Erratum in Nat Commun. 2022 Apr 22;13(1):2309.

Most cancer causal variants are found in gene regulatory elements, e.g., enhancers. However, enhancer variants predisposing to hepatocellular carcinoma (HCC) remain unreported. Here we conduct a genome-wide survey of HCC-susceptible enhancer variants through a three-stage association study in 11,958 individuals and identify rs73613962 (T > G) within the intronic region of PRMT7 at 16q22.1 as a susceptibility locus of HCC (OR = 1.41, P = 6.02 × 10-10). An enhancer dual-luciferase assay indicates that the rs73613962-harboring region has allele-specific enhancer activity. CRISPR-Cas9/dCas9 experiments further support the enhancer activity of this region to regulate PRMT7 expression. Mechanistically, transcription factor HNF4A binds to this enhancer region, with preference to the risk allele G, to promote PRMT7 expression. PRMT7 upregulation contributes to in vitro, in vivo, and clinical HCC-associated phenotypes, possibly by affecting the p53 signaling pathway. This concept of HCC pathogenesis may open a promising window for HCC prevention/treatment.

The growth of nanoparticles along one or two directions leads to anisotropic nanoparticles, but the nucleation (i.e., the formation of small seeds of specific shape) has long been elusive. Here, we show the total structure of a seed-sized Au56 nanoprism, in which the side Au{100} facets are surrounded by bridging thiolates, whereas the top/bottom {111} facets are capped by phosphine ligands at the corners and Br- at the center. The bromide has been proved to be the key to effectively stabilize the Au{111} to fulfill a complete face-centered-cubic core. In femtosecond electron dynamics analysis, the non-evolution of transient absorption spectra of Au56 is similar to that of larger-sized gold nanoclusters (n > 100), which is ascribed to the completeness of the prismatic Au56 core and an effective electron relaxation pathway created by the stronger Au-Au bonds inside. This work provides some insights for the understanding of plasmonic nanoprism formation.

In situ coordination-activated n-doping by air-stable metals in electron-transport organic ligands has proven to be a viable method to achieve Ohmic electron injection for organic optoelectronics. However, the mutual exclusion of ligands with high nucleophilic quality and strong electron affinity limits the injection efficiency. Here, we propose meta-linkage diphenanthroline-type ligands, which not only possess high electron affinity and good electron transport ability but also favour the formation of tetrahedrally coordinated double-helical metal complexes to decrease the ionization energy of air-stable metals. An electron injection layer (EIL) compatible with various cathodes and electron transport materials is developed with silver as an n-dopant, and the injection efficiency outperforms conventional EILs such as lithium compounds. A deep-blue organic light-emitting diode with an optimized EIL achieves a high current efficiency calibrated by the y colour coordinate (0.045) of 237 cd A-1 and a superb LT95 of 104.1 h at 5000 cd m-2.

The mechanism underlying unwanted structural variations induced by CRISPR-Cas9 remains poorly understood, and no effective strategy is available to inhibit the generation of these byproducts. Here we find that the generation of a high level of translocations is dependent on repeated cleavage at the Cas9-targeting sites. Therefore, we employ a strategy in which Cas9 is fused with optimized TREX2 to generate Cas9TX, a Cas9 exo-endonuclease, which prevents perfect DNA repair and thereby avoids repeated cleavage. In comparison with CRISPR-Cas9, CRISPR-Cas9TX greatly suppressed translocation levels and enhanced the editing efficiency of single-site editing. The number of large deletions associated with Cas9TX was also reduced to very low level. The application of CRISPR-Cas9TX for multiplex gene editing in chimeric antigen receptor T cells nearly eliminated deleterious chromosomal translocations. We report the mechanism underlying translocations induced by Cas9, and propose a general strategy for reducing chromosomal abnormalities induced by CRISPR-RNA-guided endonucleases.

V/A-ATPase is a motor protein that shares a common rotary catalytic mechanism with FoF1 ATP synthase. When powered by ATP hydrolysis, the V1 domain rotates the central rotor against the A3B3 hexamer, composed of three catalytic AB dimers adopting different conformations (ABopen, ABsemi, and ABclosed). Here, we report the atomic models of 18 catalytic intermediates of the V1 domain of V/A-ATPase under different reaction conditions, determined by single particle cryo-EM. The models reveal that the rotor does not rotate immediately after binding of ATP to the V1. Instead, three events proceed simultaneously with the 120˚ rotation of the shaft: hydrolysis of ATP in ABsemi, zipper movement in ABopen by the binding ATP, and unzipper movement in ABclosed with release of both ADP and Pi. This indicates the unidirectional rotation of V/A-ATPase by a ratchet-like mechanism owing to ATP hydrolysis in ABsemi, rather than the power stroke model proposed previously for F1-ATPase.

Present-day Tibetans have adapted both genetically and culturally to the high altitude environment of the Tibetan Plateau, but fundamental questions about their origins remain unanswered. Recent archaeological and genetic research suggests the presence of an early population on the Plateau within the past 40 thousand years, followed by the arrival of subsequent groups within the past 10 thousand years. Here, we obtain new genome-wide data for 33 ancient individuals from high elevation sites on the southern fringe of the Tibetan Plateau in Nepal, who we show are most closely related to present-day Tibetans. They derive most of their ancestry from groups related to Late Neolithic populations at the northeastern edge of the Tibetan Plateau but also harbor a minor genetic component from a distinct and deep Paleolithic Eurasian ancestry. In contrast to their Tibetan neighbors, present-day non-Tibetan Tibeto-Burman speakers living at mid-elevations along the southern and eastern margins of the Plateau form a genetic cline that reflects a distinct genetic history. Finally, a comparison between ancient and present-day highlanders confirms ongoing positive selection of high altitude adaptive alleles.

We describe an exceptionally well-preserved vampyropod, Syllipsimopodi bideni gen. et sp. nov., from the Carboniferous (Mississippian) Bear Gulch Lagerstätte of Montana, USA. The specimen possesses a gladius and ten robust arms bearing biserial rows of suckers; it is the only known vampyropod to retain the ancestral ten-arm condition. Syllipsimopodi is the oldest definitive vampyropod and crown coleoid, pushing back the fossil record of this group by ~81.9 million years, corroborating molecular clock estimates. Using a Bayesian tip-dated phylogeny of fossil neocoleoid cephalopods, we demonstrate that Syllipsimopodi is the earliest-diverging known vampyropod. This strongly challenges the common hypothesis that vampyropods descended from a Triassic phragmoteuthid belemnoid. As early as the Mississippian, vampyropods were evidently characterized by the loss of the chambered phragmocone and primordial rostrum-traits retained in belemnoids and many extant decabrachians. A pair of arms may have been elongated, which when combined with the long gladius and terminal fins, indicates that the morphology of the earliest vampyropods superficially resembled extant squids.

The Sun sporadically produces eruptive events leading to intense fluxes of solar energetic particles (SEPs) that dramatically disrupt the near-Earth radiation environment. Such events have been directly studied for the last decades but little is known about the occurrence and magnitude of rare, extreme SEP events. Presently, a few events that produced measurable signals in cosmogenic radionuclides such as 14C, 10Be and 36Cl have been found. Analyzing annual 14C concentrations in tree-rings from Switzerland, Germany, Ireland, Russia, and the USA we discovered two spikes in atmospheric 14C occurring in 7176 and 5259 BCE. The ~2% increases of atmospheric 14C recorded for both events exceed all previously known 14C peaks but after correction for the geomagnetic field, they are comparable to the largest event of this type discovered so far at 775 CE. These strong events serve as accurate time markers for the synchronization with floating tree-ring and ice core records and provide critical information on the previous occurrence of extreme solar events which may threaten modern infrastructure.

Recent advances in metal additive manufacturing (AM) have provided new opportunities for prompt designs of prototypes and facile personalization of products befitting the fourth industrial revolution. In this regard, its feasibility of becoming a green technology, which is not an inherent aspect of AM, is gaining more interests. A particular interest in adapting and understanding of eco-friendly ingredients can set its important groundworks. Here, we demonstrate a water-based solid-phase binding agent suitable for binder jetting 3D printing of metals. Sodium salts of common fruit acid chelators form stable metal-chelate bridges between metal particles, enabling elaborate 3D printing of metals with improved strengths. Even further reductions in the porosity between the metal particles are possible through post-treatments. A compatibility of this chelation chemistry with variety of metals is also demonstrated. The proposed mechanism for metal 3D printing can open up new avenues for consumer-level personalized 3D printing of metals.

The terrestrial carbon sink slows the accumulation of carbon dioxide (CO2) in the atmosphere by absorbing roughly 30% of anthropogenic CO2 emissions, but varies greatly from year to year. The resulting variations in the atmospheric CO2 growth rate (CGR) have been related to tropical temperature and water availability. The apparent sensitivity of CGR to tropical temperature ([Formula: see text]) has changed markedly over the past six decades, however, the drivers of the observation to date remains unidentified. Here, we use atmospheric observations, multiple global vegetation models and machine learning products to analyze the cause of the sensitivity change. We found that a threefold increase in [Formula: see text] emerged due to the long-term changes in the magnitude of CGR variability (i.e., indicated by one standard deviation of CGR; STDCGR), which increased 34.7% from 1960-1979 to 1985-2004 and subsequently decreased 14.4% in 1997-2016. We found a close relationship (r2 = 0.75, p < 0.01) between STDCGR and the tropical vegetated area (23°S - 23°N) affected by extreme droughts, which influenced 6-9% of the tropical vegetated surface. A 1% increase in the tropical area affected by extreme droughts led to about 0.14 Pg C yr-1 increase in STDCGR. The historical changes in STDCGR were dominated by extreme drought-affected areas in tropical Africa and Asia, and semi-arid ecosystems. The outsized influence of extreme droughts over a small fraction of vegetated surface amplified the interannual variability in CGR and explained the observed long-term dynamics of [Formula: see text].

In ordinary materials, electrons conduct both electricity and heat, where their charge-entropy relations observe the Mott formula and the Wiedemann-Franz law. In topological quantum materials, the transverse motion of relativistic electrons can be strongly affected by the quantum field arising around the topological fermions, where a simple model description of their charge-entropy relations remains elusive. Here we report the topological charge-entropy scaling in the kagome Chern magnet TbMn6Sn6, featuring pristine Mn kagome lattices with strong out-of-plane magnetization. Through both electric and thermoelectric transports, we observe quantum oscillations with a nontrivial Berry phase, a large Fermi velocity and two-dimensionality, supporting the existence of Dirac fermions in the magnetic kagome lattice. This quantum magnet further exhibits large anomalous Hall, anomalous Nernst, and anomalous thermal Hall effects, all of which persist to above room temperature. Remarkably, we show that the charge-entropy scaling relations of these anomalous transverse transports can be ubiquitously described by the Berry curvature field effects in a Chern-gapped Dirac model. Our work points to a model kagome Chern magnet for the proof-of-principle elaboration of the topological charge-entropy scaling.

Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.

The BNT162b2 COVID-19 vaccine has been shown to reduce viral load of breakthrough infections (BTIs), an important factor affecting infectiousness. This viral-load protective effect has been waning with time post the second vaccine and later restored with a booster shot. It is currently unclear though for how long this regained effectiveness lasts. Analyzing Ct values of SARS-CoV-2 qRT-PCR tests of over 22,000 infections during a Delta-variant-dominant period in Israel, we find that this viral-load reduction effectiveness significantly declines within months post the booster dose. Adjusting for age, sex and calendric date, Ct values of RdRp gene initially increases by 2.7 [CI: 2.3-3.0] relative to unvaccinated in the first month post the booster dose, yet then decays to a difference of 1.3 [CI: 0.7-1.9] in the second month and becomes small and insignificant in the third to fourth months. The rate and magnitude of this post-booster decline in viral-load reduction effectiveness mirror those observed post the second vaccine. These results suggest rapid waning of the booster's effectiveness in reducing infectiousness, possibly affecting community-level spread of the virus.

To maintain cellular identities during development, gene expression profiles must be faithfully propagated through cell generations. The reestablishment of gene expression patterns upon mitotic exit is mediated, in part, by transcription factors (TF) mitotic bookmarking. However, the mechanisms and functions of TF mitotic bookmarking during early embryogenesis remain poorly understood. In this study, taking advantage of the naturally synchronized mitoses of Drosophila early embryos, we provide evidence that GAGA pioneer factor (GAF) acts as a stable mitotic bookmarker during zygotic genome activation. We show that, during mitosis, GAF remains associated to a large fraction of its interphase targets, including at cis-regulatory sequences of key developmental genes with both active and repressive chromatin signatures. GAF mitotic targets are globally accessible during mitosis and are bookmarked via histone acetylation (H4K8ac). By monitoring the kinetics of transcriptional activation in living embryos, we report that GAF binding establishes competence for rapid activation upon mitotic exit.

Designing efficient synthetic routes for a target molecule remains a major challenge in organic synthesis. Atom environments are ideal, stand-alone, chemically meaningful building blocks providing a high-resolution molecular representation. Our approach mimics chemical reasoning, and predicts reactant candidates by learning the changes of atom environments associated with the chemical reaction. Through careful inspection of reactant candidates, we demonstrate atom environments as promising descriptors for studying reaction route prediction and discovery. Here, we present a new single-step retrosynthesis prediction method, viz. RetroTRAE, being free from all SMILES-based translation issues, yields a top-1 accuracy of 58.3% on the USPTO test dataset, and top-1 accuracy reaches to 61.6% with the inclusion of highly similar analogs, outperforming other state-of-the-art neural machine translation-based methods. Our methodology introduces a novel scheme for fragmental and topological descriptors to be used as natural inputs for retrosynthetic prediction tasks.

Comment in Autophagy. 2022 Aug;18(8):1749-1751.

