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Meiotically arrested oocytes retain transcriptional ability despite chromosome condensation. Here, the authors show that Drosophilaoocytes regulate meiotic transcription and chromatin remodelling through the programming, in early oogenesis, of an extremely diversified epigenome.

Abstract Surface charge patchiness of different charge types can influence the solution behaviours of colloidal particles and globular proteins. Herein, coiled-coil ‘bundlemer’ nanoparticles that display only a single type of surface charge (SC) are computationally designed to compare their solution behaviours to mixed charge-type (MC) counterparts with both positively and negatively charged side chains. Nematic and columnar liquid crystal phases are discovered in low concentrations of SC particles, indicative of particle end-to-end stacking into columns combined with lateral electrostatic repulsion between columns, while MC particles with the same net charge and particle shape produced only amorphous, soluble aggregates. Similarly, porous lattices are formed in mixtures of SC/MC particles of opposite charges while MC/MC mixtures of opposite charges produce only amorphous aggregates. The lattice structure is inferred with a machine learning optimization approach. The differences between SC and MC particle behaviours directly show the importance of surface electrostatic patchiness.

Abstract Arterial thrombosis is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that facilitates platelet aggregation towards vessel occlusion. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in such biomechanical conditions. Using this assay, we demonstrate that different receptor–ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIbα-integrin αIIbβ3 mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying drug-disease interactions and inter-individual variability, our work reveals a need for personalized anti-thrombotic drug selection that accommodates each patient’s pathological profile.

Abstract To tackle the clinical challenge of noninvasively assessing immunotherapy efficacy in patients, here we used positron emission tomography (PET) with 68Ga-grazytracer, which targets granzyme B, a crucial effector molecule secreted by activated CD8+ T cells. In this phase 1/2 clinical trial (NCT05000372) involving a diverse cohort of 24 patients with solid tumors and lymphomas who received immunotherapies, including immune checkpoint inhibitors (either alone or with chemotherapies) and chimeric antigen receptor-T cell therapy, we examined the in vivo behaviors of 68Ga-grazytracer. Primary endpoints were safety, biodistribution, granzyme B specificity, and the predictive utility of 68Ga-grazytracer, while secondary endpoint was the relationship between 68Ga-grazytracer uptake and tumor immune phenotype. 68Ga-grazytracer exhibited a safe profile and specifically targeted granzyme B in patients. 68Ga-grazytracer PET showed superior predictive value for short-term prognosis and progression-free survival than those of conventional assessment criteria, including RECIST 1.1 and PERCIST. Moreover, the uptake of 68Ga-grazytracer in tumors was significantly higher in those with a “non-desert” immune phenotype than those with an immune “desert” phenotype, thereby meeting the primary and secondary endpoints of this trial. Collectively, we successfully visualized CD8+ T cell effector function in humans using 68Ga-grazytracer PET, offering insights for enhancing immunotherapy assessment, patient stratification and treatment planning.

Abstract The Hendra and Nipah viruses (HNVs) are highly pathogenic pathogens without approved interventions for human use. In addition, the interaction pattern between the attachment (G) and fusion (F) glycoproteins required for virus entry remains unclear. Here, we isolate a panel of Macaca-derived G-specific antibodies that cross-neutralize HNVs via multiple mechanisms. The most potent antibody, 1E5, confers adequate protection against the Nipah virus challenge in female hamsters. Crystallography demonstrates that 1E5 has a highly similar binding pattern to the receptor. In cryo-electron microscopy studies, the tendency of 1E5 to bind to the upper or lower heads results in two distinct quaternary structures of G. Furthermore, we identify the extended outer loop β1S2-β1S3 of G and two pockets on the apical region of fusion (F) glycoprotein as the essential sites for G-F interactions. This work highlights promising drug candidates against HNVs and contributes deeper insights into the viruses.

