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1.
R Soc Open Sci ; 11(8): 240317, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39144492

RESUMEN

The history and palaeoecology of the steppe bison (Bison priscus) remain incompletely understood despite its widespread distribution. Using dental microwear textural analysis (DMTA) and vegetation modelling, we reconstructed the diet and assessed the habitat of steppe bison inhabiting Eurasia and Alaska since the Middle Pleistocene. During the Late Pleistocene, steppe bison occupied a variety of biome types: from the mosaic of temperate summergreen forest and steppe/temperate grassland (Serbia) to the tundra biomes (Siberia and Alaska). Despite the differences in the identified biome types, the diet of steppe bison did not differ significantly among populations in Eurasia. DMTA classified it as a mixed forager in all populations studied. The DMTA of Bb1 bison-a recently identified genetically extinct sister-clade of Bison bonasus-was typical of a highly grazing bovid species and differed from all B. priscus populations. The results of the study temper the common perception that steppe bison were grazers in steppe habitats. The dietary plasticity of the steppe bison was lower when compared with modern European bison and may have played an important role in its extinction, even in the stable tundra biome of eastern Siberia, where it has survived the longest in all of Eurasia.

2.
Cell ; 187(14): 3541-3562.e51, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38996487

RESUMEN

Analyses of ancient DNA typically involve sequencing the surviving short oligonucleotides and aligning to genome assemblies from related, modern species. Here, we report that skin from a female woolly mammoth (†Mammuthus primigenius) that died 52,000 years ago retained its ancient genome architecture. We use PaleoHi-C to map chromatin contacts and assemble its genome, yielding 28 chromosome-length scaffolds. Chromosome territories, compartments, loops, Barr bodies, and inactive X chromosome (Xi) superdomains persist. The active and inactive genome compartments in mammoth skin more closely resemble Asian elephant skin than other elephant tissues. Our analyses uncover new biology. Differences in compartmentalization reveal genes whose transcription was potentially altered in mammoths vs. elephants. Mammoth Xi has a tetradic architecture, not bipartite like human and mouse. We hypothesize that, shortly after this mammoth's death, the sample spontaneously freeze-dried in the Siberian cold, leading to a glass transition that preserved subfossils of ancient chromosomes at nanometer scale.


Asunto(s)
Genoma , Mamuts , Piel , Animales , Mamuts/genética , Genoma/genética , Femenino , Elefantes/genética , Cromatina/genética , Fósiles , ADN Antiguo/análisis , Ratones , Humanos , Cromosoma X/genética
3.
Nat Aging ; 4(8): 1043-1052, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38834882

RESUMEN

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.


Asunto(s)
Hematopoyesis Clonal , Epigénesis Genética , Proteómica , Hematopoyesis Clonal/genética , Humanos , Metilación de ADN , Femenino , Masculino , Células Madre Hematopoyéticas/metabolismo , Persona de Mediana Edad , Proteoma/metabolismo , Proteoma/genética , Inhibidor Tisular de Metaloproteinasa-1/genética , Anciano
4.
Nanophotonics ; 13(9)2024.
Artículo en Inglés | MEDLINE | ID: mdl-38846933

RESUMEN

Hyperbolic phonon polaritons (HPhPs), hybrids of light and lattice vibrations in polar dielectric crystals, empower nanophotonic applications by enabling the confinement and manipulation of light at the nanoscale. Molybdenum trioxide (α-MoO3) is a naturally hyperbolic material, meaning that its dielectric function deterministically controls the directional propagation of in-plane HPhPs within its reststrahlen bands. Strategies such as substrate engineering, nano- and heterostructuring, and isotopic enrichment are being developed to alter the intrinsic die ectric functions of natural hyperbolic materials and to control the confinement and propagation of HPhPs. Since isotopic disorder can limit phonon-based processes such as HPhPs, here we synthesize isotopically enriched 92MoO3 (92Mo: 99.93 %) and 100MoO3 (100Mo: 99.01 %) crystals to tune the properties and dispersion of HPhPs with respect to natural α-MoO3, which is composed of seven stable Mo isotopes. Real-space, near-field maps measured with the photothermal induced resonance (PTIR) technique enable comparisons of inplane HPhPs in α-MoO3 and isotopically enriched analogues within a reststrahlen band (≈820 cm-1 to ≈ 972 cm-1). Results show that isotopic enrichment (e.g., 92MoO3 and 100MoO3) alters the dielectric function, shifting the HPhP dispersion (HPhP angular wavenumber × thickness vs IR frequency) by ≈-7% and ≈ +9 %, respectively, and changes the HPhP group velocities by ≈ ±12 %, while the lifetimes (≈ 3 ps) in 92MoO3 were found to be slightly improved (≈ 20 %). The latter improvement is attributed to a decrease in isotopic disorder. Altogether, isotopic enrichment was found to offer fine control over the properties that determine the anisotropic in-plane propagation of HPhPs in α-MoO3, which is essential to its implementation in nanophotonic applications.