A large family of E3 ligases that contain both substrate recruitment and RING domains confer specificity within the ubiquitylation cascade. Regulation of RING E3s depends on modulating their ability to stabilise the RING bound E2~ubiquitin conjugate in the activated (or closed) conformation. Here we report the structure of the Ark2C RING bound to both a regulatory ubiquitin molecule and an activated E2~ubiquitin conjugate. The structure shows that the RING domain and non-covalently bound ubiquitin molecule together make contacts that stabilise the activated conformation of the conjugate, revealing why ubiquitin is a key regulator of Ark2C activity. We also identify a charged loop N-terminal to the RING domain that enhances activity by interacting with both the regulatory ubiquitin and ubiquitin conjugated to the E2. In addition, the structure suggests how Lys48-linked ubiquitin chains might be assembled by Ark2C and UbcH5b. Together this study identifies features common to RING E3s, as well elements that are unique to Ark2C and related E3s, which enhance assembly of ubiquitin chains.

Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice leads to BBB leak from brain capillaries that convert to a barrier-incompetent state with reduced Claudin-5 and increased PLVAP expression. Loss of Unc5B decreases BBB Wnt/β-catenin signaling, and β-catenin overexpression rescues Unc5B mutant BBB defects. Mechanistically, the Unc5B ligand Netrin-1 enhances Unc5B interaction with the Wnt co-receptor LRP6, induces its phosphorylation and activates Wnt/β-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin-1 binding to Unc5B causes a transient BBB breakdown and disruption of Wnt signaling, followed by neurovascular barrier resealing. These data identify Netrin-1-Unc5B signaling as a ligand-receptor pathway that regulates BBB integrity, with implications for CNS diseases.

By the end of this century, a 50% increase in agricultural productivity is required to feed the world. Recent studies have demonstrated de novo domestication of wild plants as a new crop breeding strategy to meet future food challenges.

Recently emerged variants of SARS-CoV-2 contain in their surface spike glycoproteins multiple substitutions associated with increased transmission and resistance to neutralising antibodies. We have examined the structure and receptor binding properties of spike proteins from the B.1.1.7 (Alpha) and B.1.351 (Beta) variants to better understand the evolution of the virus in humans. Spikes of both variants have the same mutation, N501Y, in the receptor-binding domains. This substitution confers tighter ACE2 binding, dependent on the common earlier substitution, D614G. Each variant spike has acquired other key changes in structure that likely impact virus pathogenesis. The spike from the Alpha variant is more stable against disruption upon binding ACE2 receptor than all other spikes studied. This feature is linked to the acquisition of a more basic substitution at the S1-S2 furin site (also observed for the variants of concern Delta, Kappa, and Omicron) which allows for near-complete cleavage. In the Beta variant spike, the presence of a new substitution, K417N (also observed in the Omicron variant), in combination with the D614G, stabilises a more open spike trimer, a conformation required for receptor binding. Our observations suggest ways these viruses have evolved to achieve greater transmissibility in humans.

Nowadays the development of machine vision is oriented toward real-time applications such as autonomous driving. This demands a hardware solution with low latency, high energy efficiency, and good reliability. Here, we demonstrate a robust and self-powered in-sensor computing paradigm with a ferroelectric photosensor network (FE-PS-NET). The FE-PS-NET, constituted by ferroelectric photosensors (FE-PSs) with tunable photoresponsivities, is capable of simultaneously capturing and processing images. In each FE-PS, self-powered photovoltaic responses, modulated by remanent polarization of an epitaxial ferroelectric Pb(Zr0.2Ti0.8)O3 layer, show not only multiple nonvolatile levels but also sign reversibility, enabling the representation of a signed weight in a single device and hence reducing the hardware overhead for network construction. With multiple FE-PSs wired together, the FE-PS-NET acts on its own as an artificial neural network. In situ multiply-accumulate operation between an input image and a stored photoresponsivity matrix is demonstrated in the FE-PS-NET. Moreover, the FE-PS-NET is faultlessly competent for real-time image processing functionalities, including binary classification between 'X' and 'T' patterns with 100% accuracy and edge detection for an arrow sign with an F-Measure of 1 (under 365 nm ultraviolet light). This study highlights the great potential of ferroelectric photovoltaics as the hardware basis of real-time machine vision.

Cancer cells within a tumour have heterogeneous phenotypes and exhibit dynamic plasticity. How to evaluate such heterogeneity and its impact on outcome and drug response is still unclear. Here, we transcriptionally profile 35,276 individual cells from 32 breast cancer cell lines to yield a single cell atlas. We find high degree of heterogeneity in the expression of biomarkers. We then train a deconvolution algorithm on the atlas to determine cell line composition from bulk gene expression profiles of tumour biopsies, thus enabling cell line-based patient stratification. Finally, we link results from large-scale in vitro drug screening in cell lines to the single cell data to computationally predict drug responses starting from single-cell profiles. We find that transcriptional heterogeneity enables cells with differential drug sensitivity to co-exist in the same population. Our work provides a framework to determine tumour heterogeneity in terms of cell line composition and drug response.

The rapidly growing popularity of RNA structure probing methods is leading to increasingly large amounts of available RNA structure information. This demands the development of efficient tools for the identification of RNAs sharing regions of structural similarity by direct comparison of their reactivity profiles, hence enabling the discovery of conserved structural features. We here introduce SHAPEwarp, a largely sequence-agnostic SHAPE-guided algorithm for the identification of structurally-similar regions in RNA molecules. Analysis of Dengue, Zika and coronavirus genomes recapitulates known regulatory RNA structures and identifies novel highly-conserved structural elements. This work represents a preliminary step towards the model-free search and identification of shared and conserved RNA structural features within transcriptomes.

Brood parasites are involved in coevolutionary arms races with their hosts, whereby adaptations of one partner elicit the rapid evolution of counter-adaptations in the other partner. Hosts can also mitigate fitness costs of brood parasitism by learning from individual or social experience. In brood parasites, however, the role of learning can be obscured by their stealthy behaviour. Cuckoo catfish (Synodontis multipunctatus) parasitise clutches of mouthbrooding cichlids in Lake Tanganyika and are the only non-avian obligate brood parasites among vertebrates. We experimentally demonstrate that cuckoo catfish greatly enhance their efficiency in parasitising their hosts as they learn to overcome host defences. With increasing experience, cuckoo catfish increased their parasitism success by greater efficiency through improved timing and coordination of intrusions of host spawnings. Hence, within the coevolutionary arms races, brood parasites learn to overcome host defences during their lifetime.

Ultra-selective and fast transport of K+ are of significance for water desalination, energy conversion, and separation processes, but current bottleneck of achieving high-efficiency and exquisite transport is attributed to the competition from ions of similar dimensions and same valence through nanochannel communities. Here, inspired by biological KcsA channels, we report biomimetic charged porous subnanometer cages that enable ultra-selective K+ transport. For nanometer to subnanometer scales, conically structured double-helix columns exhibit typical asymmetric transport behaviors and conduct rapid K+ with a transport rate of 94.4 mmol m-2 h-1, resulting in the K+/Li+ and K+/Na+ selectivity ratios of 363 and 31, respectively. Experiments and simulations indicate that these results stem from the synergistic effects of cation-π and electrostatic interactions, which impose a higher energy barrier for Li+ and Na+ and lead to selective K+ transport. Our findings provide an effective methodology for creating in vitro biomimetic devices with high-performance K+ ion sieving.

Engineered signaling networks can impart cells with new functionalities useful for directing differentiation and actuating cellular therapies. For such applications, the engineered networks must be tunable, precisely regulate target gene expression, and be robust to perturbations within the complex context of mammalian cells. Here, we use bacterial two-component signaling proteins to develop synthetic phosphoregulation devices that exhibit these properties in mammalian cells. First, we engineer a synthetic covalent modification cycle based on kinase and phosphatase proteins derived from the bifunctional histidine kinase EnvZ, enabling analog tuning of gene expression via its response regulator OmpR. By regulating phosphatase expression with endogenous miRNAs, we demonstrate cell-type specific signaling responses and a new strategy for accurate cell type classification. Finally, we implement a tunable negative feedback controller via a small molecule-stabilized phosphatase, reducing output expression variance and mitigating the context-dependent effects of off-target regulation and resource competition. Our work lays the foundation for establishing tunable, precise, and robust control over cell behavior with synthetic signaling networks.

During fixation and between saccades, our eyes undergo diffusive random motion called fixational drift. The role of fixational drift in visual coding and inference has been debated in the past few decades, but the mechanisms that underlie this motion remained unknown. In particular, it has been unclear whether fixational drift arises from peripheral sources, or from central sources within the brain. Here we show that fixational drift is correlated with neural activity, and identify its origin in central neural circuitry within the oculomotor system, upstream to the ocular motoneurons (OMNs). We analyzed a large data set of OMN recordings in the rhesus monkey, alongside precise measurements of eye position, and found that most of the variance of fixational eye drifts must arise upstream of the OMNs. The diffusive statistics of the motion points to the oculomotor integrator, a memory circuit responsible for holding the eyes still between saccades, as a likely source of the motion. Theoretical modeling, constrained by the parameters of the primate oculomotor system, supports this hypothesis by accounting for the amplitude as well as the statistics of the motion. Thus, we propose that fixational ocular drift provides a direct observation of diffusive dynamics in a neural circuit responsible for storage of continuous parameter memory in persistent neural activity. The identification of a mechanistic origin for fixational drift is likely to advance the understanding of its role in visual processing and inference.

Categorical neural responses underlie various forms of selection and decision-making. Such binary-like responses promote robust signaling of the winner in the presence of input ambiguity and neural noise. Here, we show that a 'donut-like' inhibitory mechanism in which each competing option suppresses all options except itself, is highly effective at generating categorical neural responses. It surpasses motifs of feedback inhibition, recurrent excitation, and divisive normalization invoked frequently in decision-making models. We demonstrate experimentally not only that this mechanism operates in the midbrain spatial selection network in barn owls, but also that it is necessary for categorical signaling by it. The functional pattern of neural inhibition in the midbrain forms an exquisitely structured 'multi-holed' donut consistent with this network's combinatorial inhibitory function for stimulus selection. Additionally, modeling reveals a generalizable neural implementation of the donut-like motif for categorical selection. Self-sparing inhibition may, therefore, be a powerful circuit module central to categorization.

The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings.

Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design.

Matrigel, a mouse tumor extracellular matrix protein mixture, is an indispensable component of most organoid tissue culture. However, it has limited the utility of organoids for drug development and regenerative medicine due to its tumor-derived origin, batch-to-batch variation, high cost, and safety issues. Here, we demonstrate that gastrointestinal tissue-derived extracellular matrix hydrogels are suitable substitutes for Matrigel in gastrointestinal organoid culture. We found that the development and function of gastric or intestinal organoids grown in tissue extracellular matrix hydrogels are comparable or often superior to those in Matrigel. In addition, gastrointestinal extracellular matrix hydrogels enabled long-term subculture and transplantation of organoids by providing gastrointestinal tissue-mimetic microenvironments. Tissue-specific and age-related extracellular matrix profiles that affect organoid development were also elucidated through proteomic analysis. Together, our results suggest that extracellular matrix hydrogels derived from decellularized gastrointestinal tissues are effective alternatives to the current gold standard, Matrigel, and produce organoids suitable for gastrointestinal disease modeling, drug development, and tissue regeneration.

The study of chemo-mechanical stress taking place in the electrodes of a battery during cycling is of paramount importance to extend the lifetime of the device. This aspect is particularly relevant for all-solid-state batteries where the stress can be transmitted across the device due to the stiff nature of the solid electrolyte. However, stress monitoring generally relies on sensors located outside of the battery, therefore providing information only at device level and failing to detect local changes. Here, we report a method to investigate the chemo-mechanical stress occurring at both positive and negative electrodes and at the electrode/electrolyte interface during battery operation. To such effect, optical fiber Bragg grating sensors were embedded inside coin and Swagelok cells containing either liquid or solid-state electrolyte. The optical signal was monitored during battery cycling, further translated into stress and correlated with the voltage profile. This work proposes an operando technique for stress monitoring with potential use in cell diagnosis and battery design.

Erratum in Nat Commun. 2022 Jun 20;13(1):3531.

Recent rapid thinning of West Antarctic ice shelves are believed to be caused by intrusions of warm deep water that induce basal melting and seaward meltwater export. This study uses data from three bottom-mounted mooring arrays to show seasonal variability and local forcing for the currents moving into and out of the Dotson ice shelf cavity. A southward flow of warm, salty water had maximum current velocities along the eastern channel slope, while northward outflows of freshened ice shelf meltwater spread at intermediate depth above the western slope. The inflow correlated with the local ocean surface stress curl. At the western slope, meltwater outflows followed the warm influx along the eastern slope with a ~2-3 month delay. Ocean circulation near Dotson Ice Shelf, affected by sea ice distribution and wind, appears to significantly control the inflow of warm water and subsequent ice shelf melting on seasonal time-scales.

Horizontal gene transfer facilitates dissemination of favourable traits among bacteria. However, foreign DNA can also reduce host fitness: incoming sequences with a higher AT content than the host genome can misdirect transcription. Xenogeneic silencing proteins counteract this by modulating RNA polymerase binding. In this work, we compare xenogeneic silencing strategies of two distantly related model organisms: Escherichia coli and Bacillus subtilis. In E. coli, silencing is mediated by the H-NS protein that binds extensively across horizontally acquired genes. This prevents spurious non-coding transcription, mostly intragenic in origin. By contrast, binding of the B. subtilis Rok protein is more targeted and mostly silences expression of functional mRNAs. The difference reflects contrasting transcriptional promiscuity in E. coli and B. subtilis, largely attributable to housekeeping RNA polymerase σ factors. Thus, whilst RNA polymerase specificity is key to the xenogeneic silencing strategy of B. subtilis, transcriptional promiscuity must be overcome to silence horizontally acquired DNA in E. coli.

