New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Large-scale fabrication method of heterostructured materials using conventional cold-rolling for industrial applications

Heterostructured materials offer great promise as next-generation structural materials, providing excellent combinations of strength and elongation. However, the need for additional equipment for heterostructuring poses challenges for scalability. In this study, we propose a strategy to fabricate heterostructured materials using conventional cold-rolling, eliminating the need for additional pre- or post-treatments. This newly developed method refines only surface grains with shear stress induced by cold-rolling performed at a slight thickness reduction. The cold-rolled samples exhibited improved strengths at the expense of ductility compared to the as-received homogeneous sample, primarily attributed to the heterogeneous strengthening effect and the increased pre-existing dislocation densities. Depending on the cold-rolling process conditions, yield strength increased from 85.6 MPa to 138.6 MPa, and the corresponding elongation loss was 5.5% and 14.8%, respectively. The increase in yield strength of the cold-rolled samples at the same uniform elongation as the as-received sample, calculated using a trend line, was about 51.5 MPa. This proposed strategy has the potential to advance the industrialization of heterostructured materials by enabling large-scale fabrication using conventional processing equipment

Unprecedented bake hardening responses of interstitial high-entropy alloy by synergistic effect with lattice distortion

High-entropy alloys (HEAs) composed of multiple principal elements have attracted considerable interest in recent decades as a new class of metallic materials. Among them, the equi-atomic CoCrFeMnNi HEA system has great potential for application as a structural material due to its excellent properties in various fields, but it has a drawback of relatively low yield strength (YS) at room temperature. Here, for the first time, we propose the bake hardening (BH) as a breakthrough to overcome the relatively inferior YS of the CoCrFeMnNi HEA system. We found that the carbon-added CoCrFeMnNi HEAs are not only bake-hardenable, but also exhibit unprecedented BH responses than conventional bake-hardenable materials, with BH responses up to 120.0 MPa depending on the carbon concentration in the matrix. It is the outcome of the mutual synergistic effect between the massive solid solution strengthening characteristic from lattice distortion of the HEAs and the Cottrell atmosphere generated during the BH process. This study demonstrates that the carbon-added CoCrFeMnNi HEAs are more advantageous to apply the BH effect than conventional bake-hardenable materials, which suggests the possibility of industrialization of various interstitial HEA systems as well as carbon-added CoCrFeMnNi HEAs

Multi-layered heterostructured CoCrFeMnNi high-entropy alloy processed using direct energy deposition and ultrasonic nanocrystalline surface modification

The advantages of heterostructured materials as structural materials include superior mechanical properties and the ability to tailor the strength-ductility combination via microstructure customization. To maximize heterostructure effects, this study combined direct energy deposition and ultrasonic nanocrystalline surface modification processes to create a CoCrFeMnNi equiatomic high-entropy alloy with multi-layered microstructures. The fabricated CoCrFeMnNi high-entropy alloy has a novel microstructure composed of multiple layers of repetitive microstructures with heterogeneity and demonstrates a remarkable synergetic strengthening effect in comparison to conventional heterogeneous materials. The outstanding mechanical properties derived from various hard and soft layer interfaces, as well as the effects of each layer and interface, were quantitatively analyzed using grain-scale digital image correlation technology. By combining the direct energy deposition and ultrasonic nanocrystalline surface modification processes, this study presents a method for fabricating a new class of heterostructured materials with multi-layered microstructure that exhibit deformation heterogeneity and grain size heterogeneity. The multi-layered microstructure with multiple heterogeneous boundaries breaks the conventional wisdom regarding heterostructured materials having only one or two heterogeneous interfaces

Novel deep learning approach for practical applications of indentation

© 2022 The AuthorsThe instrumented indentation technique has been investigated to efficiently evaluate the mechanical responses of materials with few limitations on the shape and size of the specimen. There have been attempts to discover a direct correlation between the stress-strain curve and the indenting load-displacement curve by introducing the concept of representative strain and stress. However, it is still difficult to find relible parameters and to distinguish similar load-displacement curves that correspond to different stress-strain curves with a limited number of experimental datasets. The present study introduces a finite element method (FEM)-based simulation that can output various load-displacement datasets corresponding to intrinsic properties of materials, including strain rate; these datasets are validated using experimental indentation results for diverse metallic materials at different indenting speeds (0.6, 0.9, 1.2 mm/min). In addition, an autoencoder (AE)-shaped artificial neural network (ANN) model is designed to efficiently characterize those datasets. Then, the indenting load-displacement datasets are extracted into effective physically meaningful datasets by introducing a data post-processing procedure. The proposed indentation FEM-AE-shaped ANN model demonstrates that a long-range true stress-strain curve can be attained even from a noisy experimental load-displacement dataset.11Nsciescopu

Synergy of tensile strength-ductility in IN718/CoCrFeMnNi/IN718 multi-material processed by powder high-pressure torsion and annealing

© 2022 Acta Materialia Inc.Materials manufactured through conventional powder metallurgy (PM) techniques generally exhibit inferior tensile properties due to structural defects. Nevertheless, a recently proposed cold-consolidation technique using powder high-pressure torsion represents well-manufactured structures with ultra-high tensile properties in the absence of cracks or pores. This novel PM-based technique is utilized in the present investigation to fabricate a multi-material Inconel 718/CoCrFeMnNi/Inconel 718 layered structure. By a combination of uttermost high densification, ultra-fine-grained microstructure, and hetero-deformation induced strengthening effect, the present cold-consolidated multi-material exhibits tensile properties with yield strength of 1255.4 MPa, uniform elongation of 13.7%, and total elongation of 25.0%, overcoming monolithic Inconel 718 and CoCrFeMnNi systems. These findings shed light on the capability of the cold-consolidation technique to manufacture multi-layered and gradient multi-functional structures with excellent mechanical response under tensile stress.11Nsciescopu

Novel multi-metal stainless steel (316L)/high-modulus steel (Fe-TiB2) composite with enhanced specific modulus and strength using high-pressure torsion

A novel multi-metal composite with 316L stainless steel matrix and Fe-TiB2 high-modulus steel reinforcement was successfully fabricated using high-pressure torsion (HPT). After post-HPT annealing at 800 degrees C for 60 min, the composite demonstrated a superior combination of high specific modulus (similar to 5.5 GPa center dot cm(3)center dot g(-1)), high yield strength (881 MPa), and good ductility (31%). The improved properties can be ascribed to the high relative density, sound metallurgical bonded 316L/Fe-TiB2 interface, ultra-fine grains and heterogeneous microstructures.11Nsciescopu