5.
Adv Sci (Weinh) ; : e2308574, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38943261

RESUMEN

The vast high entropy alloy (HEA) composition space is promising for discovery of new material phases with unique properties. This study explores the potential to achieve rare-earth-free high magnetic anisotropy materials in single-phase HEA thin films. Thin films of FeCoNiMnCu sputtered on thermally oxidized Si/SiO2 substrates at room temperature are magnetically soft, with a coercivity on the order of 10 Oe. After post-deposition rapid thermal annealing (RTA), the films exhibit a single face-centered-cubic phase, with an almost 40-fold increase in coercivity. Inclusion of 50 at.% Pt in the film leads to ordering of a single L10 high entropy intermetallic phase after RTA, along with high magnetic anisotropy and 3 orders of magnitude coercivity increase. These results demonstrate a promising HEA approach to achieve high magnetic anisotropy materials using RTA.

6.
Nucleic Acids Res ; 52(W1): W70-W77, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38709879

RESUMEN

Polygenic scores (PGS) enable the prediction of genetic predisposition for a wide range of traits and diseases by calculating the weighted sum of allele dosages for genetic variants associated with the trait or disease in question. Present approaches for calculating PGS from genotypes are often inefficient and labor-intensive, limiting transferability into clinical applications. Here, we present 'Imputation Server PGS', an extension of the Michigan Imputation Server designed to automate a standardized calculation of polygenic scores based on imputed genotypes. This extends the widely used Michigan Imputation Server with new functionality, bringing the simplicity and efficiency of modern imputation to the PGS field. The service currently supports over 4489 published polygenic scores from publicly available repositories and provides extensive quality control, including ancestry estimation to report population stratification. An interactive report empowers users to screen and compare thousands of scores in a fast and intuitive way. Imputation Server PGS provides a user-friendly web service, facilitating the application of polygenic scores to a wide range of genetic studies and is freely available at https://imputationserver.sph.umich.edu.


Asunto(s)
Predisposición Genética a la Enfermedad , Herencia Multifactorial , Programas Informáticos , Herencia Multifactorial/genética , Humanos , Internet , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Genotipo , Alelos , Puntuación de Riesgo Genético
7.
Nanoscale Adv ; 6(9): 2260-2269, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38694454

RESUMEN

The International Roadmap for Devices and Systems (IRDS) predicts the integration of 2D materials into high-volume manufacturing as channel materials within the next decade, primarily in ultra-scaled and low-power devices. While their widespread adoption in advanced chip manufacturing is evolving, the need for diverse characterization methods is clear. This is necessary to assess structural, electrical, compositional, and mechanical properties to control and optimize 2D materials in mass-produced devices. Although the lab-to-fab transition remains nascent and a universal metrology solution is yet to emerge, rapid community progress underscores the potential for significant advancements. This paper reviews current measurement capabilities, identifies gaps in essential metrology for CMOS-compatible 2D materials, and explores fundamental measurement science limitations when applying these techniques in high-volume semiconductor manufacturing.