Developing high-performance electrocatalysts for hydrogen evolution reaction (HER) is crucial for sustainable hydrogen production, yet still challenging. Here, we report boron-modulated osmium (B-Os) aerogels with rich defects and ultra-fine diameter as a pH-universal HER electrocatalyst. The catalyst shows the small overpotentials of 12, 19, and 33 mV at a current density of 10 mA cm-2 in acidic, alkaline, and neutral electrolytes, respectively, as well as excellent stability, surpassing commercial Pt/C. Operando X-ray absorption spectroscopy shows that interventional interstitial B atoms can optimize the electron structure of B-Os aerogels and stabilize Os as active sites in an electron-deficient state under realistic working conditions, and simultaneously reveals the HER catalytic mechanisms of B-Os aerogels in pH-universal electrolytes. The density functional theory calculations also indicate introducing B atoms can tailor the electronic structure of Os, resulting in the reduced water dissociation energy and the improved adsorption/desorption behavior of hydrogen, which synergistically accelerate HER.

Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam's utility as an  HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion.

The interplay between band topology and magnetism can give rise to exotic states of matter. For example, magnetically doped topological insulators can realize a Chern insulator that exhibits quantized Hall resistance at zero magnetic field. While prior works have focused on ferromagnetic systems, little is known about band topology and its manipulation in antiferromagnets. Here, we report that MnBi2Te4 is a rare platform for realizing a canted-antiferromagnetic (cAFM) Chern insulator with electrical control. We show that the Chern insulator state with Chern number C = 1 appears as the AFM to canted-AFM phase transition happens. The Chern insulator state is further confirmed by observing the unusual transition of the C = 1 state in the cAFM phase to the C = 2 orbital quantum Hall states in the magnetic field induced ferromagnetic phase. Near the cAFM-AFM phase boundary, we show that the dissipationless chiral edge transport can be toggled on and off by applying an electric field alone. We attribute this switching effect to the electrical field tuning of the exchange gap alignment between the top and bottom surfaces. Our work paves the way for future studies on topological cAFM spintronics and facilitates the development of proof-of-concept Chern insulator devices.

The pulmonary immune system consists of a network of tissue-resident cells as well as immune cells that are recruited to the lungs during infection and/or inflammation. How these immune components function during an acute poxvirus infection is not well understood. Intranasal infection of mice with vaccinia virus causes lethal pneumonia and systemic dissemination. Here we report that vaccinia C7 is a crucial virulence factor that blocks activation of the transcription factor IRF3. We provide evidence that type II alveolar epithelial cells (AECIIs) respond to pulmonary infection of vaccinia virus by inducing IFN-β and IFN-stimulated genes via the activation of the MDA5 and STING-mediated nucleic acid-sensing pathways and the type I IFN positive feedback loop. This leads to the recruitment and activation of CCR2+ inflammatory monocytes in the infected lungs and subsequent differentiation into Lyve1- interstitial macrophages (Lyve1- IMs), which efficiently engulf viral particles and block viral replication. Our results provide insights into how innate immune sensing of viral infection by lung AECIIs influences the activation and differentiation of CCR2+ inflammatory monocytes to defend against pulmonary poxvirus infection.

Rho is a general transcription termination factor in bacteria, but many aspects of its mechanism of action are unclear. Diverse models have been proposed for the initial interaction between the RNA polymerase (RNAP) and Rho (catch-up and stand-by pre-terminational models); for the terminational release of the RNA transcript (RNA shearing, RNAP hyper-translocation or displacing, and allosteric models); and for the post-terminational outcome (whether the RNAP dissociates or remains bound to the DNA). Here, we use single-molecule fluorescence assays to study those three steps in transcription termination mediated by E. coli Rho. We find that different mechanisms previously proposed for each step co-exist, but apparently occur on various timescales and tend to lead to specific outcomes. Our results indicate that three kinetically distinct routes take place: (1) the catch-up mode leads first to RNA shearing for RNAP recycling on DNA, and (2) later to RNAP displacement for decomposition of the transcriptional complex; (3) the last termination usually follows the stand-by mode with displacing for decomposing. This three-route model would help reconcile current controversies on the mechanisms.

The relationship between social media use and life satisfaction changes across adolescent development. Our analyses of two UK datasets comprising 84,011 participants (10-80 years old) find that the cross-sectional relationship between self-reported estimates of social media use and life satisfaction ratings is most negative in younger adolescents. Furthermore, sex differences in this relationship are only present during this time. Longitudinal analyses of 17,409 participants (10-21 years old) suggest distinct developmental windows of sensitivity to social media in adolescence, when higher estimated social media use predicts a decrease in life satisfaction ratings one year later (and vice-versa: lower estimated social media use predicts an increase in life satisfaction ratings). These windows occur at different ages for males (14-15 and 19 years old) and females (11-13 and 19 years old). Decreases in life satisfaction ratings also predicted subsequent increases in estimated social media use, however, these were not associated with age or sex.

Erratum in Nat Commun. 2022 Oct 3;13(1):5806.

Filopodia are actin-rich structures, present on the surface of eukaryotic cells. These structures play a pivotal role by allowing cells to explore their environment, generate mechanical forces or perform chemical signaling. Their complex dynamics includes buckling, pulling, length and shape changes. We show that filopodia additionally explore their 3D extracellular space by combining growth and shrinking with axial twisting and buckling. Importantly, the actin core inside filopodia performs a twisting or spinning motion which is observed for a range of cell types spanning from earliest development to highly differentiated tissue cells. Non-equilibrium physical modeling of actin and myosin confirm that twist is an emergent phenomenon of active filaments confined in a narrow channel which is supported by measured traction forces and helical buckles that can be ascribed to accumulation of sufficient twist. These results lead us to conclude that activity induced twisting of the actin shaft is a general mechanism underlying fundamental functions of filopodia.

The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.

PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under-explored. Here, we report that Pum1 and Pum2 display increased expression in human colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 in mice significantly inhibits the progression of colitis-associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 in human CRC cells result in a significant decrease in the tumorigenicity and delayed G1/S transition. We identify p21/Cdkn1a as a direct target of PUM1. Abrogation of the PUM1 binding site in the p21 mRNA also results in decreased cancer cell growth and delayed G1/S transition. Furthermore, intravenous injection of nanoparticle-encapsulated anti-Pum1 and Pum2 siRNAs reduces colorectal tumor growth in murine orthotopic colon cancer models. These findings reveal the requirement of PUM proteins for CRC progression and their potential as therapeutic targets.

Patient-derived xenografts (PDX) are widely used as human cancer models. Previous studies demonstrated clonal discordance between PDX and primary cells. However, in acute myeloid leukemia (AML)-PDX models, the significance of the clonal dynamics occurring in PDX remains unclear. By evaluating changes in the variant allele frequencies (VAF) of somatic mutations in serial samples of paired primary AML and their PDX bone marrow cells, we identify the skewing engraftment of relapsed or refractory (R/R) AML clones in 57% of PDX models generated from multiclonal AML cells at diagnosis, even if R/R clones are minor at <5% of VAF in patients. The event-free survival rate of patients whose AML cells successfully engraft in PDX models is consistently lower than that of patients with engraftment failure. We herein demonstrate that primary AML cells including potentially chemotherapy-resistant clones dominantly engraft in AML-PDX models and they enrich pre-existing treatment-resistant subclones.

Rapid urban expansion has profound impacts on global biodiversity through habitat conversion, degradation, fragmentation, and species extinction. However, how future urban expansion will affect global biodiversity needs to be better understood. We contribute to filling this knowledge gap by combining spatially explicit projections of urban expansion under shared socioeconomic pathways (SSPs) with datasets on habitat and terrestrial biodiversity (amphibians, mammals, and birds). Overall, future urban expansion will lead to 11-33 million hectares of natural habitat loss by 2100 under the SSP scenarios and will disproportionately cause large natural habitat fragmentation. The urban expansion within the current key biodiversity priority areas is projected to be higher (e.g., 37-44% higher in the WWF's Global 200) than the global average. Moreover, the urban land conversion will reduce local within-site species richness by 34% and species abundance by 52% per 1 km grid cell, and 7-9 species may be lost per 10 km cell. Our study suggests an urgent need to develop a sustainable urban development pathway to balance urban expansion and biodiversity conservation.

The U. S. National Institutes of Health is committed to addressing gender discrimination and fostering inclusive excellence, which is critical for the advancement of creativity and innovation in science. Strategies and processes aimed at achieving these goals are discussed.

Many living tissues achieve functions through architected constituents with strong adhesion. An Achilles tendon, for example, transmits force, elastically and repeatedly, from a muscle to a bone through staggered alignment of stiff collagen fibrils in a soft proteoglycan matrix. The collagen fibrils align orderly and adhere to the proteoglycan strongly. However, synthesizing architected materials with strong adhesion has been challenging. Here we fabricate architected polymer networks by sequential polymerization and photolithography, and attain adherent interface by topological entanglement. We fabricate tendon-inspired hydrogels by embedding hard blocks in topological entanglement with a soft matrix. The staggered architecture and strong adhesion enable high elastic limit strain and high toughness simultaneously. This combination of attributes is commonly desired in applications, but rarely achieved in synthetic materials. We further demonstrate architected polymer networks of various geometric patterns and material combinations to show the potential for expanding the space of material properties.

Mentor relationships are crucial to retention, success, and wellbeing of women and underrepresented minority scientists in academia. A network of diverse mentors may support achieving long-term career goals, advancement, and retention of both mentors and mentees, thus enhancing diversity, equity, and inclusion initiatives.

Cell membranes provide a selective semi-permeable barrier to the passive transport of molecules. This property differs greatly between organisms. While the cytoplasmic membrane of bacterial cells is highly permeable for weak acids and glycerol, yeasts can maintain large concentration gradients. Here we show that such differences can arise from the physical state of the plasma membrane. By combining stopped-flow kinetic measurements with molecular dynamics simulations, we performed a systematic analysis of the permeability of a variety of small molecules through synthetic membranes of different lipid composition to obtain detailed molecular insight into the permeation mechanisms. While membrane thickness is an important parameter for the permeability through fluid membranes, the largest differences occur when the membranes transit from the liquid-disordered to liquid-ordered and/or to gel state, which is in agreement with previous work on passive diffusion of water. By comparing our results with in vivo measurements from yeast, we conclude that the yeast membrane exists in a highly ordered and rigid state, which is comparable to synthetic saturated DPPC-sterol membranes.

Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Here, we examined human airway epithelium infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.

Mining a large cohort of single-cell transcriptomics data, here we employ combinatorial optimization techniques to chart the landscape of optimal combination therapies in cancer. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. We find that in most cancer types, personalized combinations composed of at most four targets are then sufficient for killing at least 80% of tumor cells while sparing at least 90% of nontumor cells in the tumor microenvironment. However, as more stringent and selective killing is required, the number of targets needed rises rapidly. Emerging individual targets include PTPRZ1 for brain and head and neck cancers and EGFR in multiple tumor types. In sum, this study provides a computational estimate of the identity and number of targets needed in combination to target cancers selectively and precisely.

The thermoelectric effects of topological semimetals have attracted tremendous research interest because many topological semimetals are excellent thermoelectric materials and thermoelectricity serves as one of their most important potential applications. In this work, we reveal the transient photothermoelectric response of Dirac semimetallic Cd3As2, namely the photo-Seebeck effect and photo-Nernst effect, by studying the terahertz (THz) emission from the transient photocurrent induced by these effects. Our excitation polarization and power dependence confirm that the observed THz emission is due to photothermoelectric effect instead of other nonlinear optical effect. Furthermore, when a weak magnetic field (~0.4 T) is applied, the response clearly indicates an order of magnitude enhancement on transient photothermoelectric current generation compared to the photo-Seebeck effect. Such enhancement supports an ambipolar transport nature of the photo-Nernst current generation in Cd3As2. These results highlight the enhancement of thermoelectric performance can be achieved in topological Dirac semimetals based on the Nernst effect, and our transient studies pave the way for thermoelectric devices applicable for high field circumstance when nonequilibrium state matters. The large THz emission due to highly efficient photothermoelectric conversion is comparable to conventional semiconductors through optical rectification and photo-Dember effect.

Whether grain boundaries (GBs) premelt is a longstanding question, because of the difficulty of direct experimental tests. Here, we focused an optical beam to locally heat single GBs within bulk hard-sphere colloidal crystals, observing the melting dynamics at single-particle resolution by video microscopy. The melting point is determined by analysing both the Lindemann parameter and the critical nucleus size for homogeneous nucleation. We found that all the GBs, including the high-energy GBs, can be superheated and melt via a heterogeneous nucleation mechanism. Based on the classical nucleation theory of GBs, we measured the incubation time and contact angle of the critical nucleus to compute all relevant kinetic factors, as well as the energy barrier, nucleation rate and the diffusion coefficient at the solid-liquid interface under weak superheating. The superheat limits of GBs with various misorientations have also been measured to further explore the instability mechanism. Under traditional uniform heating, premelting occurs only at triple junctions, whereas GBs retain their original structures up to the melting point. The premelted regions at triple junctions further interrupt high-energy GBs from superheating, through intrusion by uniform liquid layers. Overall, our experiments confirm the existence of superheating of GBs.

