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Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Wang et al. report that LUAD cells entering dormancy transition into a TGFβ-induced atypical mesenchymal state characterized by a soft spheroidal morphology and strong EMT signature, which protects disseminated cancer cells from immune clearance.

Jose Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Inês Barroso and colleagues perform large-scale association analyses using the Metabochip to gain further insights into the genetic architecture of glucose regulation. They identify 38 new loci influencing 1 or more glycemic traits and show that many of these loci also modify risk of type 2 diabetes.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Analysis of soundscape data from 139 globally distributed sites reveals that sounds of biological origin exhibit predictable rhythms depending on location and season, whereas sounds of anthropogenic origin are less predictable. Comparisons between paired urban–rural sites show that urban green spaces are noisier and dominated by sounds of technological origin.

Battery recycling LCA shows that recycling can reduce 58% of environmental impacts of making mixed salt solutions compared to conventional mining. Electricity and hydrometallurgical processes dominate impacts and show improvement opportunities.

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

John Chambers, Jaspal Kooner, Pim van der Harst, Shyong Tai, Paul Elliott, Jiang He, Norihiro Kato and colleagues performed a genome-wide association study of blood pressure phenotypes in individuals of European, East Asian and South Asian ancestry. They find trait-associated SNPs at 12 loci, some of which are associated with methylation at nearby CpG sites.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Genome-wide association analyses of two oral glucose tolerance test-derived measures of postprandial insulin resistance discover ten new loci. Functional characterization identifies nine candidate genes implicated in the regulation of GLUT4.

Elevated viscosity counterintuitively increases the motility of various cell types in vitro and imprints mechanical memory to tumour cells, which enables them to disseminate more efficiently in vivo.

Here, Easter et al. generate a single-cell atlas of human periodontium including sulcular and junctional keratinocytes. Cell-cell communication analysis is used to predict keratinocyte-specific immune cell interactions.

Analyses of whole-exome sequencing data identify rare loss-of-function variants in BSN associated with adult-onset obesity, type 2 diabetes and fatty liver disease, with stronger effect sizes than those observed for variants in known obesity risk genes such as MC4R.

Neurons expressing pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here the authors show that Steroid Receptor Coactivator-1 (SRC-1) regulates the function of Pomc expressing neurons, and that rare heterozygous variants found in obese individuals lead to loss of SRC-1 function.

Implant-associated infections with Staphylococcus aureus pose serious clinical challenges. Here, the authors develop a biosensor based on toxin-responsive liposomes encapsulating gold nanoclusters, providing a non-invasive, colourimetric diagnostic tool for bacterial infection detection with urinary readout.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

Lipid concentration in the serum is one of the most important risk factors for coronary artery disease and can be targeted for therapeutic intervention. A genome-wide association study in >100,000 individuals of European ancestry now finds 95 significantly associated loci that also affect lipid traits in non-European populations. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and those that contribute to normal variation in lipid traits and to extreme lipid phenotypes.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, the authors perform discovery GWAS for BP in East Asians and meta-analysis in East Asians and Europeans and report ancestry-specific BP SNPs and selection signals.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for cis-regulatory elements, particularly in vascular endothelial cells.

This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.