8.
Int J Mol Sci ; 25(8)2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38673819

RESUMEN

Perineuronal nets (PNN) are a special highly structured type of extracellular matrix encapsulating synapses on large populations of CNS neurons. PNN undergo structural changes in schizophrenia, epilepsy, Alzheimer's disease, stroke, post-traumatic conditions, and some other brain disorders. The functional role of the PNN microstructure in brain pathologies has remained largely unstudied until recently. Here, we review recent research implicating PNN microstructural changes in schizophrenia and other disorders. We further concentrate on high-resolution studies of the PNN mesh units surrounding synaptic boutons to elucidate fine structural details behind the mutual functional regulation between the ECM and the synaptic terminal. We also review some updates regarding PNN as a potential pharmacological target. Artificial intelligence (AI)-based methods are now arriving as a new tool that may have the potential to grasp the brain's complexity through a wide range of organization levels-from synaptic molecular events to large scale tissue rearrangements and the whole-brain connectome function. This scope matches exactly the complex role of PNN in brain physiology and pathology processes, and the first AI-assisted PNN microscopy studies have been reported. To that end, we report here on a machine learning-assisted tool for PNN mesh contour tracing.


Asunto(s)
Inteligencia Artificial , Encéfalo , Animales , Humanos , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Encefalopatías/patología , Matriz Extracelular/metabolismo , Microscopía/métodos , Red Nerviosa/patología , Neuronas/patología , Neuronas/metabolismo , Sinapsis/patología
9.
Nat Commun ; 15(1): 13, 2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-38253559

RESUMEN

Data-centric applications are pushing the limits of energy-efficiency in today's computing systems, including those based on phase-change memory (PCM). This technology must achieve low-power and stable operation at nanoscale dimensions to succeed in high-density memory arrays. Here we use a novel combination of phase-change material superlattices and nanocomposites (based on Ge4Sb6Te7), to achieve record-low power density ≈ 5 MW/cm2 and ≈ 0.7 V switching voltage (compatible with modern logic processors) in PCM devices with the smallest dimensions to date (≈ 40 nm) for a superlattice technology on a CMOS-compatible substrate. These devices also simultaneously exhibit low resistance drift with 8 resistance states, good endurance (≈ 2 × 108 cycles), and fast switching (≈ 40 ns). The efficient switching is enabled by strong heat confinement within the superlattice materials and the nanoscale device dimensions. The microstructural properties of the Ge4Sb6Te7 nanocomposite and its high crystallization temperature ensure the fast-switching speed and stability in our superlattice PCM devices. These results re-establish PCM technology as one of the frontrunners for energy-efficient data storage and computing.

10.
ACS Appl Mater Interfaces ; 15(51): 59693-59703, 2023 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-38090759

RESUMEN

Two-dimensional materials, such as transition metal dichalcogenides (TMDCs), have the potential to revolutionize the field of electronics and photonics due to their unique physical and structural properties. This research presents a novel method for synthesizing crystalline TMDCs crystals with <10 nm size using ultrafast migration of vacancies at elevated temperatures. Through in situ and ex situ processing and using atomic-level characterization techniques, we analyzed the shape, size, crystallinity, composition, and strain distribution of these nanocrystals. These nanocrystals exhibit electronic structure signatures that differ from the 2D bulk: i.e., uniform mono- and multilayers. Further, our in situ, vacuum-based synthesis technique allows observation and comparison of defect and phase evolution in these crystals formed under van der Waals heterostructure confinement versus unconfined conditions. Overall, this research demonstrates a solid-state route to synthesizing uniform nanocrystals of TMDCs and lays the foundation for materials science in confined 2D spaces under extreme conditions.

11.
Front Genet ; 14: 1235337, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38028628

RESUMEN

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

12.
Nat Commun ; 14(1): 6691, 2023 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-37872165

RESUMEN

Ferromagnetism and superconductivity are two key ingredients for topological superconductors, which can serve as building blocks of fault-tolerant quantum computers. Adversely, ferromagnetism and superconductivity are typically also two hostile orderings competing to align spins in different configurations, and thus making the material design and experimental implementation extremely challenging. A single material platform with concurrent ferromagnetism and superconductivity is actively pursued. In this paper, we fabricate van der Waals Josephson junctions made with iron-based superconductor Fe(Te,Se), and report the global device-level transport signatures of interfacial ferromagnetism emerging with superconducting states for the first time. Magnetic hysteresis in the junction resistance is observed only below the superconducting critical temperature, suggesting an inherent correlation between ferromagnetic and superconducting order parameters. The 0-π phase mixing in the Fraunhofer patterns pinpoints the ferromagnetism on the junction interface. More importantly, a stochastic field-free superconducting diode effect was observed in Josephson junction devices, with a significant diode efficiency up to 10%, which unambiguously confirms the spontaneous time-reversal symmetry breaking. Our work demonstrates a new way to search for topological superconductivity in iron-based superconductors for future high Tc fault-tolerant qubit implementations from a device perspective.