Writing, erasing and computing are three fundamental operations required by any working electronic device. Magnetic skyrmions could be essential bits in promising in emerging topological spintronic devices. In particular, skyrmions in chiral magnets have outstanding properties like compact texture, uniform size, and high mobility. However, creating, deleting, and driving isolated skyrmions, as prototypes of aforementioned basic operations, have been a grand challenge in chiral magnets ever since the discovery of skyrmions, and achieving all these three operations in a single device is even more challenging. Here, by engineering chiral magnet Co8Zn10Mn2 into the customized micro-devices for in-situ Lorentz transmission electron microscopy observations, we implement these three operations of skyrmions using nanosecond current pulses with a low current density of about 1010 A·m-2 at room temperature. A notched structure can create or delete magnetic skyrmions depending on the direction and magnitude of current pulses. We further show that the magnetic skyrmions can be deterministically shifted step-by-step by current pulses, allowing the establishment of the universal current-velocity relationship. These experimental results have immediate significance towards the skyrmion-based memory or logic devices.

Chirality and topology are intimately related fundamental concepts, which are heavily explored to establish spin-textures as potential magnetic bits in information technology. However, this ambition is inhibited since the electrical reading of chiral attributes is highly non-trivial with conventional current perpendicular-to-plane (CPP) sensing devices. Here we demonstrate from extensive first-principles simulations and multiple scattering expansion the emergence of the chiral spin-mixing magnetoresistance (C-XMR) enabling highly efficient all-electrical readout of the chirality and helicity of respectively one- and two-dimensional magnetic states of matter. It is linear with spin-orbit coupling in contrast to the quadratic dependence associated with the unveiled non-local spin-mixing anisotropic MR (X-AMR). Such transport effects are systematized on various non-collinear magnetic states - spin-spirals and skyrmions - and compared to the uncovered spin-orbit-independent multi-site magnetoresistances. Owing to their simple implementation in readily available reading devices, the proposed magnetoresistances offer exciting and decisive ingredients to explore with all-electrical means the rich physics of topological and chiral magnetic objects.

The application of artificial intelligence (AI) for automated diagnosis of electrocardiograms (ECGs) can improve care in remote settings but is limited by the reliance on infrequently available signal-based data. We report the development of a multilabel automated diagnosis model for electrocardiographic images, more suitable for broader use. A total of 2,228,236 12-lead ECGs signals from 811 municipalities in Brazil are transformed to ECG images in varying lead conformations to train a convolutional neural network (CNN) identifying 6 physician-defined clinical labels spanning rhythm and conduction disorders, and a hidden label for gender. The image-based model performs well on a distinct test set validated by at least two cardiologists (average AUROC 0.99, AUPRC 0.86), an external validation set of 21,785 ECGs from Germany (average AUROC 0.97, AUPRC 0.73), and printed ECGs, with performance superior to signal-based models, and learning clinically relevant cues based on Grad-CAM. The model allows the application of AI to ECGs across broad settings.

The hippocampus interacts with the neocortical network for memory retrieval and consolidation. Here, we found the lateral entorhinal cortex (LEC) modulates learning-induced cortical long-range gamma synchrony (20-40 Hz) in a hippocampal-dependent manner. The long-range gamma synchrony, which was coupled to the theta (7-10 Hz) rhythm and enhanced upon learning and recall, was mediated by inter-cortical projections from layer 5 neurons of the LEC to layer 2 neurons of the sensory and association cortices. Artificially induced cortical gamma synchrony across cortical areas improved memory encoding in hippocampal lesioned mice for originally hippocampal-dependent tasks. Mechanistically, we found that activities of cortical c-Fos labeled neurons, which showed egocentric map properties, were modulated by LEC-mediated gamma synchrony during memory recall, implicating a role of cortical synchrony to generate an integrative memory representation from disperse features. Our findings reveal the hippocampal mediated organization of cortical memories and suggest brain-machine interface approaches to improve cognitive function.

The unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum (ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. Here, we identify binding sites for the RNA-binding protein Pumilio in the 3'UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio binds both the Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stress, which is required for its stabilization of Xbp1spliced. hIRE1 can phosphorylate Pumilio directly, and phosphorylated Pumilio protects Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an unexpected regulatory link between an RNA-binding protein and the UPR.

CHKB encodes one of two mammalian choline kinase enzymes that catalyze the first step in the synthesis of the membrane phospholipid phosphatidylcholine. In humans and mice, inactivation of the CHKB gene (Chkb in mice) causes a recessive rostral-to-caudal muscular dystrophy. Using Chkb knockout mice, we reveal that at no stage of the disease is phosphatidylcholine level significantly altered. We observe that in affected muscle a temporal change in lipid metabolism occurs with an initial inability to utilize fatty acids for energy via mitochondrial β-oxidation resulting in shunting of fatty acids into triacyglycerol as the disease progresses. There is a decrease in peroxisome proliferator-activated receptors and target gene expression specific to Chkb-/- affected muscle. Treatment of Chkb-/- myocytes with peroxisome proliferator-activated receptor agonists enables fatty acids to be used for β-oxidation and prevents triacyglyerol accumulation, while simultaneously increasing expression of the compensatory choline kinase alpha (Chka) isoform, preventing muscle cell injury.

For >70 years, a 4-fold or greater rise in antibody titer has been used to confirm influenza virus infections in paired sera, despite recognition that this heuristic can lack sensitivity. Here we analyze with a novel Bayesian model a large cohort of 2353 individuals followed for up to 5 years in Hong Kong to characterize influenza antibody dynamics and develop an algorithm to improve the identification of influenza virus infections. After infection, we estimate that hemagglutination-inhibiting (HAI) titers were boosted by 16-fold on average and subsequently decrease by 14% per year. In six epidemics, the infection risks for adults were 3%-19% while the infection risks for children were 1.6-4.4 times higher than that of younger adults. Every two-fold increase in pre-epidemic HAI titer was associated with 19%-58% protection against infection. Our inferential framework clarifies the contributions of age and pre-epidemic HAI titers to characterize individual infection risk.

Machine learning has the potential to revolutionize the field of molecular simulation through the development of efficient and accurate models of interatomic interactions. Neural networks can model interactions with the accuracy of quantum mechanics-based calculations, but with a fraction of the cost, enabling simulations of large systems over long timescales. However, implicit in the construction of neural network potentials is an assumption of locality, wherein atomic arrangements on the nanometer-scale are used to learn interatomic interactions. Because of this assumption, the resulting neural network models cannot describe long-range interactions that play critical roles in dielectric screening and chemical reactivity. Here, we address this issue by introducing the self-consistent field neural network - a general approach for learning the long-range response of molecular systems in neural network potentials that relies on a physically meaningful separation of the interatomic interactions - and demonstrate its utility by modeling liquid water with and without applied fields.

Permafrost thaw can accelerate climate warming by releasing carbon from previously frozen soil in the form of greenhouse gases. Rainfall extremes have been proposed to increase permafrost thaw, but the magnitude and duration of this effect are poorly understood. Here we present empirical evidence showing that one extremely wet summer (+100 mm; 120% increase relative to average June-August rainfall) enhanced thaw depth by up to 35% in a controlled irrigation experiment in an ice-rich Siberian tundra site. The effect persisted over two subsequent summers, demonstrating a carry-over effect of extremely wet summers. Using soil thermal hydrological modelling, we show that rainfall extremes delayed autumn freeze-up and rainfall-induced increases in thaw were most pronounced for warm summers with mid-summer precipitation rainfall extremes. Our results suggest that, with rainfall and temperature both increasing in the Arctic, permafrost will likely degrade and disappear faster than is currently anticipated based on rising air temperatures alone.

Hardware implementation in resource-efficient reservoir computing is of great interest for neuromorphic engineering. Recently, various devices have been explored to implement hardware-based reservoirs. However, most studies were mainly focused on the reservoir layer, whereas an end-to-end reservoir architecture has yet to be developed. Here, we propose a versatile method for implementing cyclic reservoirs using rotating elements integrated with signal-driven dynamic neurons, whose equivalence to standard cyclic reservoir algorithm is mathematically proven. Simulations show that the rotating neuron reservoir achieves record-low errors in a nonlinear system approximation benchmark. Furthermore, a hardware prototype was developed for near-sensor computing, chaotic time-series prediction and handwriting classification. By integrating a memristor array as a fully-connected output layer, the all-analog reservoir computing system achieves 94.0% accuracy, while simulation shows >1000× lower system-level power than prior works. Therefore, our work demonstrates an elegant rotation-based architecture that explores hardware physics as computational resources for high-performance reservoir computing.

Protected areas are key to meeting biodiversity conservation goals, but direct measures of effectiveness have proven difficult to obtain. We address this challenge by using environmental DNA from leech-ingested bloodmeals to estimate spatially-resolved vertebrate occupancies across the 677 km2 Ailaoshan reserve in Yunnan, China. From 30,468 leeches collected by 163 park rangers across 172 patrol areas, we identify 86 vertebrate species, including amphibians, mammals, birds and squamates. Multi-species occupancy modelling shows that species richness increases with elevation and distance to reserve edge. Most large mammals (e.g. sambar, black bear, serow, tufted deer) follow this pattern; the exceptions are the three domestic mammal species (cows, sheep, goats) and muntjak deer, which are more common at lower elevations. Vertebrate occupancies are a direct measure of conservation outcomes that can help guide protected-area management and improve the contributions that protected areas make towards global biodiversity goals. Here, we show the feasibility of using invertebrate-derived DNA to estimate spatially-resolved vertebrate occupancies across entire protected areas.

Recent attempts to synthesize hybrid perovskites with large chirality have been hampered by large size mismatch and weak interaction between their structure and the wavelength of light. Here we adopt a planar nanostructure design to overcome these limitations and realize all-dielectric perovskite metasurfaces with giant superstructural chirality. We identify a direct spectral correspondence between the near- and the far- field chirality, and tune the electric and magnetic multipole moments of the resonant chiral metamolecules to obtain large anisotropy factor of 0.49 and circular dichroism of 6350 mdeg. Simulations show that larger area metasurfaces could yield even higher optical activity, approaching the theoretical limits. Our results clearly demonstrate the advantages of nanostructrure engineering for the implementation of perovskite chiral photonic, optoelectronic, and spintronic devices.

While advances in biologging have revealed many spectacular animal migrations, it remains poorly understood how young animals learn to migrate. Even in social species, it is unclear how migratory skills are transmitted from one generation to another and what implications this may have. Here we show that in Caspian terns Hydroprogne caspia family groups, genetic and foster male parents carry the main responsibility for migrating with young. During migration, young birds stayed close to an adult at all times, with the bond dissipating on the wintering grounds. Solo-migrating adults migrated faster than did adults accompanying young. Four young that lost contact with their parent at an early stage of migration all died. During their first solo migration, subadult terns remained faithful to routes they took with their parents as young. Our results provide evidence for cultural inheritance of migration knowledge in a long-distance bird migrant and show that sex-biased (allo)parental care en route shapes migration through social learning.

RCOR1 is a known transcription repressor that recruits and positions LSD1 and HDAC1/2 on chromatin to erase histone methylation and acetylation. However, there is currently an incomplete understanding of RCOR1's range of localization and function. Here, we probe RCOR1's distribution on a genome-wide scale and unexpectedly find that RCOR1 is predominantly associated with transcriptionally active genes. Biochemical analysis reveals that RCOR1 associates with RNA Polymerase II (POL-II) during transcription and deacetylates its carboxy-terminal domain (CTD) at lysine 7. We provide evidence that this non-canonical RCOR1 activity is linked to dampening of POL-II productive elongation at actively transcribing genes. Thus, RCOR1 represses transcription in two ways-first, via a canonical mechanism by erasing transcriptionally permissive histone modifications through associating with HDACs and, second, via a non-canonical mechanism that deacetylates RNA POL-II's CTD to inhibit productive elongation. We conclude that RCOR1 is a transcription rheostat.

The Chengjiang Biota is the earliest Phanerozoic soft-bodied fossil assemblage offering the most complete snapshot of Earth's initial diversification, the Cambrian Explosion. Although palaeobiologic aspects of this biota are well understood, the precise sedimentary environment inhabited by this biota remains debated. Herein, we examine a non-weathered core from the Yu'anshan Formation including the interval preserving the Chengjiang Biota. Our data indicate that the succession was deposited as part of a delta influenced by storm floods (i.e., produced by upstream river floods resulting from ocean storms). Most Chengjiang animals lived in an oxygen and nutrient-rich delta front environment in which unstable salinity and high sedimentation rates were the main stressors. This unexpected finding allows for sophisticated ecological comparisons with other Burgess Shale-type deposits and emphasizes that the long-held view of Burgess Shale-type faunas as snapshots of stable distal shelf and slope communities needs to be revised based on recent sedimentologic advances.

Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorβ1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease.

Materials with tunable thermal properties enable on-demand control of temperature and heat flow, which is an integral component in the development of solid-state refrigeration, energy scavenging, and thermal circuits. Although gap-based and liquid-based thermal switches that work on the basis of mechanical movements have been an effective approach to control the flow of heat in the devices, their complex mechanisms impose considerable costs in latency, expense, and power consumption. As a consequence, materials that have multiple solid-state phases with distinct thermal properties are appealing for thermal management due to their simplicity, fast switching, and compactness. Thus, an ideal thermal switch should operate near or above room temperature, have a simple trigger mechanism, and offer a quick and large on/off switching ratio. In this study, we experimentally demonstrate that manipulating phonon scattering rates can switch the thermal conductivity of antiferroelectric PbZrO3 bidirectionally by -10% and +25% upon applying electrical and thermal excitation, respectively. Our approach takes advantage of two separate phase transformations in PbZrO3 that alter the phonon scattering rate in different manners. In this study, we demonstrate that PbZrO3 can serve as a fast (<1 second), repeatable, simple trigger, and reliable thermal switch with a net switching ratio of nearly 38% from ~1.20 to ~1.65 W m-1 K-1.

