Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Nature Metabolism

The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily, producing a growing public health concern that disproportionately affects minority groups. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant (P < 2.6 × 10−6) gene-level associations (HNF1A, MC4R, ATXN2L). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and β-cell function. Many youth-onset T2D associations are shared with …

In high-income countries, rates of atherosclerotic complications in type 2 diabetes have declined markedly over time due to better management of traditional risk factors including lipids, blood pressure and glycemia levels. Population-wide reductions in smoking have also helped lower atherosclerotic complications and so reduce premature mortality in type 2 diabetes. However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Excess weight is also an underrecognized risk factor for chronic kidney disease (CKD). Based on evidence from a range of sources, we explain how excess adiposity must be influencing most risks well before diabetes develops, particularly in younger-onset diabetes, which is linked to …

medRxiv

BACKGROUND Prediabetes has been associated with increased all-cause and cardiovascular mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations. METHODS We analyzed data from 115,919 adults without diabetes (diagnosed or undiagnosed) aged 35-84 years who participated in the Mexico City Prospective Study between 1998 and 2004. Participants were followed until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c 5.7% to 6.4%) and the International Expert Committee (IEC, HbA1c 6.0-6.4%) definitions. Cox regression adjusted for confounders was used to estimate all-cause and cause-specific mortality rate ratios (RR) at ages 35-74 years associated with prediabetes. FINDINGS During 2,085,392 person-years of follow-up (median in survivors 19 years), there were 6,810 deaths at ages 35-74, including 1,742 from cardiovascular disease, 892 from renal disease and 108 from acute diabetic crises. Of 110,405 participants aged 35-74 years at recruitment, 28,852 (26%) had ADA-defined prediabetes and 7,203 (7%) had IEC-defined prediabetes. Compared with those without prediabetes, individuals with prediabetes had higher risk of all-cause mortality at ages 35-74 years (RR 1.13, 95% CI 1.07-1.19 for ADA-defined prediabetes and RR 1.28, 1.18-1.39 for IEC-defined prediabetes), as well as increased risk of cardiovascular mortality (RR 1.22 [1.10-1.35] and 1.42 [1.22-1.65], respectively), renal mortality (RR 1.35 [1.08-1.68] and 1.69 [1.24-2.31], respectively), and death from an acute …

Scientific Reports

Joint modelling of genetic and environmental risk factors can provide important information to predict the risk of type 2 diabetes (T2D). Therefore, to predict the genetic risk of T2D, we constructed a polygenic risk score (PRS) using genotype data of one Korean cohort, KARE (745 cases and 2549 controls), and the genome-wide association study summary statistics of Biobank Japan. We evaluated the performance of PRS in an independent Korean cohort, HEXA (5684 cases and 35,703 controls). Individuals with T2D had a significantly higher mean PRS than controls (0.492 vs. − 0.078, p). PRS predicted the risk of T2D with an AUC of 0.658 (95% CI 0.651–0.666). We also evaluated interaction between PRS and waist circumference (WC) in the HEXA cohort. PRS exhibited a significant sub-multiplicative interaction with WC (ORinteraction 0.991, 95% CI 0.987–0.995, pinteraction = 4.93 × 10–6) in T2D. The …

Journal of the National Medical Association

MethodsInvestigated the association of multiple cardiometabolic comorbidities with total/major cause-specific mortality and evaluate if this association might be modified by race among predominantly low-income Black and White participants.MethodsThe Southern Community Cohort Study, prospective cohort study. Participants (40-79 years) recruited predominantly from community health centers across 12 states in southeastern United States. Enrollment began in 2002 and concluded in 2009, follow-up until 2020. Cardiometabolic comorbidities (diabetes, hypertension, myocardial infarction, stroke) ascertained at the baseline survey. Cox proportional hazard models used.ResultsStudy included 76,721 participants; 16,197, 41,944, 5,247, and 4,919 participants with prior diagnosis of diabetes, hypertension, myocardial infarction, and stroke, respectively at baseline. Compared to individuals with no comorbidity …

medRxiv

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank. The mean PRS313 differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS313 distribution to categorise individuals leads to overestimation and underestimation of risk in some individuals from south-eastern and north-western countries, respectively. Adjustment for principal components explained most of the observed heterogeneity in mean PRS. Country-specific PRS distributions may be used to calibrate risk categories in individuals from different countries.

