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Summary statistics from genome-wide association studies (GWAS) have facilitated the development of various summary data-based methods, which typically require a reference sample for linkage disequilibrium (LD) estimation. Analyses using these methods may be biased by errors in GWAS summary data or LD reference or heterogeneity between GWAS and LD reference. Here we propose a quality control method, DENTIST, that leverages LD among genetic variants to detect and eliminate errors in GWAS or LD reference and heterogeneity between the two. Through simulations, we demonstrate that DENTIST substantially reduces false-positive rate in detecting secondary signals in the summary-data-based conditional and joint association analysis, especially for imputed rare variants (false-positive rate reduced from >28% to, Analyses of summary statistics from GWAS are subject to biases due to errors in the discovery GWAS or linkage disequilibrium reference data set or heterogeneity between data sets. Here, the authors propose a quality control method to be added to analysis of GWAS summary data that can reduce such biases.

Understanding how natural selection has shaped genetic architecture of complex traits is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level GWAS data to estimate multiple genetic architecture parameters including selection signature. Here, we present a method (SBayesS) that only requires GWAS summary statistics. We analyse data for 155 complex traits (n = 27k–547k) and project the estimates onto those obtained from evolutionary simulations. We estimate that, on average across traits, about 1% of human genome sequence are mutational targets with a mean selection coefficient of ~0.001. Common diseases, on average, show a smaller number of mutational targets and have been under stronger selection, compared to other traits. SBayesS analyses incorporating functional annotations reveal that selection signatures vary across genomic regions, among which coding regions have the strongest selection signature and are enriched for both the number of associated variants and the magnitude of effect sizes., Methods to study how natural selection shapes genetic architecture of complex traits rely on individual level genome-wide association study (GWAS) data. Here, the authors present a Bayesian method using GWAS summary statistics to study genetic architecture and apply this to 155 complex traits.

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470–495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450–458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic., Neutralizing antibodies are currently one versatile strategy to treat SARS-CoV-2 infection. Here, Li et al. characterize three monoclonal antibodies neutralizing authentic virus infection in vitro and in vivo by targeting the receptor binding domain as evidenced by Cryo-EM.

The intrinsic antiferromagnetic topological insulator MnBi2Te4 provides an ideal platform for exploring exotic topological quantum phenomena. Recently, the Chern insulator and axion insulator phases have been realized in few-layer MnBi2Te4 devices at low magnetic field regime. However, the fate of MnBi2Te4 in high magnetic field has never been explored in experiment. In this work, we report transport studies of exfoliated MnBi2Te4 flakes in pulsed magnetic fields up to 61.5 T. In the high-field limit, the Chern insulator phase with Chern number C = −1 evolves into a robust zero Hall resistance plateau state. Nonlocal transport measurements and theoretical calculations demonstrate that the charge transport in the zero Hall plateau state is conducted by two counter-propagating edge states that arise from the combined effects of Landau levels and large Zeeman effect in strong magnetic fields. Our result demonstrates the intricate interplay among intrinsic magnetic order, external magnetic field, and nontrivial band topology in MnBi2Te4., The antiferromagnetic topological insulator MnBi2Te4 exhibits Chern and axion insulator phases at low magnetic field; however, its behaviour in high magnetic field has remained unexplored. Here, using transport measurements at high magnetic field, the authors report a zero Hall plateau composed of two counter-propagating edge channels.

18 p.-8 fig., Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration., This work was supported by National Institutes of Health grants AG054108, AG021904, and AG017617 (to AMC) and AG038072 (to AMC, FM, and EG), the JPB Foundation (to AMC), the Michael J. Fox Foundation (to AMC and EG), the Rainwater Charitable Foundation (to AMC and EG) and the Backus Foundation (to AMC). Chemical synthesis, NMR and MS data were in part supported by NIH awards P30 CA013330 and 1S10OD016305. Research in PB and RGS lab is funded by Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018-098557-B-I00 to PB and RTI2018-098990-J-I00 to RGS. CAR was supported by T32 GM007491 and MM by T32 AG023475.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells., Enzalutamide, an approved drug for prostate cancer, acts on TMPRSS2 expression, a key mediator for SARS-CoV-2 infection. Here, the authors characterize the anti-SARS-CoV-2 effects of Enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and in hACE2-transduced Tmprss2 knockout mice and show lack antiviral action in human lung cells and human lung organoids, likely due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells.

BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAFV600E signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors., FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which limits their clinical efficacy in tumors expressing BRAFV600E mutant monomers. Here the authors identify FDA-approved Ponatinib as an effective inhibitor of BRAF monomers and dimers and designed PHI1, an inhibitor with a unique mode of action and selectivity for oncogenic BRAF dimers.

The use of an endogenous stimulus instead of external trigger has an advantage for targeted and controlled release in drug delivery. Here, we report on cascade nanoreactors for bacterial toxin-triggered antibiotic release by wrapping calcium peroxide (CaO2) and antibiotic in a eutectic mixture of two fatty acids and a liposome coating. When encountering pathogenic bacteria in vivo these nanoreactors capture the toxins, without compromising their structural integrity, and the toxins form pores. Water enters the nanoreactors through the pores to react with CaO2 and produce hydrogen peroxide which decomposes to oxygen and drives antibiotic release. The bound toxins reduce the toxicity and also stimulate the body’s immune response. This works to improve the therapeutic effect in bacterially infected mice. This strategy provides a Domino Effect approach for treating infections caused by bacteria that secrete pore-forming toxins., Endogenous triggered delivery of antibiotics over an external triggered delivery has distinct advantages. Here, the authors report on a nanoreactor triggered by bacterial toxin to trigger a drug release mechanism and capture the toxin for reduced toxicity of toxins and improved immune response.

The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and >40% of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm., The identification of the causal gene at a GWAS locus remains to be a challenging task. Here, using the SMR & HEIDI method to integrate GWAS, eQTL and mQTL data, Wu et al. map DNA methylation sites to the transcriptome and thereby prioritize functionally relevant genes for 12 human complex traits.

Topological insulators with spin-momentum-locked topological surface states are expected to exhibit a giant spin-orbit torque in the topological insulator/ferromagnet systems. To date, the topological insulator spin-orbit torque-driven magnetization switching is solely reported in a Cr-doped topological insulator at 1.9 K. Here we directly show giant spin-orbit torque-driven magnetization switching in a Bi2Se3/NiFe heterostructure at room temperature captured using a magneto-optic Kerr effect microscope. We identify a large charge-to-spin conversion efficiency of ~1–1.75 in the thin Bi2Se3 films, where the topological surface states are dominant. In addition, we find the current density required for the magnetization switching is extremely low, ~6 × 105 A cm–2, which is one to two orders of magnitude smaller than that with heavy metals. Our demonstration of room temperature magnetization switching of a conventional 3d ferromagnet using Bi2Se3 may lead to potential innovations in topological insulator-based spintronic applications., The application of spin-orbit torque in topological insulator heterostructures is limited only under low temperature. Here, the authors report room temperature magnetization switching in topological insulator-ferromagnet heterostructures by spin-orbit torques.

Topological semimetals have recently attracted extensive research interests as host materials to condensed matter physics counterparts of Dirac and Weyl fermions originally proposed in high energy physics. These fermions with linear dispersions near the Dirac or Weyl points obey Lorentz invariance, and the chiral anomaly leads to novel quantum phenomena such as negative magnetoresistance. The Lorentz invariance is, however, not necessarily respected in condensed matter physics, and thus Lorentz-violating type-II Dirac fermions with strongly tilted cones can be realized in topological semimetals. Here, we report the first experimental evidence of type-II Dirac fermions in bulk stoichiometric PtTe$_2$ single crystal. Angle-resolved photoemission spectroscopy (ARPES) measurements and first-principles calculations reveal a pair of strongly tilted Dirac cones along the $\Gamma$-A direction under the symmetry protection, confirming PtTe$_2$ as a type-II Dirac semimetal. The realization of type-II Dirac fermions opens a new door for exotic physical properties distinguished from type-I Dirac fermions in condensed matter materials., Comment: 12 pages, 4 figures