In vivo two-photon calcium imaging is a powerful approach in neuroscience. However, processing two-photon calcium imaging data is computationally intensive and time-consuming, making online frame-by-frame analysis challenging. This is especially true for large field-of-view (FOV) imaging. Here, we present CITE-On (Cell Identification and Trace Extraction Online), a convolutional neural network-based algorithm for fast automatic cell identification, segmentation, identity tracking, and trace extraction in two-photon calcium imaging data. CITE-On processes thousands of cells online, including during mesoscopic two-photon imaging, and extracts functional measurements from most neurons in the FOV. Applied to publicly available datasets, the offline version of CITE-On achieves performance similar to that of state-of-the-art methods for offline analysis. Moreover, CITE-On generalizes across calcium indicators, brain regions, and acquisition parameters in anesthetized and awake head-fixed mice. CITE-On represents a powerful tool to speed up image analysis and facilitate closed-loop approaches, for example in combined all-optical imaging and manipulation experiments.

Update of bioRxiv. 2021 Mar 30;:

Erratum in Nat Commun. 2022 Oct 3;13(1):5817.

Anxiety disorders are complex diseases, and often co-occur with depression. It is as yet unclear if a common neural circuit controls anxiety-related behaviors in both anxiety-alone and comorbid conditions. Here, utilizing the chronic social defeat stress (CSDS) paradigm that induces singular or combined anxiety- and depressive-like phenotypes in mice, we show that a ventral tegmental area (VTA) dopamine circuit projecting to the basolateral amygdala (BLA) selectively controls anxiety- but not depression-like behaviors. Using circuit-dissecting ex vivo electrophysiology and in vivo fiber photometry approaches, we establish that expression of anxiety-like, but not depressive-like, phenotypes are negatively correlated with VTA → BLA dopamine neuron activity. Further, our optogenetic studies demonstrate a causal link between such neuronal activity and anxiety-like behaviors. Overall, these data establish a functional role for VTA → BLA dopamine neurons in bi-directionally controlling anxiety-related behaviors not only in anxiety-alone, but also in anxiety-depressive comorbid conditions in mice.

Reconstructing axonal projections of single neurons at the whole-brain level is currently a converging goal of the neuroscience community that is fundamental for understanding the logic of information flow in the brain. Thousands of single neurons from different brain regions have recently been morphologically reconstructed, but the corresponding physiological functional features of these reconstructed neurons are unclear. By combining two-photon Ca2+ imaging with targeted single-cell plasmid electroporation, we reconstruct the brain-wide morphologies of single neurons that are defined by a sound-evoked response map in the auditory cortices (AUDs) of awake mice. Long-range interhemispheric projections can be reliably labelled via co-injection with an adeno-associated virus, which enables enhanced expression of indicator protein in the targeted neurons. Here we show that this method avoids the randomness and ambiguity of conventional methods of neuronal morphological reconstruction, offering an avenue for developing a precise one-to-one map of neuronal projection patterns and physiological functional features.

RNA excited states represent a class of high-energy-level and thus low-populated conformational states of RNAs that are sequestered within the free energy landscape until being activated by cellular cues. In recent years, there has been growing interest in structural and functional studies of these transient states, but the rational design of excited states remains unexplored. Here we developed a method to design small hairpin RNAs with predefined excited states that exchange with ground states through base pair reshuffling, and verified these transient states by combining NMR relaxation dispersion technique and imino chemical shift prediction. Using van't Hoff analysis and accelerated molecular dynamics simulations, a mechanism of multi-step sequential transition has been revealed. The efforts made in this study will expand the scope of RNA rational design, and also contribute towards improved predictions of RNA secondary structure.

One of the most common approaches for quenching single-photon avalanche diodes is to use a passive resistor in series with it. A drawback of this approach has been the limited recovery speed of the single-photon avalanche diodes. High resistance is needed to quench the avalanche, leading to slower recharging of the single-photon avalanche diodes depletion capacitor. We address this issue by replacing a fixed quenching resistor with a bias-dependent adaptive resistive switch. Reversible generation of metallic conduction enables switching between low and high resistance states under unipolar bias. As an example, using a Pt/Al2O3/Ag resistor with a commercial silicon single-photon avalanche diodes, we demonstrate avalanche pulse widths as small as ~30 ns, 10× smaller than a passively quenched approach, thus significantly improving the single-photon avalanche diodes frequency response. The experimental results are consistent with a model where the adaptive resistor dynamically changes its resistance during discharging and recharging the single-photon avalanche diodes.

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A-/-, CPT2-/-, ACAD9-/- cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.

CRISPR/Cas has been mainly used for mutagenesis through the induction of double strand breaks (DSBs) within unique protein-coding genes. Using the SaCas9 nuclease to induce multiple DSBs in functional repetitive DNA of Arabidopsis thaliana, we can now show that cell death can be induced in a controlled way. This approach, named CRISPR-Kill, can be used as tool for tissue engineering. By simply exchanging the constitutive promoter of SaCas9 with cell type-specific promoters, it is possible to block organogenesis in Arabidopsis. By AP1-specific expression of CRISPR-Kill, we are able to restore the apetala1 phenotype and to specifically eliminate petals. In addition, by expressing CRISPR-Kill in root-specific pericycle cells, we are able to dramatically reduce the number and the length of lateral roots. In the future, the application of CRISPR-Kill may not only help to control development but could also be used to change the biochemical properties of plants.

Author information: (1)Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2)Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA. (3)Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4)Alzheimer's Disease Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5)Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6)Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA. David.Wolk@pennmedicine.upenn.edu. (7)Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. David.Wolk@pennmedicine.upenn.edu. (8)Alzheimer's Disease Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. David.Wolk@pennmedicine.upenn.edu. (9)Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Ilya.Nasrallah@pennmedicine.upenn.edu. (10)Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA. Ilya.Nasrallah@pennmedicine.upenn.edu. (11)Alzheimer's Disease Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Ilya.Nasrallah@pennmedicine.upenn.edu. (#)Contributed equally

Development of islet autoimmunity precedes the onset of type 1 diabetes in children, however, the presence of autoantibodies does not necessarily lead to manifest disease and the onset of clinical symptoms is hard to predict. Here we show, by longitudinal sampling of islet autoantibodies (IAb) to insulin, glutamic acid decarboxylase and islet antigen-2 that disease progression follows distinct trajectories. Of the combined Type 1 Data Intelligence cohort of 24662 participants, 2172 individuals fulfill the criteria of two or more follow-up visits and IAb positivity at least once, with 652 progressing to type 1 diabetes during the 15 years course of the study. Our Continuous-Time Hidden Markov Models, that are developed to discover and visualize latent states based on the collected data and clinical characteristics of the patients, show that the health state of participants progresses from 11 distinct latent states as per three trajectories (TR1, TR2 and TR3), with associated 5-year cumulative diabetes-free survival of 40% (95% confidence interval [CI], 35% to 47%), 62% (95% CI, 57% to 67%), and 88% (95% CI, 85% to 91%), respectively (p < 0.0001). Age, sex, and HLA-DR status further refine the progression rates within trajectories, enabling clinically useful prediction of disease onset.

There is an urgent need for developing electromechanical sensor with both ultralow detection limits and ultrahigh sensitivity to promote the progress of intelligent technology. Here we propose a strategy for fabricating a soft polysiloxane crosslinked MXene aerogel with multilevel nanochannels inside its cellular walls for ultrasensitive pressure detection. The easily shrinkable nanochannels and optimized material synergism endow the piezoresistive aerogel with an ultralow Young's modulus (140 Pa), numerous variable conductive pathways, and mechanical robustness. This aerogel can detect extremely subtle pressure signals of 0.0063 Pa, deliver a high pressure sensitivity over 1900 kPa-1, and exhibit extraordinarily sensing robustness. These sensing properties make the MXene aerogel feasible for monitoring ultra-weak force signals arising from a human's deep-lying internal jugular venous pulses in a non-invasive manner, detecting the dynamic impacts associated with the landing and take-off of a mosquito, and performing static pressure mapping of a hair.

The COVID-19 pandemic has illustrated the fragility of food security and associated supply chains for remote and Indigenous communities. Here we highlight challenges faced by the Tribal Population of Noepe (Martha’s Vineyard) and argue for the inclusion of Resilience-by-Design and Resilience-by-Intervention in supply chain management.

CRISPR-Cas9 expression independent of its cognate synthetic guide RNA (gRNA) causes widespread genomic DNA damage in human cells. To investigate whether Cas9 can interact with endogenous human RNA transcripts independent of its guide, we perform eCLIP (enhanced CLIP) of Cas9 in human cells and find that Cas9 reproducibly interacts with hundreds of endogenous human RNA transcripts. This association can be partially explained by a model built on gRNA secondary structure and sequence. Critically, transcriptome-wide Cas9 binding sites do not appear to correlate with published genome-wide Cas9 DNA binding or cut-site loci under gRNA co-expression. However, even under gRNA co-expression low-affinity Cas9-human RNA interactions (which we term CRISPR crosstalk) do correlate with published elevated transcriptome-wide RNA editing. Our findings do not support the hypothesis that human RNAs can broadly guide Cas9 to bind and cleave human genomic DNA, but they illustrate a cellular and RNA impact likely inherent to CRISPR-Cas systems.

Macroevolution posed difficulties for Darwin and later theorists because species' phenotypes frequently change abruptly, or experience long periods of stasis, both counter to the theory of incremental change or gradualism. We introduce a statistical model that accommodates this uneven evolutionary landscape by estimating two kinds of historical change: directional changes that shift the mean phenotype along the branches of a phylogenetic tree, and evolvability changes that alter a clade's ability to explore its trait-space. In mammals, we find that both processes make substantial independent contributions to explaining macroevolution, and are rarely linked. 'Watershed' moments of increased evolvability greatly outnumber reductions in evolutionary potentials, and large or abrupt phenotypic shifts are explicable statistically as biased random walks, allowing macroevolutionary theory to engage with the language and concepts of gradualist microevolution. Our findings recast macroevolutionary phenomena, illustrating the necessity of accounting for a variety of evolutionary processes simultaneously.

Reducing the switching energy of ferroelectric thin films remains an important goal in the pursuit of ultralow-power ferroelectric memory and logic devices. Here, we elucidate the fundamental role of lattice dynamics in ferroelectric switching by studying both freestanding bismuth ferrite (BiFeO3) membranes and films clamped to a substrate. We observe a distinct evolution of the ferroelectric domain pattern, from striped, 71° ferroelastic domains (spacing of ~100 nm) in clamped BiFeO3 films, to large (10's of micrometers) 180° domains in freestanding films. By removing the constraints imposed by mechanical clamping from the substrate, we can realize a ~40% reduction of the switching voltage and a consequent ~60% improvement in the switching speed. Our findings highlight the importance of a dynamic clamping process occurring during switching, which impacts strain, ferroelectric, and ferrodistortive order parameters and plays a critical role in setting the energetics and dynamics of ferroelectric switching.

Porcine deltacoronavirus (PDCoV) can experimentally infect a variety of animals. Human infection by PDCoV has also been reported. Consistently, PDCoV can use aminopeptidase N (APN) from different host species as receptors to enter cells. To understand this broad receptor usage and interspecies transmission of PDCoV, we determined the crystal structures of the receptor binding domain (RBD) of PDCoV spike protein bound to human APN (hAPN) and porcine APN (pAPN), respectively. The structures of the two complexes exhibit high similarity. PDCoV RBD binds to common regions on hAPN and pAPN, which are different from the sites engaged by two alphacoronaviruses: HCoV-229E and porcine respiratory coronavirus (PRCoV). Based on structure guided mutagenesis, we identified conserved residues on hAPN and pAPN that are essential for PDCoV binding and infection. We report the detailed mechanism for how a deltacoronavirus recognizes homologous receptors and provide insights into the cross-species transmission of PDCoV.

Eukaryotic chromosomes are folded into hierarchical domains, forming functional compartments. Nuclear periphery and nucleolus are two nuclear landmarks contributing to repressive chromosome architecture. However, while the role of nuclear lamina (NL) in genome organization has been well documented, the function of the nucleolus remains under-investigated due to the lack of methods for the identification of nucleolar associated domains (NADs). Here we have established DamID- and HiC-based methodologies to generate accurate genome-wide maps of NADs in embryonic stem cells (ESCs) and neural progenitor cells (NPCs), revealing layers of genome compartmentalization with distinct, repressive chromatin states based on the interaction with the nucleolus, NL, or both. NADs show higher H3K9me2 and lower H3K27me3 content than regions exclusively interacting with NL. Upon ESC differentiation into NPCs, chromosomes around the nucleolus acquire a more compact, rigid architecture with neural genes moving away from nucleoli and becoming unlocked for later activation. Further, histone modifications and the interaction strength within A and B compartments of NADs and LADs in ESCs set the choice to associate with NL or nucleoli upon dissociation from their respective compartments during differentiation. The methodologies here developed will make possible to include the nucleolar contribution in nuclear space and genome function in diverse biological systems.

The effective application of graphene and other 2D materials is strongly dependent on the industrial-scale manufacturing of films and powders of appropriate morphology and quality. Here, we discuss three state-of-the-art mass production techniques, their limitations, and opportunities for future improvement.

Non-invasive optical imaging techniques are essential diagnostic tools in many fields. Although various recent methods have been proposed to utilize and control light in multiple scattering media, non-invasive optical imaging through and inside scattering layers across a large field of view remains elusive due to the physical limits set by the optical memory effect, especially without wavefront shaping techniques. Here, we demonstrate an approach that enables non-invasive fluorescence imaging behind scattering layers with field-of-views extending well beyond the optical memory effect. The method consists in demixing the speckle patterns emitted by a fluorescent object under variable unknown random illumination, using matrix factorization and a novel fingerprint-based reconstruction. Experimental validation shows the efficiency and robustness of the method with various fluorescent samples, covering a field of view up to three times the optical memory effect range. Our non-invasive imaging technique is simple, neither requires a spatial light modulator nor a guide star, and can be generalized to a wide range of incoherent contrast mechanisms and illumination schemes.