Abstract Investigating interface engineering by piezoelectric, flexoelectric and ferroelectric polarizations in semiconductor devices is important for their applications in electronics, optoelectronics, catalysis and many more. The interface engineering by polarizations strongly depends on the property of interface barrier. However, the fixed value and uncontrollability of interface barrier once it is constructed limit the performance and application scenarios of interface engineering by polarizations. Here, we report a strategy of tuning piezotronic effect (interface barrier and transport controlled by piezoelectric polarization) reversibly and accurately by electric pulse. Our results show that for Ag/HfO2/n-ZnO piezotronic tunneling junction, the interface barrier height can be reversibly tuned as high as 168.11 meV by electric pulse, and the strain (0–1.34‰) modulated current range by piezotronic effect can be switched from 0–18 nA to 44–72 nA. Moreover, piezotronic modification on interface barrier tuned by electric pulse can be up to 148.81 meV under a strain of 1.34‰, which can totally switch the piezotronic performance of the electronics. This study provides opportunities to achieve reversible control of piezotronics, and extend them to a wider range of scenarios and be better suitable for micro/nano-electromechanical systems.

Abstract Epstein-Barr virus (EBV) uses a biphasic lifecycle of latency and lytic reactivation to infect >95% of adults worldwide. Despite its central role in EBV persistence and oncogenesis, much remains unknown about how EBV latency is maintained. We used a human genome-wide CRISPR/Cas9 screen to identify that the nuclear protein SFPQ was critical for latency. SFPQ supported expression of linker histone H1, which stabilizes nucleosomes and regulates nuclear architecture, but has not been previously implicated in EBV gene regulation. H1 occupied latent EBV genomes, including the immediate early gene BZLF1 promoter. Upon reactivation, SFPQ was sequestered into sub-nuclear puncta, and EBV genomic H1 occupancy diminished. Enforced H1 expression blocked EBV reactivation upon SFPQ knockout, confirming it as necessary downstream of SFPQ. SFPQ knockout triggered reactivation of EBV in B and epithelial cells, as well as of Kaposi’s sarcoma-associated herpesvirus in B cells, suggesting a conserved gamma-herpesvirus role. These findings highlight SFPQ as a major regulator of H1 expression and EBV latency.

Abstract Intriguing “slidetronics” has been reported in van der Waals (vdW) layered non-centrosymmetric materials and newly-emerging artificially-tuned twisted moiré superlattices, but correlative experiments that spatially track the interlayer sliding dynamics at atomic-level remain elusive. Here, we address the decisive challenge to in-situ trace the atomic-level interlayer sliding and the induced polarization reversal in vdW-layered yttrium-doped γ-InSe, step by step and atom by atom. We directly observe the real-time interlayer sliding by a 1/3-unit cell along the armchair direction, corresponding to vertical polarization reversal. The sliding driven only by low energetic electron-beam illumination suggests rather low switching barriers. Additionally, we propose a new sliding mechanism that supports the observed reversal pathway, i.e., two bilayer units slide towards each other simultaneously. Our insights into the polarization reversal via the atomic-scale interlayer sliding provide a momentous initial progress for the ongoing and future research on sliding ferroelectrics towards non-volatile storages or ferroelectric field-effect transistors.

Abstract Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.

Abstract Carbon-introducing difunctionalization of C-C double bonds enabled by transition-metal catalysis is one of most straightforward and efficient strategies to construct C-C and C-X bonds concurrently from readily available feedstocks towards structurally diverse molecules in one step; however, analogous difunctionalization for introducing germanium group and other functionalities remains elusive. Herein, we describe a nickel-catalyzed germylative alkylation of activated olefins with easily accessible primary, secondary and tertiary alkyl bromides and chlorogermanes as the electrophiles to form C-Ge and C-Calkyl bonds simultaneously. This method provides a modular and facile approach for the synthesis of a broad range of alkylgermanes with good functional group compatibility, and can be further applied to the late-stage modification of natural products and pharmaceuticals, as well as ligation of drug fragments. More importantly, this platform enables the expedient synthesis of germanium substituted ospemifene-Ge-OH, which shows improved properties compared to ospemifene in the treatment of breast cancer cells, demonstrating high potential of our protocol in drug development.

