid use.

Light inhibition of hydrogenation reactions on Au-Pd nanocoronals as plasmonic switcher in catalysis.

Light, as a powerful energy source, has motivated the many endeavors of chemists in photochemical transformations. We were delighted to find that light has an inhibition effect on hydrogenation reactions. Exploring this previously unperceived effect will bring renewed understanding of interactions of light and matter. This work provides a breakthrough in ways to remotely control chemical reactions by light.