Glucuronoyl esterases (GEs) are α/β serine hydrolases and a relatively new addition in the toolbox to reduce the recalcitrance of lignocellulose, the biggest obstacle in cost-effective utilization of this important renewable resource. While biochemical and structural characterization of GEs have progressed greatly recently, there have yet been no mechanistic studies shedding light onto the rate-limiting steps relevant for biomass conversion. The bacterial GE OtCE15A possesses a classical yet distinctive catalytic machinery, with easily identifiable catalytic Ser/His completed by two acidic residues (Glu and Asp) rather than one as in the classical triad, and an Arg side chain participating in the oxyanion hole. By QM/MM calculations, we identified deacylation as the decisive step in catalysis, and quantified the role of Asp, Glu and Arg, showing the latter to be particularly important. The results agree well with experimental and structural data. We further calculated the free-energy barrier of post-catalysis dissociation from a complex natural substrate, suggesting that in industrial settings non-catalytic processes may constitute the rate-limiting step, and pointing to future directions for enzyme engineering in biomass utilization.

The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the Cd4 locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of Cd4 gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of histone H3K4me3 levels during T cell replication, which is critical for preventing de novo DNA methylation at the Cd4 promoter. A failure to undergo epigenetic programming during development leads to gene silencing during effector T cell replication. Our study thus provides evidence of early developmental events shaping the functional fitness of mature effector T cells.

This study deploys newly available data to examine the exposure of multinational companies' overseas investments to physical climate risks. Globally, foreign investments are significantly exposed to lower physical climate risks, compared with local firms across countries. Within countries however, the differences of physical climate risks between foreign and local facilities are small. We also examine China, as it is fast becoming one of the largest sources of outward foreign investment across the globe. We find that foreign direct investment from China is significantly more exposed to water stress, floods, hurricanes and typhoon risks across countries, compared with other foreign facilities. Within host countries however, once again the physical climate risks of Chinese overseas facilities are comparable to those of non-Chinese foreign investments.

Retroviruses utilize the viral integrase (IN) protein to integrate a DNA copy of their genome into host chromosomal DNA. HIV-1 integration sites are highly biased towards actively transcribed genes, likely mediated by binding of the IN protein to specific host factors, particularly LEDGF, located at these gene regions. We here report a substantial redirection of integration site distribution induced by a single point mutation in HIV-1 IN. Viruses carrying the K258R IN mutation exhibit a high frequency of integrations into centromeric alpha satellite repeat sequences, as assessed by deep sequencing, a more than 10-fold increase over wild-type. Quantitative PCR and in situ immunofluorescence assays confirm this bias of the K258R mutant virus for integration into centromeric DNA. Immunoprecipitation studies identify host factors binding to IN that may account for the observed bias for integration into centromeres. Centromeric integration events are known to be enriched in the latent reservoir of infected memory T cells, as well as in elite controllers who limit viral replication without intervention. The K258R point mutation in HIV-1 IN is also present in databases of latent proviruses found in patients, and may reflect an unappreciated aspect of the establishment of viral latency.

Immune checkpoint blockade (ICB) is a powerful approach for cancer therapy although good responses are only observed in a fraction of cancer patients. Breast cancers caused by deficiency of breast cancer-associated gene 1 (BRCA1) do not have an improved response to the treatment. To investigate this, here we analyze BRCA1 mutant mammary tissues and tumors derived from both BRCA1 mutant mouse models and human xenograft models to identify intrinsic determinants governing tumor progression and ICB responses. We show that BRCA1 deficiency activates S100A9-CXCL12 signaling for cancer progression and triggers the expansion and accumulation of myeloid-derived suppressor cells (MDSCs), creating a tumor-permissive microenvironment and rendering cancers insensitive to ICB. These oncogenic actions can be effectively suppressed by the combinatory treatment of inhibitors for S100A9-CXCL12 signaling with αPD-1 antibody. This study provides a selective strategy for effective immunotherapy in patients with elevated S100A9 and/or CXCL12 protein levels.

Gpr125 is an orphan G-protein coupled receptor, with homology to cell adhesion and axonal guidance factors, that is implicated in planar polarity and control of cell movements. By lineage tracing we demonstrate that Gpr125 is a highly specific marker of bipotent mammary stem cells in the embryo and of multiple long-lived unipotent basal mammary progenitors in perinatal and postnatal glands. Nipple-proximal Gpr125+ cells express a transcriptomic profile indicative of chemo-repulsion and cell movement, whereas Gpr125+ cells concentrated at invasive ductal tips display a hybrid epithelial-mesenchymal phenotype and are equipped to bind chemokine and growth factors and secrete a promigratory matrix. Gpr125 progenitors acquire bipotency in the context of transplantation and cancer and are greatly expanded and massed at the pushing margins of short latency MMTV-Wnt1 tumors. High Gpr125 expression identifies patients with particularly poor outcome within the basal breast cancer subtype highlighting its potential utility as a factor to stratify risk.

There has been a global increase in rates of obesity with a parallel epidemic of non-alcoholic fatty liver disease (NAFLD). Autophagy is an essential mechanism involved in the degradation of cellular material and has an important function in the maintenance of liver homeostasis. Here, we explore the effect of Autophagy-related 5 (Atg5) deficiency in liver CD11c+ cells in mice fed HFD. When compared to control mice, Atg5-deficient CD11c+ mice exhibit increased glucose intolerance and decreased insulin sensitivity when fed HFD. This phenotype is associated with the development of NAFLD. We observe that IL-23 secretion is induced in hepatic CD11c+ myeloid cells following HFD feeding. We demonstrate that both therapeutic and preventative IL-23 blockade alleviates glucose intolerance, insulin resistance and protects against NAFLD development. This study provides insights into the function of autophagy and IL-23 production by hepatic CD11c+ cells in NAFLD pathogenesis and suggests potential therapeutic targets.

Ultra-high-speed imaging serves as a foundation for modern science. While in biomedicine, optical-fiber-based endoscopy is often required for in vivo applications, the combination of high speed with the fiber endoscopy, which is vital for exploring transient biomedical phenomena, still confronts some challenges. We propose all-fiber imaging at high speeds, which is achieved based on the transformation of two-dimensional spatial information into one-dimensional temporal pulsed streams by leveraging high intermodal dispersion in a multimode fiber. Neural networks are trained to reconstruct images from the temporal waveforms. It can not only detect content-aware images with high quality, but also detect images of different kinds from the training images with slightly reduced quality. The fiber probe can detect micron-scale objects with a high frame rate (15.4 Mfps) and large frame depth (10,000). This scheme combines high speeds with high mechanical flexibility and integration and may stimulate future research exploring various phenomena in vivo.

Utilizing the spin degree of freedom of photoexcitations in hybrid organic inorganic perovskites for quantum information science applications has been recently proposed and explored. However, it is still unclear whether the stable photoexcitations in these compounds correspond to excitons, free/trapped electron-hole pairs, or charged exciton complexes such as trions. Here we investigate quantum beating oscillations in the picosecond time-resolved circularly polarized photoinduced reflection of single crystal methyl-ammonium tri-iodine perovskite (MAPbI3) measured at cryogenic temperatures. We observe two quantum beating oscillations (fast and slow) whose frequencies increase linearly with B with slopes that depend on the crystal orientation with respect to the applied magnetic field. We assign the quantum beatings to positive and negative trions whose Landé g-factors are determined by those of the electron and hole, respectively, or by the carriers left behind after trion recombination. These are [Formula: see text] = 2.52 and [Formula: see text]= 2.63 for electrons, whereas [Formula: see text]= 0.28 and [Formula: see text]= 0.57 for holes. The obtained g-values are in excellent agreement with an 8-band K.P calculation for orthorhombic MAPbI3. Using the technique of resonant spin amplification of the quantum beatings we measure a relatively long spin coherence time of ~ 11 (6) nanoseconds for electrons (holes) at 4 K.

Scanning probe microscopy techniques, such as atomic force microscopy and scanning tunnelling microscopy, are harnessed to image nanoscale structures with an exquisite resolution, which has been of significant value in a variety of areas of nanotechnology. These scanning probe techniques, however, are not generally suitable for high-throughput imaging, which has, from the outset, been a primary challenge. Traditional approaches to increasing the scalability have involved developing multiple probes for imaging, but complex probe design and electronics are required to carry out the detection method. Here, we report a probe-based imaging method that utilizes scalable cantilever-free elastomeric probe design and hierarchical measurement architecture, which readily reconstructs high-resolution and high-throughput topography images. In a single scan, we demonstrate imaging with a 100-tip array to obtain 100 images over a 1-mm2 area with 106 pixels in less than 10 min. The potential for large-scale tip integration and the advantage of a simple probe array suggest substantial promise for our approach to high-throughput imaging far beyond what is currently possible.

During aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We found that the ability of MuSCs to regenerate is regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia inhibited MuSC proliferation in vitro and severely impaired injury-induced muscle regeneration in vivo. In aged muscle, a cell intrinsic defect in MuSC ciliation was associated with the decrease in regenerative capacity. Exogenous activation of Hedgehog signaling, known to be localized in the primary cilium, promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG1.3) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aged MuSCs and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.

Progressive degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinson's disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons causes mitochondrial abnormalities and locomotor impairments in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modeling and treating PD.

Lip language is an effective method of voice-off communication in daily life for people with vocal cord lesions and laryngeal and lingual injuries without occupying the hands. Collection and interpretation of lip language is challenging. Here, we propose the concept of a novel lip-language decoding system with self-powered, low-cost, contact and flexible triboelectric sensors and a well-trained dilated recurrent neural network model based on prototype learning. The structural principle and electrical properties of the flexible sensors are measured and analysed. Lip motions for selected vowels, words, phrases, silent speech and voice speech are collected and compared. The prototype learning model reaches a test accuracy of 94.5% in training 20 classes with 100 samples each. The applications, such as identity recognition to unlock a gate, directional control of a toy car and lip-motion to speech conversion, work well and demonstrate great feasibility and potential. Our work presents a promising way to help people lacking a voice live a convenient life with barrier-free communication and boost their happiness, enriches the diversity of lip-language translation systems and will have potential value in many applications.

Solid-state batteries possess the potential to significantly impact energy storage industries by enabling diverse benefits, such as increased safety and energy density. However, challenges persist with physicochemical properties and processes at electrode/electrolyte interfaces. Thus, there is great need to characterize such interfaces in situ, and unveil scientific understanding that catalyzes engineering solutions. To address this, we conduct multiscale in situ microscopies (optical, atomic force, and infrared near-field) and Fourier transform infrared spectroscopies (near-field nanospectroscopy and attenuated total reflection) of intact and electrochemically operational graphene/solid polymer electrolyte interfaces. We find nanoscale structural and chemical heterogeneities intrinsic to the solid polymer electrolyte initiate a cascade of additional interfacial nanoscale heterogeneities during Li plating and stripping; including Li-ion conductivity, electrolyte decomposition, and interphase formation. Moreover, our methodology to nondestructively characterize buried interfaces and interphases in their native environment with nanoscale resolution is readily adaptable to a number of other electrochemical systems and battery chemistries.

Non-collinear spin textures in ferromagnetic ultrathin films are attracting a renewed interest fueled by possible fine engineering of several magnetic interactions, notably the interfacial Dzyaloshinskii-Moriya interaction. This allows for the stabilization of complex chiral spin textures such as chiral magnetic domain walls (DWs), spin spirals, and magnetic skyrmions among others. We report here on the behavior of chiral DWs at ultrashort timescale after optical pumping in perpendicularly magnetized asymmetric multilayers. The magnetization dynamics is probed using time-resolved circular dichroism in x-ray resonant magnetic scattering (CD-XRMS). We observe a picosecond transient reduction of the CD-XRMS, which is attributed to the spin current-induced coherent and incoherent torques within the continuously varying spin texture of the DWs. We argue that a specific demagnetization of the inner structure of the DW induces a flow of spins from the interior of the neighboring magnetic domains. We identify this time-varying change of the DW texture shortly after the laser pulse as a distortion of the homochiral Néel shape toward a transient mixed Bloch-Néel-Bloch texture along a direction transverse to the DW.

Importance of heat storage materials has recently been increasing. Although various types of heat storage materials have been reported to date, there are few well-balanced energy storage materials in terms of long lifetime, reversibility, energy density, reasonably fast charge/discharge capability, and treatability. Here we report an interesting discovery that a commonly known substance, birnessite-type layered manganese dioxide with crystal water (δ-type K0.33MnO2 ⋅ nH2O), exhibits a water-intercalation mechanism and can be an excellently balanced heat storage material, from the above views, that can be operated in a solid state with water as a working pair. The volumetric energy density exceeds 1000 MJ m-3 (at n ~ 0.5), which is close to the ideally maximum value and the best among phase-change materials. The driving force for the water intercalation is also validated by the ab initio calculations. The proposed mechanism would provide an optimal solution for a heat-storage strategy towards low-grade waste-heat applications.

There is significant interest in establishing a capability for tailored synthesis of next-generation carbon-based nanomaterials due to their broad range of applications and high degree of tunability. High pressure (e.g., shockwave-driven) synthesis holds promise as an effective discovery method, but experimental challenges preclude elucidating the processes governing nanocarbon production from carbon-rich precursors that could otherwise guide efforts through the prohibitively expansive design space. Here we report findings from large scale atomistically-resolved simulations of carbon condensation from C/O mixtures subjected to extreme pressures and temperatures, made possible by machine-learned reactive interatomic potentials. We find that liquid nanocarbon formation follows classical growth kinetics driven by Ostwald ripening (i.e., growth of large clusters at the expense of shrinking small ones) and obeys dynamical scaling in a process mediated by carbon chemistry in the surrounding reactive fluid. The results provide direct insight into carbon condensation in a representative system and pave the way for its exploration in higher complexity organic materials. They also suggest that simulations using machine-learned interatomic potentials could eventually be employed as in-silico design tools for new nanomaterials.