Abstract Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We performed integrative analyses in a Chinese cohort of peri-/post-menopausal women with metagenomics/targeted metabolomics/whole-genome sequencing to identify novel microbiome-related biomarkers for bone health. Bacteroides vulgatus was found to be negatively associated with bone mineral density (BMD), which was validated in US white people. Serum valeric acid (VA), a microbiota derived metabolite, was positively associated with BMD and causally downregulated by B. vulgatus. Ovariectomized mice fed B. vulgatus demonstrated increased bone resorption and poorer bone micro-structure, while those fed VA demonstrated reduced bone resorption and better bone micro-structure. VA suppressed RELA protein production (pro-inflammatory), and enhanced IL10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells and enhanced maturation of osteoblasts in vitro. The findings suggest that B. vulgatus and VA may represent promising targets for osteoporosis prevention/treatment.

Abstract Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO-mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility.

Abstract Mechanical sensors are mainly divided into two types (vertical force sensing and lateral strain sensing). Up to now, one sensor with two working modes is still a challenge. Here, we demonstrate a structural design concept combing a piezoelectric nano/microwire with a flexible polymer with protrusions that enables a dual-modal piezotronic transistor (DPT) with two working modes for highly sensitive vertical force sensing and lateral strain sensing. For vertical force sensing, DPT exhibits a force sensitivity up to 221.5 N−1 and a minimum identifiable force down to 21 mN, corresponding to a pressure sensitivity of 1.759 eV/MPa. For lateral strain sensing, DPT can respond to a large compression strain (~5.8%) with an on/off ratio up to 386.57 and a gauge factor up to 8988.6. It is a universal design that can integrate vertical force sensing and lateral strain sensing into only one nanodevice, providing a feasible strategy for multimodal devices.

Abstract Catalytic asymmetric α-alkylation of carbonyl compounds represents a long-standing challenge in synthetic organic chemistry. Herein, we advance a dual biocatalytic platform for the efficient asymmetric alkylation of α-keto acids. First, guided by our recently obtained crystal structures, we develop SgvMVAV as a general biocatalyst for the enantioselective methylation, ethylation, allylation and propargylation of a range of α-keto acids with total turnover numbers (TTNs) up to 4,600. Second, we mine a family of bacterial HMTs from Pseudomonas species sharing less than 50% sequence identities with known HMTs and evaluated their activities in SAM regeneration. Our best performing HMT from P. aeruginosa, PaHMT, displays the highest SAM regeneration efficiencies (TTN up to 7,700) among HMTs characterized to date. Together, the synergistic use of SgvMVAV and PaHMT affords a fully biocatalytic protocol for asymmetric methylation featuring a record turnover efficiency, providing a solution to the notorious problem of asymmetric alkylation.

Abstract The lack of available protons severely lowers the activity of alkaline hydrogen evolution reaction process than that in acids, which can be efficiently accelerated by tuning the coverage and chemical environment of protons on catalyst surface. However, the cycling of active sites by proton transfer is largely dependent on the utilization of noble metal catalysts because of the appealing electronic interaction between noble metal atoms and protons. Herein, an all-non-noble W/WO2 metallic heterostructure serving as an efficient solid-acid catalyst exhibits remarkable hydrogen evolution reaction performance with an ultra-low overpotential of −35 mV at −10 mA/cm2 and a small Tafel slope (−34 mV/dec), as well as long-term durability of hydrogen production (>50 h) at current densities of −10 and −50 mA/cm2 in alkaline electrolyte. Multiple in situ and ex situ spectroscopy characterizations combining with first-principle density functional theory calculations discover that a dynamic proton-concentrated surface can be constructed on W/WO2 solid-acid catalyst under ultra-low overpotentials, which enables W/WO2 catalyzing alkaline hydrogen production to follow a kinetically fast Volmer-Tafel pathway with two neighboring protons recombining into a hydrogen molecule. Our strategy of solid-acid catalyst and utilization of multiple spectroscopy characterizations may provide an interesting route for designing advanced all-non-noble catalytic system towards boosting hydrogen evolution reaction performance in alkaline electrolyte.