13.
ACS Nano ; 17(23): 23692-23701, 2023 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-37861986

RESUMEN

Quantum confinement of two-dimensional excitons in van der Waals materials via electrostatic trapping, lithographic patterning, Moiré potentials, and chemical implantation has enabled significant advances in tailoring light emission from nanostructures. While such approaches rely on complex preparation of materials, natural edges are a ubiquitous feature in layered materials and provide a different approach for investigating quantum-confined excitons. Here, we observe that certain edge sites of monolayer black phosphorus (BP) strongly localize the intrinsic quasi-one-dimensional excitons, yielding sharp spectral lines in photoluminescence, with nearly an order of magnitude line width reduction. Through structural characterization of BP edges using transmission electron microscopy and first-principles GW plus Bethe-Salpeter equation (GW-BSE) calculations of exemplary BP nanoribbons, we find that certain atomic reconstructions can strongly quantum-confine excitons resulting in distinct emission features, mediated by local strain and screening. We observe linearly polarized luminescence emission from edge reconstructions that preserve the mirror symmetry of the parent BP lattice, in agreement with calculations. Furthermore, we demonstrate efficient electrical switching of localized edge excitonic luminescence, whose sites act as excitonic transistors for emission. Localized emission from BP edges motivates exploration of nanoribbons and quantum dots as hosts for tunable narrowband light generation, with future potential to create atomic-like structures for quantum information processing applications as well as exploration of exotic phases that may reside in atomic edge structures.

14.
Nat Genet ; 55(10): 1640-1650, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37709864

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estudio de Asociación del Genoma Completo , Cirrosis Hepática/genética , Aciltransferasas/genética , Aciltransferasas/metabolismo , Fosfolipasas/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Hígado/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo
15.
Nat Genet ; 55(10): 1651-1664, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37770635

RESUMEN

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.


Asunto(s)
Aterosclerosis , Enfermedad de la Arteria Coronaria , Humanos , Aterosclerosis/genética , Población Negra/genética , Enfermedad de la Arteria Coronaria/genética , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Pueblo Europeo/genética
16.
Anesthesiology ; 139(6): 827-839, 2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-37774411

RESUMEN

BACKGROUND: Postsurgical pain is a key component of surgical recovery. However, the genetic drivers of postsurgical pain remain unclear. A broad review and meta-analyses of variants of interest will help investigators understand the potential effects of genetic variation. METHODS: This article is a systematic review of genetic variants associated with postsurgical pain in humans, assessing association with postsurgical pain scores and opioid use in both acute (0 to 48 h postoperatively) and chronic (at least 3 months postoperatively) settings. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from 2000 to 2022 for studies using search terms related to genetic variants and postsurgical pain in humans. English-language studies in adult patients examining associations of one or more genetic variants with postsurgical pain were included. The primary outcome was association of genetic variants with either acute or chronic postsurgical pain. Pain was measured by patient-reported pain score or analgesic or opioid consumption. RESULTS: A total of 163 studies were included, evaluating 129 unique genes and 594 unique genetic variants. Many of the reported significant associations fail to be replicated in other studies. Meta-analyses were performed for seven variants for which there was sufficient data (OPRM1 rs1799971; COMT rs4680, rs4818, rs4633, and rs6269; and ABCB1 rs1045642 and rs2032582). Only two variants were associated with small differences in postsurgical pain: OPRM1 rs1799971 (for acute postsurgical opioid use standard mean difference = 0.25; 95% CI, 0.16 to 0.35; cohort size, 8,227; acute postsurgical pain score standard mean difference = 0.20; 95% CI, 0.09 to 0.31; cohort size, 4,619) and COMT rs4680 (chronic postsurgical pain score standard mean difference = 0.26; 95% CI, 0.08 to 0.44; cohort size, 1,726). CONCLUSIONS: Despite much published data, only two alleles have a small association with postsurgical pain. Small sample sizes, potential confounding variables, and inconsistent findings underscore the need to examine larger cohorts with consistent outcome measures.