Based on new and published cosmic-ray exposure chronologies, we show that glacier extent in the tropical Andes and the north Atlantic regions (TANAR) varied in-phase on millennial timescales during the Holocene, distinct from other regions. Glaciers experienced an early Holocene maximum extent, followed by a strong mid-Holocene retreat and a re-advance in the late Holocene. We further explore the potential forcing of TANAR glacier variations using transient climate simulations. Since the Atlantic Meridional Overturning Circulation (AMOC) evolution is poorly represented in these transient simulations, we develop a semi-empirical model to estimate the "AMOC-corrected" temperature and precipitation footprint at regional scales. We show that variations in the AMOC strength during the Holocene are consistent with the observed glacier changes. Our findings highlight the need to better constrain past AMOC behavior, as it may be an important driver of TANAR glacier variations during the Holocene, superimposed on other forcing mechanisms.

Tailored nanoscale quantum light sources, matching the specific needs of use cases, are crucial building blocks for photonic quantum technologies. Several different approaches to realize solid-state quantum emitters with high performance have been pursued and different concepts for energy tuning have been established. However, the properties of the emitted photons are always defined by the individual quantum emitter and can therefore not be controlled with full flexibility. Here we introduce an all-optical nonlinear method to tailor and control the single photon emission. We demonstrate a laser-controlled down-conversion process from an excited state of a semiconductor quantum three-level system. Based on this concept, we realize energy tuning and polarization control of the single photon emission with a control-laser field. Our results mark an important step towards tailored single photon emission from a photonic quantum system based on quantum optical principles.

Microbial communities provide protection to their hosts by resisting pathogenic invasion. Microbial residents of a host often exclude subsequent colonizers, but this protection is not well understood. The Enterococcus faecalis plasmid pCF10, whose conjugative transfer functions are induced by a peptide pheromone, efficiently transfers in the intestinal tract of mice. Here we show that an invading donor strain established in the gastrointestinal tract of mice harboring resident recipients, resulting in a stable, mixed population comprised of approximately 10% donors and 90% recipients. We also show that the plasmid-encoded surface protein PrgB (Aggregation Substance), enhanced donor invasion of resident recipients, and resistance of resident donors to invasion by recipients. Imaging of the gastrointestinal mucosa of mice infected with differentially labeled recipients and donors revealed pheromone induction within microcolonies harboring both strains in close proximity, suggesting that adherent microcolonies on the mucosal surface of the intestine comprise an important niche for cell-cell signaling and plasmid transfer.

The instability of organic field-effect transistors (OFETs) is one key obstacle to practical application and is closely related to the unstable aggregate state of organic semiconductors (OSCs). However, the underlying reason for this instability remains unclear, and no effective solution has been developed. Herein, we find that the intrinsic tensile and compressive strains that exist in OSC films are the key origins for aggregate state instability and device degradation. We further report a strain balance strategy to stabilize the aggregate state by regulating film thickness, which is based on the unique transition from tensile strain to compressive strain with increasing film thickness. Consequently, a strain-free and ultrastable OSC film is obtained by regulating the film thickness, with which an ultrastable OFET with a five-year lifetime is realized. This work provides a deeper understanding of and a solution to the instability of OFETs and sheds light on their industrialization.

Photonic generation of Terahertz (THz) carriers displays high potential for THz communications with a large tunable range and high modulation bandwidth. While many photonics-based THz generations have recently been demonstrated with discrete bulky components, their practical applications are significantly hindered by the large footprint and high energy consumption. Herein, we present an injection-locked heterodyne source based on generic foundry-fabricated photonic integrated circuits (PIC) attached to a uni-traveling carrier photodiode generating high-purity THz carriers. The generated THz carrier is tunable within the range of 0-1.4 THz, determined by the wavelength spacing between the two monolithically integrated distributed feedback (DFB) lasers. This scheme generates and transmits a 131 Gbits-1 net rate signal over a 10.7-m distance with -24 dBm emitted power at 0.4 THz. This monolithic dual-DFB PIC-based THz generation approach is a significant step towards fully integrated, cost-effective, and energy-efficient THz transmitters.

Orbital-free density functional theory (OF-DFT) is an electronic structure method with a low computational cost that scales linearly with the number of simulated atoms, making it suitable for large-scale material simulations. It is generally considered that OF-DFT strictly requires the use of local pseudopotentials, rather than orbital-dependent nonlocal pseudopotentials, for the calculation of electron-ion interaction energies, as no orbitals are available. This is unfortunate situation since the nonlocal pseudopotentials are known to give much better transferability and calculation accuracy than local ones. We report here the development of a theoretical scheme that allows the direct use of nonlocal pseudopotentials in OF-DFT. In this scheme, a nonlocal pseudopotential energy density functional is derived by the projection of nonlocal pseudopotential onto the non-interacting density matrix (instead of "orbitals") that can be approximated explicitly as a functional of electron density. Our development defies the belief that nonlocal pseudopotentials are not applicable to OF-DFT, leading to the creation for an alternate theoretical framework of OF-DFT that works superior to the traditional approach.

Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1L). SREK1L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1L/B-T signalling loop to accelerate the hepatocarcinogenesis.

μ-1,2-Peroxo-diferric intermediates (P) of non-heme diiron enzymes are proposed to convert upon protonation either to high-valent active species or to activated P' intermediates via hydroperoxo-diferric intermediates. Protonation of synthetic μ-1,2-peroxo model complexes occurred at the μ-oxo and not at the μ-1,2-peroxo bridge. Here we report a stable μ-1,2-peroxo complex {FeIII(μ-O)(μ-1,2-O2)FeIII} using a dinucleating ligand and study its reactivity. The reversible oxidation and protonation of the μ-1,2-peroxo-diferric complex provide μ-1,2-peroxo FeIVFeIII and μ-1,2-hydroperoxo-diferric species, respectively. Neither the oxidation nor the protonation induces a strong electrophilic reactivity. Hence, the observed intramolecular C-H hydroxylation of preorganized methyl groups of the parent μ-1,2-peroxo-diferric complex should occur via conversion to a more electrophilic high-valent species. The thorough characterization of these species provides structure-spectroscopy correlations allowing insights into the formation and reactivities of hydroperoxo intermediates in diiron enzymes and their conversion to activated P' or high-valent intermediates.

Engineering the microbial production of secondary metabolites is limited by the known reactions of correctly annotated enzymes. Therefore, the machine learning discovery of specialized enzymes offers great potential to expand the range of biosynthesis pathways. Benzylisoquinoline alkaloid production is a model example of metabolic engineering with potential to revolutionize the paradigm of sustainable biomanufacturing. Existing bacterial studies utilize a norlaudanosoline pathway, whereas plants contain a more stable norcoclaurine pathway, which is exploited in yeast. However, committed aromatic precursors are still produced using microbial enzymes that remain elusive in plants, and additional downstream missing links remain hidden within highly duplicated plant gene families. In the current study, machine learning is applied to predict and select plant missing link enzymes from homologous candidate sequences. Metabolomics-based characterization of the selected sequences reveals potential aromatic acetaldehyde synthases and phenylpyruvate decarboxylases in reconstructed plant gene-only benzylisoquinoline alkaloid pathways from tyrosine. Synergistic application of the aryl acetaldehyde producing enzymes results in enhanced benzylisoquinoline alkaloid production through hybrid norcoclaurine and norlaudanosoline pathways.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples (n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Coupling between molecules and vacuum photon fields inside an optical cavity has proven to be an effective way to engineer molecular properties, in particular reactivity. To ease the rationalization of cavity induced effects we introduce an ab initio method leading to the first fully consistent molecular orbital theory for quantum electrodynamics environments. Our framework is non-perturbative and explains modifications of the electronic structure due to the interaction with the photon field. In this work, we show that the newly developed orbital theory can be used to predict cavity induced modifications of molecular reactivity and pinpoint classes of systems with significant cavity effects. We also investigate electronic cavity-induced modifications of reaction mechanisms in vibrational strong coupling regimes.

The extraction of meaningful biological knowledge from high-throughput mass spectrometry data relies on limiting false discoveries to a manageable amount. For targeted approaches in metabolomics a main challenge is the detection of false positive metabolic features in the low signal-to-noise ranges of data-independent acquisition results and their filtering. Another factor is that the creation of assay libraries for data-independent acquisition analysis and the processing of extracted ion chromatograms have not been automated in metabolomics. Here we present a fully automated open-source workflow for high-throughput metabolomics that combines data-dependent and data-independent acquisition for library generation, analysis, and statistical validation, with rigorous control of the false-discovery rate while matching manual analysis regarding quantification accuracy. Using an experimentally specific data-dependent acquisition library based on reference substances allows for accurate identification of compounds and markers from data-independent acquisition data in low concentrations, facilitating biomarker quantification.

In recent years, increasing attention has been given to the potential supply risks of critical battery materials, such as cobalt, for electric mobility transitions. While battery technology and recycling advancement are two widely acknowledged strategies for addressing such supply risks, the extent to which they will relieve global and regional cobalt demand-supply imbalance remains poorly understood. Here, we address this gap by simulating historical (1998-2019) and future (2020-2050) global cobalt cycles covering both traditional and emerging end uses with regional resolution (China, the U.S., Japan, the EU, and the rest of the world). We show that cobalt-free batteries and recycling progress can indeed significantly alleviate long-term cobalt supply risks. However, the cobalt supply shortage appears inevitable in the short- to medium-term (during 2028-2033), even under the most technologically optimistic scenario. Our results reveal varying cobalt supply security levels by region and indicate the urgency of boosting primary cobalt supply to ensure global e-mobility ambitions.

Successful establishment of pregnancy requires adhesion of an embryo to the endometrium and subsequent invasion into the maternal tissue. Abnormalities in this critical process of implantation and placentation lead to many pregnancy complications. Here we present a microenigneered system to model a complex sequence of orchestrated multicellular events that plays an essential role in early pregnancy. Our implantation-on-a-chip is capable of reconstructing the three-dimensional structural organization of the maternal-fetal interface to model the invasion of specialized fetal extravillous trophoblasts into the maternal uterus. Using primary human cells isolated from clinical specimens, we demonstrate in vivo-like directional migration of extravillous trophoblasts towards a microengineered maternal vessel and their interactions with the endothelium necessary for vascular remodeling. Through parametric variation of the cellular microenvironment and proteomic analysis of microengineered tissues, we show the important role of decidualized stromal cells as a regulator of extravillous trophoblast migration. Furthermore, our study reveals previously unknown effects of pre-implantation maternal immune cells on extravillous trophoblast invasion. This work represents a significant advance in our ability to model early human pregnancy, and may enable the development of advanced in vitro platforms for basic and clinical research of human reproduction.

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.

A contribution of DNA methylation to defense against invading nucleic acids and maintenance of genome integrity is uncontested; however, our understanding of the extent of involvement of this epigenetic mark in genome-wide gene regulation and plant developmental control is incomplete. Here, we knock out all five known DNA methyltransferases in Arabidopsis, generating DNA methylation-free plants. This quintuple mutant exhibits a suite of developmental defects, unequivocally demonstrating that DNA methylation is essential for multiple aspects of plant development. We show that CG methylation and non-CG methylation are required for a plethora of biological processes, including pavement cell shape, endoreduplication, cell death, flowering, trichome morphology, vasculature and meristem development, and root cell fate determination. Moreover, we find that DNA methylation has a strong dose-dependent effect on gene expression and repression of transposable elements. Taken together, our results demonstrate that DNA methylation is dispensable for Arabidopsis survival but essential for the proper regulation of multiple biological processes.

The burial of organic carbon, which prevents its remineralization via oxygen-consuming processes, is considered one of the causes of Earth's oxygenation. Yet, higher levels of oxygen are thought to inhibit burial. Here we propose a resolution of this conundrum, wherein Earth's initial oxygenation is favored by oxidative metabolisms generating partially oxidized organic matter (POOM), increasing burial via interaction with minerals in sediments. First, we introduce the POOM hypothesis via a mathematical argument. Second, we reconstruct the evolutionary history of one key enzyme family, flavin-dependent Baeyer-Villiger monooxygenases, that generates POOM, and show the temporal consistency of its diversification with the Proterozoic and Phanerozoic atmospheric oxygenation. Finally, we propose that the expansion of oxidative metabolisms instigated a positive feedback, which was amplified by the chemical changes to minerals on Earth's surface. Collectively, these results suggest that Earth's oxygenation is an autocatalytic transition induced by a combination of biological innovations and geological changes.

Aluminum nanoclusters (Aln NCs), particularly Al13- (n = 13), exhibit superatomic behavior with interplay between electron shell closure and geometrical packing in an anionic state. To fabricate superatom (SA) assemblies, substrates decorated with organic molecules can facilitate the optimization of cluster-surface interactions, because the molecularly local interactions for SAs govern the electronic properties via molecular complexation. In this study, Aln NCs are soft-landed on organic substrates pre-deposited with n-type fullerene (C60) and p-type hexa-tert-butyl-hexa-peri-hexabenzocoronene (HB-HBC, C66H66), and the electronic states of Aln are characterized by X-ray photoelectron spectroscopy and chemical oxidative measurements. On the C60 substrate, Aln is fixed to be cationic but highly oxidative; however, on the HB-HBC substrate, they are stably fixed as anionic Aln- without any oxidations. The results reveal that the careful selection of organic molecules controls the design of assembled materials containing both Al13- and boron-doped B@Al12- SAs through optimizing the cluster-surface interactions.

Update of bioRxiv. 2021 Sep 06;:

Comment in Nat Commun. 2022 Mar 14;13(1):1302.