European Journal of Clinical Investigation

Background Disturbances in habitual sleep have been associated with multiple age‐associated diseases. However, the biological mechanisms underpinning these associations remain largely unclear. We assessed the possible involvement of the circulating immune system by determining the associations between sleep traits and white blood cell counts using multivariable‐adjusted linear regression and Mendelian randomization. Methods Cross‐sectional multivariable‐adjusted linear regression analyses were done using participants within the normal range of total white blood cell counts (>4.5 × 109 and <11.0 × 109/μL) from UK Biobank. For the sleep traits, we examined (short and long) sleep duration, chronotype, insomnia symptoms and daytime dozing. Two‐sample Mendelian randomization analyses were done using instruments for sleep traits derived from European‐ancestry participants from UK …

Journal of Diabetes Investigation

The potential liability to hypercatabolism in lipodystrophy remains to be fully elucidated. Here we report a 28‐year‐old Japanese woman with acquired generalized lipodystrophy, who presented with recurrence of panniculitis and anemia. After corticosteroid treatment was started, she showed rapid reductions in body weight and lean mass by 15% at maximum, accompanied by an elevated urea nitrogen/creatinine ratio, which recovered almost fully as the corticosteroid treatment was tapered and discontinued. She had multiple risk factors for hypercatabolism: lack of metabolic reserves, insulin resistance, and hyperglycemia due to lipodystrophy, lowered daily activity due to anemia, persistent inflammation, and wasting associated with panniculitis, and relatively insufficient energy and protein intake during hospitalization. More attention should be paid to the potential liability to hypercatabolism in patients with …

medRxiv

BACKGROUNDType 2 diabetes mellitus (T2D) confers a two-to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.METHODSFrom 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level …

Stroke

BACKGROUND The American Heart Association’s Life’s Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two. METHODS Targeted metabolomic profiling of 162 metabolites by liquid chromatography–tandem mass spectrometry was used to identify candidate metabolites in a stroke case–cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 …

medRxiv

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism–. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases–. Here we present a genome-wide association study of 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 predominantly population-based cohorts. We discover over 400 independent loci and assign likely causal genes at two-thirds of these using detailed manual curation of highly plausible biological candidates. We highlight the importance of sample- and participant characteristics, such as fasting status and sample type, that can have significant impact on genetic associations, revealing direct and indirect associations on glucose and phenylalanine. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing for the first time the metabolic associations of an understudied phenotype, intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetoacetate and hypertension. Our publicly available results …

Nature Genetics

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study …

Nature Communications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses …

Cancer Epidemiology, Biomarkers & Prevention

Background: Microsatellite instability (MSI) and tumor mutational burden (TMB) are predictive biomarkers for pan-cancer immunotherapy. The interrelationship between MSI-high (MSI-H) and TMB-high (TMB-H) in human cancers and their predictive value for immunotherapy in lung cancer remain unclear. Methods: We analyzed somatic mutation data from the Genomics Evidence Neoplasia Information Exchange (n = 46,320) to determine the relationship between MSI-H and TMB-H in human cancers using adjusted multivariate regression models. Patient survival was examined using the Cox proportional hazards model. The association between MSI and genetic mutations was assessed. Results: Patients (31–89 %) with MSI-H had TMB-low phenotypes across 22 cancer types. Colorectal and stomach cancers showed the strongest association between TMB and MSI. TMB-H patients with lung cancer who …

BMC Research Notes

ObjectiveData from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.ResultsPrecise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09 …