Thermal electron transfer through hydrogen bonds remains largely unexplored. Here we report the study of electron transfer through amide-amide hydrogen bonded interfaces in mixed-valence complexes with covalently bonded Mo2 units as the electron donor and acceptor. The rate constants for electron transfer through the dual hydrogen bonds across a distance of 12.5 Å are on the order of ∼ 1010 s−1, as determined by optical analysis based on Marcus–Hush theory and simulation of ν(NH) vibrational band broadening, with the electron transfer efficiencies comparable to that of π conjugated bridges. This work demonstrates that electron transfer across a hydrogen bond may proceed via the known proton-coupled pathway, as well as an overlooked proton-uncoupled pathway that does not involve proton transfer. A mechanistic switch between the two pathways can be achieved by manipulation of the strengths of electronic coupling and hydrogen bonding. The knowledge of the non-proton coupled pathway has shed light on charge and energy transport in biological systems., Thermal electron transfer across hydrogen bond remains largely unexplored. Here the authors demonstrate that electron self-exchange through hydrogen bonds is highly efficient and can proceed either via the known proton-coupled pathway or an overlooked proton-uncoupled pathway

There are mean differences in complex traits among global human populations. We hypothesize that part of the phenotypic differentiation is due to natural selection. To address this hypothesis, we assess the differentiation in allele frequencies of trait-associated SNPs among African, Eastern Asian, and European populations for ten complex traits using data of large sample size (up to ~405,000). We show that SNPs associated with height (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 2.46 \times 10^{ - 5}$$\end{document}P=2.46×10-5), waist-to-hip ratio (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 2.77 \times 10^{ - 4}$$\end{document}P=2.77×10-4), and schizophrenia (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 3.96 \times 10^{ - 5}$$\end{document}P=3.96×10-5) are significantly more differentiated among populations than matched “control” SNPs, suggesting that these trait-associated SNPs have undergone natural selection. We further find that SNPs associated with height (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 2.01 \times 10^{ - 6}$$\end{document}P=2.01×10-6) and schizophrenia (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 5.16 \times 10^{ - 18}$$\end{document}P=5.16×10-18) show significantly higher variance in linkage disequilibrium (LD) scores across populations than control SNPs. Our results support the hypothesis that natural selection has shaped the genetic differentiation of complex traits, such as height and schizophrenia, among worldwide populations., Human complex traits and disorders often show differentiation among populations. Here, the authors analyze SNPs associated with 10 complex traits using data of large sample size from African, East Asian and European populations, and find significant genetic differentiation among global populations shaped by natural selection.

The design of smart surfaces with switchable adhesive properties in a wet environment has remained a challenge in adhesion science and materials engineering. Despite intense demands in various industrial applications and exciting progress in mimicking the remarkable wet adhesion through the delicate control of catechol chemistry, polyelectrolyte complex, and supramolecular architectures, the full recapitulation of nature’s dynamic function is limited. Here, we show a facile approach to synthesize bioinspired adhesive, which entails the reversible, tunable, and fast regulation of the wet adhesion on diverse surfaces. The smart wet adhesive takes advantage of the host–guest molecular interaction and the adhesive nature of catechol chemistry, as well as the responsive polymer, allowing for screening and activation of the interfacial interaction simply by a local temperature trigger in an on-demand manner. Our work opens up an avenue for the rational design of bioinspired adhesives with performances even beyond nature., Many industrial applications require switchable adhesive properties in wet conditions, but this still remains challenging to achieve. Here the authors synthesize an adhesive based on host-guest interactions that exhibits reversible, tunable and fast regulation of the wet adhesion on diverse surfaces.

Graphene, exhibiting superior mechanical, thermal, optical and electronic properties, has attracted great interest. Considering it being one-atom-thick, and the reduced mechanical strength at grain boundaries, the fabrication of large-area suspended chemical vapour deposition graphene remains a challenge. Here we report the fabrication of an ultra-thin free-standing carbon nanotube/graphene hybrid film, inspired by the vein-membrane structure found in nature. Such a square-centimetre-sized hybrid film can realize the overlaying of large-area single-layer chemical vapour deposition graphene on to a porous vein-like carbon nanotube network. The vein-membrane-like hybrid film, with graphene suspended on the carbon nanotube meshes, possesses excellent mechanical performance, optical transparency and good electrical conductivity. The ultra-thin hybrid film features an electron transparency close to 90%, which makes it an ideal gate electrode in vacuum electronics and a high-performance sample support in transmission electron microscopy.