Abstract Mammalian spermatogenesis shows prominent chromatin and transcriptomic switches in germ cells, but it is unclear how such dynamics are controlled. Here we identify RNA helicase DDX43 as an essential regulator of the chromatin remodeling process during spermiogenesis. Testis-specific Ddx43 knockout mice show male infertility with defective histone-to-protamine replacement and post-meiotic chromatin condensation defects. The loss of its ATP hydrolysis activity by a missense mutation replicates the infertility phenotype in global Ddx43 knockout mice. Single-cell RNA sequencing analyses of germ cells depleted of Ddx43 or expressing the Ddx43 ATPase-dead mutant reveals that DDX43 regulates dynamic RNA regulatory processes that underlie spermatid chromatin remodeling and differentiation. Transcriptomic profiling focusing on early-stage spermatids combined with enhanced crosslinking immunoprecipitation and sequencing further identifies Elfn2 as DDX43-targeted hub gene. These findings illustrate an essential role for DDX43 in spermiogenesis and highlight the single-cell-based strategy to dissect cell-state-specific regulation of male germline development.

Ji and colleagues identify Sirt6 as a regulator of chondrocyte senescence. Mechanistically, Sirt6 physically interacts with STAT5 and deacetylates it at K163, which reduces the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus.

Synthetic methodologies that enable the formation of C‒Si bonds in organic molecules are desirable. Here, the authors report the nickel-catalyzed reductive alkylsilylation of acrylonitrile with unactivated alkyl bromides and chlorosilanes.

Deep learning-based methods have been proposed to substitute CT-based PET attenuation and scatter correction to achieve CT-free PET imaging. Here, the authors present a simple way to integrate domain knowledge in deep learning for CT-free PET imaging.

Waterlogging tolerance is important in direct seeding rice cultivation practice. Here, the authors identify a 14-3-3 protein-coding gene OsGF14h in weedy rice that confers anaerobic germination and anaerobic seedling development tolerance by balancing ABA signaling and GA biosynthesis.

Mechanism driving continental growth on modern Earth has long been debated. By interpreting the long deep seismic reflection data across the ongoing India-Eurasia collision zone, the authors report crustal-scale magma accretion onto the south of central Lhasa terrane produced net continental growth.

It is of high interests to design catalysts for CO2 electroreduction with enhanced selectivity and activity. Here, the authors report Sn-Bi bimetallic interface-rich material with enhanced performance for CO2 reduction to formate comparing to that of Sn-Bi bulk alloy.

While platinum is a highly active catalyst for H2 evolution, its low abundance prompts research into earth-abundant alternatives. Here, authors prepare tungsten atomic clusters on phosphorus doped carbon by thermal migration and demonstrate excellent activities for hydrogen evolution electrocatalysis.

Strain-induced piezoelectric polarization can be used to modulate the interface electrical transport. Here, the authors achieved a piezotronic tunneling strain sensor at device scale with optimized performance based on the structure of Ag/HfO2/n-ZnO.

Plants and algae associate with microbial communities that affect their growth and development. Here, the authors characterize the microbiota associated with a unicellular alga in soil, revealing extensive taxonomic and functional overlap with the root microbiota of land plants.

Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.

Applying neutralizing antibodies against SARS-CoV-2 to infected patients is a promising anti-viral treatment strategy. Here, Zhao et al. derive RBD-targeting monoclonal antibodies from a naïve human phage-displayed Fab library and show their prophylactic and therapeutic potential in hACE2-transgenic mice.

Viruses rely on host metabolism for replication. Here, the authors perform transcriptional and metabolomic analyses at 8 hours after SARS-CoV-2 infection and find that the virus alters host folate and one-carbon metabolism at a post-transcriptional level.

Low intrinsic activity and accessibility of active sites limit the application of metal-organic framework as catalyst for Zn-air battery. Here, authors present a cation substitution strategy to regulate the electronic state of metal sites and modify its porosity, which enables battery operation.

The COVID-19 pandemic has stopped many human activities, which has had significant impact on emissions of greenhouse gases. Here, the authors present daily estimates of country-level CO2 emissions for different economic sectors and show that there has been a 8.8% decrease in global CO2 emissions in the first half of 2020.