Nature Communications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses …

Diabetes & Metabolic Syndrome: Clinical Research & Reviews

AimsWe evaluated whether incorporating information on ethnic background and polygenic risk enhanced the Leicester Risk Assessment (LRA) score for predicting 10-year risk of type 2 diabetes.MethodsThe sample included 202,529 UK Biobank participants aged 40–69 years. We computed the LRA score, and developed two new risk scores using training data (80% sample): LRArev, which incorporated additional information on ethnic background, and LRAprs, which incorporated polygenic risk for type 2 diabetes. We assessed discriminative and reclassification performance in a test set (20% sample). Type 2 diabetes was ascertained using primary care, hospital inpatient and death registry records.ResultsOver 10 years, 7,476 participants developed type 2 diabetes. The Harrell's C indexes were 0.796 (95% Confidence Interval [CI] 0.785, 0.806), 0.802 (95% CI 0.792, 0.813), and 0.829 (95% CI 0.820, 0.839) for …

Restless legs syndrome (RLS) affects up to 10% of older adults. Their health care is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find novel entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 cases and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including 3 on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg= 0.96). Locus annotation prioritized druggable genes such as glutamate-receptors 1 and 4 and Mendelian randomization indicated RLS as a causal risk factor of diabetes. Machine-learning approaches combining genetic and non-genetic information performed best in risk prediction (AUC= 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up, and provided evidence that gene-environment interactions are likely relevant to RLS risk prediction.

The American Journal of Clinical Nutrition

BackgroundThere are few resources available for researchers aiming to conduct 24-h dietary record and recall analysis using R.ObjectivesWe aimed to develop DietDiveR, which is a toolkit of functions written in R for the analysis of recall or record data collected with the Automated Self-Administered 24-h Dietary Assessment Tool or 2-d 24-h dietary recall data from the National Health and Nutrition Examination Survey (NHANES). The R functions are intended for food and nutrition researchers who are not computational experts.MethodsDietDiveR provides users with functions to 1) clean dietary data, 2) analyze 24-h dietary intakes in relation to other study-specific metadata variables, 3) visualize percentages of energy intake from macronutrients, 4) perform principal component analysis or k-means clustering to group participants by similar data-driven dietary patterns, 5) generate foodtrees based on the hierarchical …

Nature

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes, and molecular mechanisms that are often specific to cell type,. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10−8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster …

Nature

Author Correction: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion Author Correction: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion Nature. 2024 Feb 9. doi: 10.1038/s41586-024-07164-y. Online ahead of print. Authors Yu-Hwa Huang 1 , Chen Zhu # 2 , Yasuyuki Kondo # 1 , Ana C Anderson 2 , Amit Gandhi 1 , Andrew Russell 3 , Stephanie K Dougan 4 , Britt-Sabina Petersen 5 , Espen Melum 1 6 , Thomas Pertel 2 , Kiera L Clayton 7 , Monika Raab 8 , Qiang Chen 9 , Nicole Beauchemin 10 , Paul J Yazaki 11 , Michal Pyzik 1 , Mario A Ostrowski 7 12 , Jonathan N Glickman 13 , Christopher E Rudd 8 , Hidde L Ploegh 4 , Andre Franke 5 , Gregory A Petsko 3 , Vijay K Kuchroo 2 , Richard S Blumberg 14 Affiliations 1 Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, 02115, Massachusetts, USA. 2 …