While the electrooxidative activation of carboxylic acids is an attractive synthetic methodology, the resulting transformations are generally limited to either homocoupling or further oxidation followed by solvent capture. These reactions require extensive electrolysis at high potentials, which ultimately renders the methodology incompatible with metal catalysts that could possibly provide new and complementary product distributions. This work establishes a proof-of-concept for a rare and synthetically-underutilized strategy for selective electrooxidation of carboxylic acids in the presence of oxidatively-sensitive catalysts that control reaction selectivity. We leverage the formation of self-adsorbed monolayers of carboxylate substrates at the anode to promote selective oxidation of the adsorbed carboxylate over a more easily-oxidized catalyst. Consequently, reactions operate at lower potentials, greater faradaic efficiencies, and improved catalyst compatibility over conventional approaches, which enables reactions to be performed with inexpensive Fe complexes that catalyze selective radical additions to olefins.

Copper-based materials can reliably convert carbon dioxide into multi-carbon products but they suffer from poor activity and product selectivity. The atomic structure-activity relationship of electrocatalysts for the selectivity is controversial due to the lacking of systemic multiple dimensions for operando condition study. Herein, we synthesized high-performance CO2RR catalyst comprising of CuO clusters supported on N-doped carbon nanosheets, which exhibited high C2+ products Faradaic efficiency of 73% including decent ethanol selectivity of 51% with a partial current density of 14.4 mA/cm-2 at -1.1 V vs. RHE. We evidenced catalyst restructuring and tracked the variation of the active states under reaction conditions, presenting the atomic structure-activity relationship of this catalyst. Operando XAS, XANES simulations and Quasi-in-situ XPS analyses identified a reversible potential-dependent transformation from dispersed CuO clusters to Cu2-CuN3 clusters which are the optimal sites. This cluster can't exist without the applied potential. The N-doping dispersed the reduced Cun clusters uniformly and maintained excellent stability and high activity with adjusting the charge distribution between the Cu atoms and N-doped carbon interface. By combining Operando FTIR and DFT calculations, it was recognized that the Cu2-CuN3 clusters displayed charge-asymmetric sites which were intensified by CH3* adsorbing, beneficial to the formation of the high-efficiency asymmetric ethanol.

Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on samples enriched for isolated OSs show that Bbs1 is required for BBSome-complex stability and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a role for Bbs1/BBSome in OS lipid homeostasis, suggesting a pathomechanism underlying retinal degeneration in BBS.

Single-site cocatalysts engineered on supports offer a cost-efficient pathway to utilize precious metals, yet improving the performance further with minimal catalyst loading is still highly desirable. Here we have conducted a photochemical reaction to stabilize ultralow Pt co-catalysts (0.26 wt%) onto the basal plane of hexagonal ZnIn2S4 nanosheets (PtSS-ZIS) to form a Pt-S3 protrusion tetrahedron coordination structure. Compared with the traditional defect-trapped Pt single-site counterparts, the protruding Pt single-sites on h-ZIS photocatalyst enhance the H2 evolution yield rate by a factor of 2.2, which could reach 17.5 mmol g-1 h-1 under visible light irradiation. Importantly, through simple drop-casting, a thin PtSS-ZIS film is prepared, and large amount of observable H2 bubbles are generated, providing great potential for practical solar-light-driven H2 production. The protruding single Pt atoms in PtSS-ZIS could inhibit the recombination of electron-hole pairs and cause a tip effect to optimize the adsorption/desorption behavior of H through effective proton mass transfer, which synergistically promote reaction thermodynamics and kinetics.

Solid-state microwave systems offer strong interactions for fast quantum logic and sensing but photons at telecom wavelength are the ideal choice for high-density low-loss quantum interconnects. A general-purpose interface that can make use of single photon effects requires < 1 input noise quanta, which has remained elusive due to either low efficiency or pump induced heating. Here we demonstrate coherent electro-optic modulation on nanosecond-timescales with only [Formula: see text] microwave input noise photons with a total bidirectional transduction efficiency of 8.7% (or up to 15% with [Formula: see text]), as required for near-term heralded quantum network protocols. The use of short and high-power optical pump pulses also enables near-unity cooperativity of the electro-optic interaction leading to an internal pure conversion efficiency of up to 99.5%. Together with the low mode occupancy this provides evidence for electro-optic laser cooling and vacuum amplification as predicted a decade ago.

Non-invasive visualization of dynamic molecular events in real-time via molecular imaging may enable the monitoring of cascade catalytic reactions in living systems, however effective imaging modalities and a robust catalytic reaction system are lacking. Here we utilize three-dimensional (3D) multispectral photoacoustic (PA) molecular imaging to monitor in vivo cascade catalytic therapy based on a dual enzyme-driven cyclic reaction platform. The system consists of a two-dimensional (2D) Pd-based nanozyme conjugated with glucose oxidase (GOx). The combination of nanozyme and GOx can induce the PA signal variation of endogenous molecules. Combined with the PA response of the nanozyme, we can simultaneously map the 3D PA signals of dynamic endogenous and exogenous molecules associated with the catalytic process, thus providing a real-time non-invasive visualization. We can also treat tumors under the navigation of the PA imaging. Therefore, our study demonstrates the imaging-guided potential of 3D multispectral PA imaging in feedback-looped cascade catalytic therapy.

During development, neural progenitors are temporally patterned to sequentially generate a variety of neural types. In Drosophila neural progenitors called neuroblasts, temporal patterning is regulated by cascades of Temporal Transcription Factors (TTFs). However, known TTFs were mostly identified through candidate approaches and may not be complete. In addition, many fundamental questions remain concerning the TTF cascade initiation, progression, and termination. In this work, we use single-cell RNA sequencing of Drosophila medulla neuroblasts of all ages to identify a list of previously unknown TTFs, and experimentally characterize their roles in temporal patterning and neuronal specification. Our study reveals a comprehensive temporal gene network that patterns medulla neuroblasts from start to end. Furthermore, the speed of the cascade progression is regulated by Lola transcription factors expressed in all medulla neuroblasts. Our comprehensive study of the medulla neuroblast temporal cascade illustrates mechanisms that may be conserved in the temporal patterning of neural progenitors.

The folding capacity of membrane and secretory proteins in the endoplasmic reticulum (ER) can be challenged by physiological and pathological perturbations, causing ER stress. If unresolved, this leads to cell death. We report a role for iRhom pseudoproteases in controlling apoptosis due to persistent ER stress. Loss of iRhoms causes cells to be resistant to ER stress-induced apoptosis. iRhom1 and iRhom2 interact with IP3 receptors, critical mediators of intracellular Ca2+ signalling, and regulate ER stress-induced transport of Ca2+ into mitochondria, a primary trigger of mitochondrial membrane depolarisation and cell death. iRhoms also bind to the anti-apoptotic regulator BCL-2, attenuating the inhibitory interaction between BCL-2 and IP3 receptors, which promotes ER Ca2+ release. The discovery of the participation of iRhoms in the control of ER stress-induced cell death further extends their potential pathological significance to include diseases dependent on protein misfolding and aggregation.

Erratum in Nat Commun. 2022 Mar 24;13(1):1694.

Author information: (1)Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. info@adrianatomic.com. (2)Peter Medawar Building for Pathogen Research, Nuffield Dept. of Clinical Medicine, University of Oxford, Oxford, UK. (3)Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (4)Nuffield Dept of Clinical Neuroscience, University of Oxford, Oxford, UK. (5)Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. (6)NIHR Oxford Biomedical Research Centre, Oxford, UK. (7)United Kingdom Health Security Agency, Porton Down, Wiltshire, England. (8)Department of Clinical Biochemistry, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (9)Jenner Institute, University of Oxford, Oxford, UK. (10)The Florey Institute for Host-Pathogen Interactions and Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK. (11)Big Data Institute, Nuffield Dept. of Population Health, University of Oxford, Oxford, UK. (12)Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK. (13)James & Lillian Martin Centre, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (14)Oxford University Medical School, Medical Sciences Division, University of Oxford, Oxford, UK. (15)Oxford Centre For Global Health Research, Nuffield Dept. of Clinical Medicine, University of Oxford, Oxford, UK. (16)Monogram Biosciences LabCorp, San Francisco, CA, USA. (17)Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (18)Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand. (19)HPRU in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. (20)Tropical and Infectious Disease Unit, Liverpool University Hospitals NHS Foundation Trust (a member of Liverpool Health Partners), Liverpool, UK. (21)Peter Medawar Building for Pathogen Research, Department of Paediatrics, University of Oxford, Oxford, UK. (22)Nuffield Department of Medicine, University of Oxford, Oxford, UK. (23)Radcliffe Department of Medicine, University of Oxford, Oxford, UK. (24)Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (25)Peter Medawar Building for Pathogen Research, Nuffield Dept. of Clinical Medicine, University of Oxford, Oxford, UK. ellie.barnes@ndm.ox.ac.uk. (26)Oxford University Hospitals NHS Foundation Trust, Oxford, UK. ellie.barnes@ndm.ox.ac.uk. (27)NIHR Oxford Biomedical Research Centre, Oxford, UK. ellie.barnes@ndm.ox.ac.uk. (28)Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. ellie.barnes@ndm.ox.ac.uk. (#)Contributed equally

Author information: (1)Institut de Biologie Computationnelle, Montpellier, France. (2)Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France. (3)SANOFI R&D, Translational Sciences, Chilly Mazarin, France. (4)LIRMM, Univ Montpellier, CNRS, Montpellier, France. (5)RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan. (6)RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama, Japan. (7)Artificial Intelligence Research Center, AIST, Tokyo, Japan. (8)Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan. (9)AIST-Waseda University CBBD-OIL, AIST, Tokyo, Japan. (10)Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. (11)Institut de Biologie Computationnelle, Montpellier, France. brehelin@lirmm.fr. (12)LIRMM, Univ Montpellier, CNRS, Montpellier, France. brehelin@lirmm.fr. (13)Institut de Biologie Computationnelle, Montpellier, France. charles.lecellier@igmm.cnrs.fr. (14)Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France. charles.lecellier@igmm.cnrs.fr. (15)LIRMM, Univ Montpellier, CNRS, Montpellier, France. charles.lecellier@igmm.cnrs.fr. (#)Contributed equally

The limitation of inert N2 molecules with their high dissociation energy has ignited research interests in probing other nitrogen-containing species for ammonia synthesis. Nitrate ions, as an alternative feedstock with high solubility and proton affinity, can be facilely dissociated for sustainable ammonia production. Here we report a nitrate to ammonia photosynthesis route (NO3-RR) catalyzed by subnanometric alkaline-earth oxide clusters. The catalyst exhibits a high ammonia photosynthesis rate of 11.97 mol gmetal-1 h-1 (89.79 mmol gcat-1 h-1) with nearly 100% selectivity. A total ammonia yield of 0.78 mmol within 72 h is achieved, which exhibits a significant advantage in the area of photocatalytic NO3-RR. The investigation of the molecular-level reaction mechanism reveals that the unique active interface between the subnanometric clusters and TiO2 substrate is beneficial for the nitrate activation and dissociation, contributing to efficient and selective nitrate reduction for ammonia production with low energy input. The practical application of NO3-RR route in simulated wastewater is developed, which demonstrates great potential for its industrial application. These findings are of general knowledge for the functional development of clusters-based catalysts and could open up a path in the exploitation of advanced ammonia synthesis routes with low energy consumption and carbon emission.

In the open ocean, calcium carbonates are mainly found in two mineral forms. Calcite, the least soluble, is widespread at the seafloor, while aragonite, the more soluble, is rarely preserved in marine sediments. Despite its greater solubility, research has shown that aragonite, whose contribution to global pelagic calcification could be at par with that of calcite, is able to reach the deep-ocean. If large quantities of aragonite settle and dissolve at the seafloor, this represents a large source of alkalinity that buffers the deep ocean and favours the preservation of less soluble calcite, acting as a deep-sea, carbonate version of galvanization. Here, we investigate the role of aragonite dissolution on the early diagenesis of calcite-rich sediments using a novel 3D, micrometric-scale reactive-transport model combined with 3D, X-ray tomography structures of natural aragonite and calcite shells. Results highlight the important role of diffusive transport in benthic calcium carbonate dissolution, in agreement with recent work. We show that, locally, aragonite fluxes to the seafloor could be sufficient to suppress calcite dissolution in the top layer of the seabed, possibly causing calcite recrystallization. As aragonite producers are particularly vulnerable to ocean acidification, the proposed galvanizing effect of aragonite could be weakened in the future, and calcite dissolution at the sediment-water interface will have to cover a greater share of CO2 neutralization.

The human hematopoietic stem cell harbors remarkable regenerative potential that can be harnessed therapeutically. During early development, hematopoietic stem cells in the fetal liver undergo active expansion while simultaneously retaining robust engraftment capacity, yet the underlying molecular program responsible for their efficient engraftment remains unclear. Here, we profile 26,407 fetal liver cells at both the transcriptional and protein level including ~7,000 highly enriched and functional fetal liver hematopoietic stem cells to establish a detailed molecular signature of engraftment potential. Integration of transcript and linked cell surface marker expression reveals a generalizable signature defining functional fetal liver hematopoietic stem cells and allows for the stratification of enrichment strategies with high translational potential. More precisely, our integrated analysis identifies CD201 (endothelial protein C receptor (EPCR), encoded by PROCR) as a marker that can specifically enrich for engraftment potential. This comprehensive, multi-modal profiling of engraftment capacity connects a critical biological function at a key developmental timepoint with its underlying molecular drivers. As such, it serves as a useful resource for the field and forms the basis for further biological exploration of strategies to retain the engraftment potential of hematopoietic stem cells ex vivo or induce this potential during in vitro hematopoietic stem cell generation.