Asunto(s)
Analgésicos Opioides , Polimorfismo de Nucleótido Simple , Adulto , Humanos , Dolor Postoperatorio/genética , Analgésicos
17.
Nat Commun ; 14(1): 4646, 2023 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-37532724

RESUMEN

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.


Asunto(s)
Fibrilación Atrial , Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/genética , Factores de Riesgo , Frecuencia Cardíaca/genética , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana/métodos , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple
18.
Nat Protoc ; 18(9): 2625-2641, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37495751

RESUMEN

The human leukocyte antigen (HLA) locus is associated with more complex diseases than any other locus in the human genome. In many diseases, HLA explains more heritability than all other known loci combined. In silico HLA imputation methods enable rapid and accurate estimation of HLA alleles in the millions of individuals that are already genotyped on microarrays. HLA imputation has been used to define causal variation in autoimmune diseases, such as type I diabetes, and in human immunodeficiency virus infection control. However, there are few guidelines on performing HLA imputation, association testing, and fine mapping. Here, we present a comprehensive tutorial to impute HLA alleles from genotype data. We provide detailed guidance on performing standard quality control measures for input genotyping data and describe options to impute HLA alleles and amino acids either locally or using the web-based Michigan Imputation Server, which hosts a multi-ancestry HLA imputation reference panel. We also offer best practice recommendations to conduct association tests to define the alleles, amino acids, and haplotypes that affect human traits. Along with the pipeline, we provide a step-by-step online guide with scripts and available software ( https://github.com/immunogenomics/HLA_analyses_tutorial ). This tutorial will be broadly applicable to large-scale genotyping data and will contribute to defining the role of HLA in human diseases across global populations.


Asunto(s)
Antígenos HLA , Antígenos de Histocompatibilidad Clase I , Humanos , Alelos , Antígenos HLA/genética , Genotipo , Haplotipos , Aminoácidos/genética , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo
19.
Nanoscale ; 15(23): 9964-9972, 2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37266913

RESUMEN

Wide bandgap semiconductors such as gallium oxide (Ga2O3) have attracted much attention for their use in next-generation high-power electronics. Although single-crystal Ga2O3 substrates can be routinely grown from melt along various orientations, the influence of such orientations has been seldom reported. Further, making rectifying p-n diodes from Ga2O3 has been difficult due to lack of p-type doping. In this study, we fabricated and optimized 2D/3D vertical diodes on ß-Ga2O3 by varying the following three factors: substrate planar orientation, choice of 2D material and metal contacts. The quality of our devices was validated using high-temperature dependent measurements, atomic-force microscopy (AFM) techniques and technology computer-aided design (TCAD) simulations. Our findings suggest that 2D/3D ß-Ga2O3 vertical heterojunctions are optimized by substrate planar orientation (-201), combined with 2D WS2 exfoliated layers and Ti contacts, and show record rectification ratios (>106) concurrently with ON-Current density (>103 A cm-2) for application in power rectifiers.


Asunto(s)
Electrónica , Semiconductores , Microscopía de Fuerza Atómica
20.
ACS Nano ; 17(8): 7685-7694, 2023 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-37043483

RESUMEN

Monolayer transition metal dichalcogenide (TMDC) semiconductors exhibit strong excitonic optical resonances, which serve as a microscopic, noninvasive probe into their fundamental properties. Like the hydrogen atom, such excitons can exhibit an entire Rydberg series of resonances. Excitons have been extensively studied in most TMDCs (MoS2, MoSe2, WS2, and WSe2), but detailed exploration of excitonic phenomena has been lacking in the important TMDC material molybdenum ditelluride (MoTe2). Here, we report an experimental investigation of excitonic luminescence properties of monolayer MoTe2 to understand the excitonic Rydberg series, up to 3s. We report a significant modification of emission energies with temperature (4 to 300 K), thereby quantifying the exciton-phonon coupling. Furthermore, we observe a strongly gate-tunable exciton-trion interplay for all the Rydberg states governed mainly by free-carrier screening, Pauli blocking, and band gap renormalization in agreement with the results of first-principles GW plus Bethe-Salpeter equation approach calculations. Our results help bring monolayer MoTe2 closer to its potential applications in near-infrared optoelectronics and photonic devices.

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