Nature

화학공학소재연구정보센터(CHERIC) | 연구정보 | 문헌DB | 학술지 검색 화학공학소재연구정보 센터 홈 로그인 로그아웃 연락처 사이트맵 센터 센터소개 회원가입/정보수정 뉴스 공지사항 연구 동향 학회참관기 우수연구자소개 취업정보 연구정보 문헌DB KDB Compound Search 전문연구 정보 동영상 심포지움 자료 연구성과보고서 저널정보 논문 작성법 참고문헌DB 분석기기DB 화학 공정DB PSPDB 연구자지식지도 상태도정보 교육정보 사이버강의-학부 사이버강의-대학원 실무 강좌 강의자료 링크 교육자료 링크 사이버실험실 물성측정실험 매뉴얼 커뮤니티 공학포럼 카페 신진연구자인터뷰 리소스 특허정보 술어DB 관련법령 자격증정보 성과소개서 연구보고서 문헌DB 학술지 검색 학술대회 발표논문집 최신 국내 저널 최신 리뷰페이퍼 KDB Periodic Table of Elements Unit Conversion Universal Constants Pure Component Properties Binary Vapor-Liquid Equil. Data Calculation Modules Research Articles Citing KDB Compound Search …

Nature

EconPapers: Why it was right to reject the Anthropocene as a geological epoch EconPapers Economics at your fingertips EconPapers Home About EconPapers Working Papers Journal Articles Books and Chapters Software Components Authors JEL codes New Economics Papers Advanced Search EconPapers FAQ Archive maintainers FAQ Cookies at EconPapers Format for printing The RePEc blog The RePEc plagiarism page Why it was right to reject the Anthropocene as a geological epoch Mark Maslin (), Matthew Edgeworth, Erle C. Ellis and Philip L. Gibbard Nature, 2024, vol. 629, issue 8010, 41-41 Abstract: Letter to the Editor Keywords: Geology; Environmental sciences; Climate change; Sustainability (search for similar items in EconPapers) Date: 2024 References: Add references at CitEc Citations: Downloads: (external link) https://www.nature.com/articles/d41586-024-01268-1 Abstract (text/html) Access to …

Nature

Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations, , , , – in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite …

Nature

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods,. A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome,. Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins, –. However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes. This 15-fold increase in genus-level sampling relative to comparable nuclear studies provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating …

Nature

Van der Waals encapsulation of two-dimensional materials in hexagonal boron nitride (hBN) stacks is a promising way to create ultrahigh-performance electronic devices 1, 2, 3, 4. However, contemporary approaches for achieving van der Waals encapsulation, which involve artificial layer stacking using mechanical transfer techniques, are difficult to control, prone to contamination and unscalable. Here we report the transfer-free direct growth of high-quality graphene nanoribbons (GNRs) in hBN stacks. The as-grown embedded GNRs exhibit highly desirable features being ultralong (up to 0.25 mm), ultranarrow (< 5 nm) and homochiral with zigzag edges. Our atomistic simulations show that the mechanism underlying the embedded growth involves ultralow GNR friction when sliding between AA′-stacked hBN layers. Using the grown structures, we demonstrate the transfer-free fabrication of embedded GNR field …

Nature

Scientific evidence regularly guides policy decisions, with behavioural science increasingly part of this process. In April 2020, an influential paper proposed 19 policy recommendations (‘claims’) detailing how evidence from behavioural science could contribute to efforts to reduce impacts and end the COVID-19 pandemic. Here we assess 747 pandemic-related research articles that empirically investigated those claims. We report the scale of evidence and whether evidence supports them to indicate applicability for policymaking. Two independent teams, involving 72 reviewers, found evidence for 18 of 19 claims, with both teams finding evidence supporting 16 (89%) of those 18 claims. The strongest evidence supported claims that anticipated culture, polarization and misinformation would be associated with policy effectiveness. Claims suggesting trusted leaders and positive social norms increased adherence to …

Nature

Topology, – and interactions are foundational concepts in the modern understanding of quantum matter. Their nexus yields three important research directions: (1) the competition between distinct interactions, as in several intertwined phases, (2) the interplay between interactions and topology that drives the phenomena in twisted layered materials and topological magnets, and (3) the coalescence of several topological orders to generate distinct novel phases. The first two examples have grown into major areas of research, although the last example remains mostly unexplored, mainly because of the lack of a material platform for experimental studies. Here, using tunnelling microscopy, photoemission spectroscopy and a theoretical analysis, we unveil a ‘hybrid’ topological phase of matter in the simple elemental-solid arsenic. Through a unique bulk-surface-edge correspondence, we uncover that arsenic features a …