Previous methods to generate strain gradient and flexoelectricity are limited to a localized effect or cannot be tuned continuously. Here, the authors achieve macroscale continuously controllable strain gradient in freestanding ferroelectric thin film. Multilevel photoconductance in BiFeO3 films can be achieved by coupling between the flexoelectric and ferroelectric photovoltaic effect.

In meiosis, BRCA2 associates to MEILB2 localising at DNA double-strand breaks (DSBs). Here, the authors identify BRCA2 and MEILB2- associating protein 1 termed BRME1 to work together in regulating meiotic recombination.

Ageing is associated with clonal hematopoiesis of indeterminate potential (CHIP), which is linked to increased risks of hematological malignancies. Here the authors uncover an epigenetic mechanism through which mutant p53 drives clonal hematopoiesis through interaction with EZH2.

The difficulty in recovering the aggregation-induced emission fluorogens (AIEgens) to the initial dispersed state upon illuminating has limited their applications. Here, the authors employ the confined space in the quartz nanopore to achieve a nanopore-size dependent restriction of AIEgens.

Controllable synthesis of single atom catalysts with sufficiently high metal loading remains challenging due to the tendency of agglomeration. Here the authors synthesize a series of stable atomically dispersed cobalt atoms on graphene with high Co loadings via the regeneration of active sites by atomic layer deposition.

Granular cell tumors (GCTs) are rare tumors that arise in multiple anatomical locations. Here, the authors investigate the genomics of GCTs, finding inactivating somatic mutations in ATP6AP1 or ATP6AP2 in 72% of the 82 GCTs analyzed. In vitro manipulation of these genes recapitulated GCT phenotypes in cellular models.

Usually, several components are needed for efficient 2-photon photodynamic therapy (PDT). Here, the authors sandwiched carboxylic acids between layered double hydroxide nanosheets to obtain a single-handed biocompatible photosensitizer that generates singlet oxygen in high quantum yield.

Mei (Prunus mume) is a woody tree that produces ornamental blossoms which symbolize spring in East Asia. Here, Zhang et al. resequence wild and domesticated mei to reveal considerable admixture and introgression from other Prunus species and identify loci associated with floral traits.

As a circadian organ, liver functions are regulated by circadian clock. Here, the authors present a comprehensive proteomics landscape of the mouse liver, including transcription factor binding profiles, phosphorylation and ubiquitylation patterns, nuclear and whole proteome, and the transcriptome.

TET2 catalyses DNA demethylation and is mutated in various blood cancers; in particularTet2null mice develop haematological neoplasms. Here the authors show that this effect could be due to the increased frequency of mutation associated with TET2 loss in haematopoietic stem/progenitor cells.

Expanded RNA repeats in non-coding region of a gene represent a hallmark of several diseases. Here, the authors identify two small molecules that selectively bind AU repeats and use them to design a compound that targets the pathogenic RNA associated with spinocerebellar ataxia type 10.

UHRF1 is involved in the maintenance of DNA methylation, but the regulatory mechanism of this epigenetic regulator is unclear. Here, the authors show that it has a closed conformation and are able to make conclusions about the mechanism of recognition of epigenetic marks.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20254-5

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Piezoelectric polymers hold great potential for various electromechanical applications, but only show low performance, with |d 33  | < 30 pC/N. We prepare a highly piezoelectric polymer (d 33  = -62 pC/N) based on a biaxially oriented poly(vinylidene fluoride) (BOPVDF, crystallinity = 0.52). After unidirectional poling, macroscopically aligned samples with pure β crystals are achieved, which show a high spontaneous polarization (P s ) of 140 mC/m 2 . Given the theoretical limit of P s,β  = 188 mC/m 2 for the neat β crystal, the high P s cannot be explained by the crystalline-amorphous two-phase model (i.e., P s,β  = 270 mC/m 2 ). Instead, we deduce that a significant amount (at least 0.25) of an oriented amorphous fraction (OAF) must be present between these two phases. Experimental data suggest that the mobile OAF resulted in the negative and high d 33 for the poled BOPVDF. The plausibility of this conclusion is supported by molecular dynamics simulations.