Nature

The Middle to Upper Palaeolithic transition in Europe is associated with the regional disappearance of Neanderthals and the spread of Homo sapiens. Late Neanderthals persisted in western Europe several millennia after the occurrence of H. sapiens in eastern Europe1. Local hybridization between the two groups occurred2, but not on all occasions3. Archaeological evidence also indicates the presence of several technocomplexes during this transition, complicating our understanding and the association of behavioural adaptations with specific hominin groups4. One such technocomplex for which the makers are unknown is the Lincombian–Ranisian–Jerzmanowician (LRJ), which has been described in northwestern and central Europe5–8. Here we present the morphological and proteomic taxonomic identification, mitochondrial DNA analysis and direct radiocarbon dating of human remains directly associated …

Nature

The glymphatic movement of fluid through the brain removes metabolic waste, , –. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer’s disease, , –. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer’s disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings …

Nature

Western Eurasia witnessed several large-scale human migrations during the Holocene, , , –. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness …

Nature

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis,, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn’s disease. Several of these compounds and …

Nature

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival …

Nature

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples,. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic …

Nature

Myeloid cells are known to suppress antitumour immunity. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells …

Nature

EconPapers: Urban trees: how to maximize their benefits for humans and the environment EconPapers Economics at your fingertips EconPapers Home About EconPapers Working Papers Journal Articles Books and Chapters Software Components Authors JEL codes New Economics Papers Advanced Search EconPapers FAQ Archive maintainers FAQ Cookies at EconPapers Format for printing The RePEc blog The RePEc plagiarism page Urban trees: how to maximize their benefits for humans and the environment Lina Tang (), Guofan Shao and Peter M. Groffman Nature, 2024, vol. 626, issue 7998, 261-261 Abstract: Letter to the Editor Keywords: Policy; Sustainability; Environmental sciences (search for similar items in EconPapers) Date: 2024 References: Add references at CitEc Citations: Track citations by RSS feed Downloads: (external link) https://www.nature.com/articles/d41586-024-00300-8 Abstract (text/…

Nature

Crop production is a large source of atmospheric ammonia (NH 3), which poses risks to air quality, human health and ecosystems 1, 2, 3, 4, 5. However, estimating global NH 3 emissions from croplands is subject to uncertainties because of data limitations, thereby limiting the accurate identification of mitigation options and efficacy 4, 5. Here we develop a machine learning model for generating crop-specific and spatially explicit NH 3 emission factors globally (5-arcmin resolution) based on a compiled dataset of field observations. We show that global NH 3 emissions from rice, wheat and maize fields in 2018 were 4.3±1.0 Tg N yr− 1, lower than previous estimates that did not fully consider fertilizer management practices 6, 7, 8, 9. Furthermore, spatially optimizing fertilizer management, as guided by the machine learning model, has the potential to reduce the NH 3 emissions by about 38%(1.6±0.4 Tg N yr− 1 …

Nature

Understanding the formation and stabilization mechanisms of soil organic carbon (SOC) is important for managing land carbon (C) and mitigating climate change. Tao et al. 1 reported that microbial C use efficiency (CUE) is the primary determinant of global SOC storage and that the relative impact of plant C inputs on SOC is minor. Although soil microbes undoubtedly play an important role in SOC cycling, we are concerned about the robustness of the approach taken by Tao et al. 1. The potential biases in their analyses may lead to misleading, model-dependent results.An important piece of evidence in support of an empirical relationship between CUE and SOC stems from a meta-analysis based on 132 paired CUE and SOC measurements. Tao et al. 1 applied a linear mixed-effects model to this dataset that included CUE, mean annual temperature (MAT), soil depth and random effects and explained 55% of the …

Nature

Western Eurasia witnessed several large-scale human migrations during the Holocene, , , –. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness …