Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The initial C.1.2 detection is associated with a high substitution rate, and includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 variants of concern or variants of interest. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta show high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2.

Assessing the timing of great megathrust earthquakes is together crucial for seismic hazard analysis and deemed impossible. Geodetic instrumentation of subduction zones has revealed unexpected deformation patterns at subduction segments adjacent to those that hosted recent mega-earthquakes: coastal sites move landward with faster velocities than before the earthquake. Here, we show observations from the largest and best-monitored megathrust earthquakes, and from a scaled analog model, to reveal that these events create coseismic and postseismic deformation patterns typical of a complete gear-like rotation about a vertical axis, hereafter called twisting. We find that such twisting alters the interseismic velocity field of adjacent subduction segments depending on the time since the last earthquake. Early interactions accelerate while late interactions decelerate local kinematics. This finding opens the possibility of using megathrust earthquakes, the characteristics of the twisting pattern, and the ensuing geodetic velocity changes, as a proxy for estimating the timing of the seismic cycle at unruptured segments along the margin.

Terrestrial evaporation (E) is a key climatic variable that is controlled by a plethora of environmental factors. The constraints that modulate the evaporation from plant leaves (or transpiration, Et) are particularly complex, yet are often assumed to interact linearly in global models due to our limited knowledge based on local studies. Here, we train deep learning algorithms using eddy covariance and sap flow data together with satellite observations, aiming to model transpiration stress (St), i.e., the reduction of Et from its theoretical maximum. Then, we embed the new St formulation within a process-based model of E to yield a global hybrid E model. In this hybrid model, the St formulation is bidirectionally coupled to the host model at daily timescales. Comparisons against in situ data and satellite-based proxies demonstrate an enhanced ability to estimate St and E globally. The proposed framework may be extended to improve the estimation of E in Earth System Models and enhance our understanding of this crucial climatic variable.

Molecularly thin, nanoporous thin films are of paramount importance in material sciences. Their use in a wide range of applications requires control over their chemical functionalities, which is difficult to achieve using current production methods. Here, the small polycyclic aromatic hydrocarbon decacyclene is used to form molecular thin films, without requiring covalent crosslinking of any kind. The 2.5 nm thin films are mechanically stable, able to be free-standing over micrometer distances, held together solely by supramolecular interactions. Using a combination of computational chemistry and microscopic imaging techniques, thin films are studied on both a molecular and microscopic scale. Their mechanical strength is quantified using AFM nanoindentation, showing their capability of withstanding a point load of 26 ± 9 nN, when freely spanning over a 1 μm aperture, with a corresponding Young's modulus of 6 ± 4 GPa. Our thin films constitute free-standing, non-covalent thin films based on a small PAH.

Assisted reproductive technology (ART) may affect fetal development through epigenetic mechanisms as the timing of ART procedures coincides with the extensive epigenetic remodeling occurring between fertilization and embryo implantation. However, it is unknown to what extent ART procedures alter the fetal epigenome. Underlying parental characteristics and subfertility may also play a role. Here we identify differences in cord blood DNA methylation, measured using the Illumina EPIC platform, between 962 ART conceived and 983 naturally conceived singleton newborns. We show that ART conceived newborns display widespread differences in DNA methylation, and overall less methylation across the genome. There were 607 genome-wide differentially methylated CpGs. We find differences in 176 known genes, including genes related to growth, neurodevelopment, and other health outcomes that have been associated with ART. Both fresh and frozen embryo transfer show DNA methylation differences. Associations persist after controlling for parents' DNA methylation, and are not explained by parental subfertility.

Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or "cancer-killing" viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.

Enhanced warming in the Arctic (Arctic amplification, AA) in the last decades has been linked to several factors including sea ice and the Atlantic Multidecadal Oscillation (AMO). However, how these factors contributed to AA variations in a long-term perspective remains unclear. By reconstructing a millennial AA index combining climate model simulations with recently available proxy data, this work determines the important influences of the AMO and anthropogenic greenhouse gas forcing on AA variations in the last millennium, leading to identification of a significant downward trend of AA on top of a sustained strong AMO modulation at the multidecadal scales. The decreased AA during the industrial era was strongly associated with the anthropogenic forcing, proving the emerging role of the forcing in reducing the AA strength.

Paramagnetic metallohost systems can bind guest molecules and find application as biomimetic catalysts. Due to the presence of the paramagnetic metal center, rigorous characterization of these systems by NMR spectroscopy can be very difficult. We report here that metallohost-guest systems can be studied by using the paramagnetic relaxation enhancement (PRE) effect. Manganese(III) porphyrin cage compounds are shown through their PRE to thread and bind viologen guests, including a polymeric one. The binding constants and dethreading activation parameters are lower than those of the metal-free porphyrin cage compounds, which is proposed to be a result of charge repulsion of the trivalent metal center and dicationic viologen guest. The threading rate of the manganese(III) porphyrin cage onto the polymer is more than 10 times faster than that of the non-metallated one, which is ascribed to initial binding of the cage to the polymer chain prior to threading, and to an entron effect.

As the simplest alkyne and an abundant chemical feedstock, acetylene is an ideal two-carbon building block. However, in contrast to substituted alkynes, catalytic methods to incorporate acetylene into fine chemicals are quite limited. Herein, we developed a photoredox-catalyzed synthetic protocol for diverse C2-linked molecules via a molecular glue strategy using gaseous acetylene under mild conditions. Initiated by addition of an acyl radical to acetylene, two cascade transformations follow. One involves a double addition for the formation of 1,4-diketones and the other where the intermediate vinyl ketone is intercepted by a radical formed from a heterocycle. In addition to making two new C-C bonds, two C-H bonds are also created in two mechanistically distinct ways: one via a C-H abstraction and the other via protonation. This system offers a reliable and safe way to incorporate gaseous acetylene into fine chemicals and expands the utility of acetylene in organic synthesis.

Electrochemical reduction of CO2 to multi-carbon fuels and chemical feedstocks is an appealing approach to mitigate excessive CO2 emissions. However, the reported catalysts always show either a low Faradaic efficiency of the C2+ product or poor long-term stability. Herein, we report a facile and scalable anodic corrosion method to synthesize oxygen-rich ultrathin CuO nanoplate arrays, which form Cu/Cu2O heterogeneous interfaces through self-evolution during electrocatalysis. The catalyst exhibits a high C2H4 Faradaic efficiency of 84.5%, stable electrolysis for ~55 h in a flow cell using a neutral KCl electrolyte, and a full-cell ethylene energy efficiency of 27.6% at 200 mA cm-2 in a membrane electrode assembly electrolyzer. Mechanism analyses reveal that the stable nanostructures, stable Cu/Cu2O interfaces, and enhanced adsorption of the *OCCOH intermediate preserve selective and prolonged C2H4 production. The robust and scalable produced catalyst coupled with mild electrolytic conditions facilitates the practical application of electrochemical CO2 reduction.

Photo- and thermo-activated reactions are dominant in Additive Manufacturing (AM) processes for polymerization or melting/deposition of polymers. However, ultrasound activated sonochemical reactions present a unique way to generate hotspots in cavitation bubbles with extraordinary high temperature and pressure along with high heating and cooling rates which are out of reach for the current AM technologies. Here, we demonstrate 3D printing of structures using acoustic cavitation produced directly by focused ultrasound which creates sonochemical reactions in highly localized cavitation regions. Complex geometries with zero to varying porosities and 280 μm feature size are printed by our method, Direct Sound Printing (DSP), in a heat curing thermoset, Poly(dimethylsiloxane) that cannot be printed directly so far by any method. Sonochemiluminescnce, high speed imaging and process characterization experiments of DSP and potential applications such as remote distance printing are presented. Our method establishes an alternative route in AM using ultrasound as the energy source.

The human parasite Plasmodium malariae has relatives infecting African apes (Plasmodium rodhaini) and New World monkeys (Plasmodium brasilianum), but its origins remain unknown. Using a novel approach to characterise P. malariae-related sequences in wild and captive African apes, we found that this group comprises three distinct lineages, one of which represents a previously unknown, highly divergent species infecting chimpanzees, bonobos and gorillas across central Africa. A second ape-derived lineage is much more closely related to the third, human-infective lineage P. malariae, but exhibits little evidence of genetic exchange with it, and so likely represents a separate species. Moreover, the levels and nature of genetic polymorphisms in P. malariae indicate that it resulted from the zoonotic transmission of an African ape parasite, reminiscent of the origin of P. falciparum. In contrast, P. brasilianum falls within the radiation of human P. malariae, and thus reflects a recent anthroponosis.

Genetically-encoded biosensors based on a single fluorescent protein are widely used to visualize analyte levels or enzymatic activities in cells, though usually to monitor relative changes rather than absolute values. We report photochromism-enabled absolute quantification (PEAQ) biosensing, a method that leverages the photochromic properties of biosensors to provide an absolute measure of the analyte concentration or activity. We develop proof-of-concept photochromic variants of the popular GCaMP family of Ca2+ biosensors, and show that these can be used to resolve dynamic changes in the absolute Ca2+ concentration in live cells. We also develop intermittent quantification, a technique that combines absolute aquisitions with fast fluorescence acquisitions to deliver fast but fully quantitative measurements. We also show how the photochromism-based measurements can be expanded to situations where the absolute illumination intensities are unknown. In principle, PEAQ biosensing can be applied to other biosensors with photochromic properties, thereby expanding the possibilities for fully quantitative measurements in complex and dynamic systems.

About 10% of people infected by severe acute respiratory syndrome coronavirus 2 experience post COVID-19 disease. We analysed data from 968 adult patients (5350 person-months) with a confirmed infection enroled in the ComPaRe long COVID cohort, a disease prevalent prospective e-cohort of such patients in France. Day-by-day prevalence of post COVID-19 symptoms was determined from patients' responses to the Long COVID Symptom Tool, a validated self-reported questionnaire assessing 53 symptoms. Among patients symptomatic after 2 months, 85% still reported symptoms one year after their symptom onset. Evolution of symptoms showed a decreasing prevalence over time for 27/53 symptoms (e.g., loss of taste/smell); a stable prevalence over time for 18/53 symptoms (e.g., dyspnoea), and an increasing prevalence over time for 8/53 symptoms (e.g., paraesthesia). The disease impact on patients' lives began increasing 6 months after onset. Our results are of importance to understand the natural history of post COVID-19 disease.

Chirality is essential for various phenomena in life and matter. However, chirality and its switching in electronic superlattices, such as charge density wave (CDW) superlattices, remain elusive. In this study, we characterize the chirality switching with atom-resolution imaging in a single-layer NbSe2 CDW superlattice by the technique of scanning tunneling microscopy. The atomic arrangement of the CDW superlattice is found continuous and intact although its chirality is switched. Several intermediate states are tracked by time-resolved imaging, revealing the fast and dynamic chirality transition. Importantly, the switching is reversibly realized with an external electric field. Our findings unveil the delicate switching process of chiral CDW superlattice in a two-dimensional (2D) crystal down to the atomic scale.

Post-translational protein modifications by ubiquitin and ubiquitin-like modifiers regulate many major pathways in the cell. These modifications can be reversed by de-ubiquitinating enzymes such as ubiquitin-specific proteases (USPs). Proteolytic activity towards ubiquitin-modified substrates is common to all USP family members except for USPL1, which shows a unique preference for the ubiquitin-like modifier SUMO. Here, we present the crystal structure of USPL1 bound to SUMO2, defining the key structural elements for the unusual deSUMOylase activity of USPL1. We identify specific contacts between SUMO2 and the USPL1 subdomains, including a unique hydrogen bond network of the SUMO2 C-terminal tail. In addition, we find that USPL1 lacks major structural elements present in all canonical USPs members such as the so-called blocking loops, which facilitates SUMO binding. Our data give insight into how a structural protein scaffold designed to bind ubiquitin has evolved to bind SUMO, providing an example of divergent evolution in the USP family.

Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an "open" state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the "closed" state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.

BiP co-chaperones ERdj4, ERdj5, and GRP170 associate in cells with peptides predicted to be aggregation prone. Here, extending these findings to a full-length protein, we examine two Interstitial Lung Disease-associated mutants (ILD) of surfactant protein C (SP-C). The TANGO algorithm, which identifies sequences prone to formation of β strand aggregates, found three such regions in SP-C: the N-terminal transmembrane (TM) domain and two sites in the intermolecular chaperone BRICHOS domain. We show the ILD mutants disrupt di-sulfide bond formation in the BRICHOS domain and expose the aggregation-prone peptides leading to binding of ERdj4, ERdj5, and GRP170. The destabilized mutant BRICHOS domain fails to properly insert its TM region in the ER membrane, exposing part of the N-terminal TM domain site. Our studies with ILD-associated mutant proteins provide insights into the specificity of ERdj4, ERdj5, and GRP170, identify context-dependent differences in their binding, and reveal molecular consequences of disease-associated mutants on folding.

Author information: (1)The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. alexander.mentzer@ndm.ox.ac.uk. (2)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. alexander.mentzer@ndm.ox.ac.uk. (3)Division of Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (4)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. (5)UK Biobank, Stockport, UK. (6)Nuffield Department of Population Health, University of Oxford, Oxford, UK. (7)The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (8)MRC-Population Health Research Unit, University of Oxford, Oxford, UK. (9)The Jenner Institute, University of Oxford, Oxford, UK. (10)Division of Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. T.Waterboer@dkfz-heidelberg.de. (#)Contributed equally

Origami crease patterns have inspired the design of reconfigurable materials that can transform their shape and properties through folding. Unfortunately, most designs cannot provide load-bearing capacity, and those that can, do so in certain directions but collapse along the direction of deployment, limiting their use as structural materials. Here, we merge notions of kirigami and origami to introduce a rigidly foldable class of cellular metamaterials that can flat-fold and lock into several states that are stiff across multiple directions, including the deployment direction. Our metamaterials rigidly fold with one degree of freedom and can reconfigure into several flat-foldable and spatially-lockable folding paths due to face contact. Locking under compression yields topology and symmetry changes that impart multidirectional stiffness. Additionally, folding paths and mixed-mode configurations can be activated in situ to modulate their properties. Their load-bearing capacity, flat-foldability, and reprogrammability can be harnessed for deployable structures, reconfigurable robots, and low-volume packaging.

Microplastics accumulate in various aquatic organisms causing serious health issues, and have raised concerns about human health by entering our food chain. The recovery techniques for the most challenging colloidal fraction are limited, even for analytical purposes. Here we show how a hygroscopic nanocellulose network acts as an ideal capturing material even for the tiniest nanoplastic particles. We reveal that the entrapment of particles from aqueous environment is primarily a result of the network's hygroscopic nature - a feature which is further intensified with the high surface area of nanocellulose. We broaden the understanding of the mechanism for particle capture by investigating the influence of pH and ionic strength on the adsorption behaviour. We determine the nanoplastic binding mechanisms using surface sensitive methods, and interpret the results with the random sequential adsorption (RSA) model. These findings hold potential for the explicit quantification of the colloidal nano- and microplastics from different aqueous environments, and eventually, provide solutions to collect them directly on-site where they are produced.

Resonant elastic X-ray scattering (REXS) offers a unique tool to investigate solid-state systems providing spatial knowledge from diffraction combined with electronic information through the enhanced absorption process, allowing the probing of magnetic, charge, spin, and orbital degrees of spatial order together with electronic structure. A new promising application of REXS is to elucidate the chiral structure of electrical polarization emergent in a ferroelectric oxide superlattice in which the polarization vectors in the REXS amplitude are implicitly described through an anisotropic tensor corresponding to the quadrupole moment. Here, we present a detailed theoretical framework and analysis to quantitatively analyze the experimental results of Ti L-edge REXS of a polar vortex array formed in a PbTiO3/SrTiO3 superlattice. Based on this theoretical framework, REXS for polar chiral structures can become a useful tool similar to x-ray resonant magnetic scattering (XRMS), enabling a comprehensive study of both electric and magnetic REXS on the chiral structures.

Earth's forests face grave challenges in the Anthropocene, including hotter droughts increasingly associated with widespread forest die-off events. But despite the vital importance of forests to global ecosystem services, their fates in a warming world remain highly uncertain. Lacking is quantitative determination of commonality in climate anomalies associated with pulses of tree mortality-from published, field-documented mortality events-required for understanding the role of extreme climate events in overall global tree die-off patterns. Here we established a geo-referenced global database documenting climate-induced mortality events spanning all tree-supporting biomes and continents, from 154 peer-reviewed studies since 1970. Our analysis quantifies a global "hotter-drought fingerprint" from these tree-mortality sites-effectively a hotter and drier climate signal for tree mortality-across 675 locations encompassing 1,303 plots. Frequency of these observed mortality-year climate conditions strongly increases nonlinearly under projected warming. Our database also provides initial footing for further community-developed, quantitative, ground-based monitoring of global tree mortality.

The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.

The structural transformations of metal nanoclusters are typically quite complex processes involving the formation and breakage of several bonds, and thus are challenging to study. Herein, we report a case where two lacunary Keggin polyoxometallate templated silver single-pods [PW9O34@Ag51] (SD/Ag51b) fuse to a double-pod [(PW9O34)2@Ag72] by reacting with 4,4'-bipyridine (bipy) or 1,4-bis(4-pyridinylmethyl)piperazine (pi-bipy). Their crystal structures reveal the formation of a 2D 44-sql layer (SD/Ag72a) with bipy and a 3D pcu framework (SD/Ag72c) with pi-bipy. The PW9O349- retains its structure during the cluster fusion and cluster-based network formation. Although the two processes, stripping of an Ag-ligands interface followed by fusion, and polymerization, are difficult to envisage, electrospray ionization mass spectrometry provides enough evidences for such a proposal to be made. Through this example, we expect the structural transformation to become a powerful method for synthesizing silver nanoclusters and their infinite networks, and to evolve from trial-and-error to rational.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the generation of variants that may diminish host immune responses to vaccine formulations. Here we show a registered observational clinical trial (NCT04795414), we assess the safety and immunogenicity of the inactivated SARS-CoV-2 vaccine BBIBP-CorV in a cohort of 1006 vaccine recipients. No serious adverse events are observed during the term of the study. Detectable virus-specific antibody is measured and determined to be neutralizing in 698/760 (91.84%) vaccine recipients on day 28 post second vaccine dose and in 220/581 (37.87%) vaccine recipients on day 180 post second vaccine dose, whereas vaccine-elicited sera show varying degrees of reduction in neutralization against a range of key SARS-CoV-2 variants, including variant Alpha, Beta, Gamma, Iota, and Delta. Our work show diminished neutralization potency against multiple variants in vaccine-elicited sera, which indicates the potential need for additional boost vaccinations.

Static stripe order is detrimental to superconductivity. Yet, it has been proposed that transverse stripe fluctuations may enhance the inter-stripe Josephson coupling and thus promote superconductivity. Direct experimental studies of stripe dynamics, however, remain difficult. From a strong-coupling perspective, transverse stripe fluctuations are realized in the form of dynamic "kinks"-sideways shifting stripe sections. Here, we show how modest uniaxial pressure tuning reorganizes directional kink alignment. Our starting point is La1.88Sr0.12CuO4 where transverse kink ordering results in a rotation of stripe order away from the crystal axis. Application of mild uniaxial pressure changes the ordering pattern and pins the stripe order to the crystal axis. This reordering occurs at a much weaker pressure than that to detwin the stripe domains and suggests a rather weak transverse stripe stiffness. Weak spatial stiffness and transverse quantum fluctuations are likely key prerequisites for stripes to coexist with superconductivity.

Hydroxycinnamic acids present in plant cuticles, the interphase and the main protective barrier between the plant and the environment, exhibit singular photochemical properties that could allow them to act as a UV shield. Here, we employ transient absorption spectroscopy on isolated cuticles and leaf epidermises to study in situ the photodynamics of these molecules in the excited state. Based on quantum chemical calculations on p-coumaric acid, the main phenolic acid present in the cuticle, we propose a model in which cuticle phenolics display a photoprotective mechanism based in an ultrafast and non-radiative excited state deactivation combined with fluorescence emission. As such, the cuticle can be regarded as the first and foremost protective barrier against UV radiation. This photostable and photodynamic mechanism seems to be universal in land plants giving a special role and function to the presence of different aromatic domains in plant cuticles and epidermises.

Despite the recent clinical success of T cell checkpoint inhibition targeting the CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance to therapy. In some cases, poor responses to checkpoint blockade have been linked to suboptimal CD28 costimulation and the inability to generate and maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution to engineer a CD80 IgV domain with increased PD-L1 affinity and fuse this to an immunoglobulin Fc domain, creating a therapeutic (ALPN-202, davoceticept) capable of providing CD28 costimulation in a PD-L1-dependent fashion while also antagonizing PD-1 - PD-L1 and CTLA-4-CD80/CD86 interactions. We demonstrate that by combining CD28 costimulation and dual checkpoint inhibition, ALPN-202 enhances T cell activation and anti-tumor efficacy in cell-based assays and mouse tumor models more potently than checkpoint blockade alone and thus has the potential to generate potent, clinically meaningful anti-tumor immunity in humans.

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune "cold" ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC.

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.

Error-free replication of DNA is essential for life. Despite the proofreading capability of several polymerases, intrinsic polymerase fidelity is in general much higher than what base-pairing energies can provide. Although researchers have investigated this long-standing question with kinetics, structural determination, and computational simulations, the structural factors that dictate polymerase fidelity are not fully resolved. Time-resolved crystallography has elucidated correct nucleotide incorporation and established a three-metal-ion-dependent catalytic mechanism for polymerases. Using X-ray time-resolved crystallography, we visualize the complete DNA misincorporation process catalyzed by DNA polymerase η. The resulting molecular snapshots suggest primer 3´-OH alignment mediated by A-site metal ion binding is the key step in substrate discrimination. Moreover, we observe that C-site metal ion binding preceded the nucleotidyl transfer reaction and demonstrate that the C-site metal ion is strictly required for misincorporation. Our results highlight the essential but separate roles of the three metal ions in DNA synthesis.

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at multi-cellular pixel resolution, thereby hindering the identification of cell-type-specific spatial patterns and gene expression variation. To address this challenge, we develop STdeconvolve as a reference-free approach to deconvolve underlying cell types comprising such multi-cellular pixel resolution spatial transcriptomics (ST) datasets. Using simulated as well as real ST datasets from diverse spatial transcriptomics technologies comprising a variety of spatial resolutions such as Spatial Transcriptomics, 10X Visium, DBiT-seq, and Slide-seq, we show that STdeconvolve can effectively recover cell-type transcriptional profiles and their proportional representation within pixels without reliance on external single-cell transcriptomics references. STdeconvolve provides comparable performance to existing reference-based methods when suitable single-cell references are available, as well as potentially superior performance when suitable single-cell references are not available. STdeconvolve is available as an open-source R software package with the source code available at https://github.com/JEFworks-Lab/STdeconvolve .

We present a machine learning framework to automate knowledge discovery through knowledge graph construction, inconsistency resolution, and iterative link prediction. By incorporating knowledge from 10 publicly available sources, we construct an Escherichia coli antibiotic resistance knowledge graph with 651,758 triples from 23 triple types after resolving 236 sets of inconsistencies. Iteratively applying link prediction to this graph and wet-lab validation of the generated hypotheses reveal 15 antibiotic resistant E. coli genes, with 6 of them never associated with antibiotic resistance for any microbe. Iterative link prediction leads to a performance improvement and more findings. The probability of positive findings highly correlates with experimentally validated findings (R2 = 0.94). We also identify 5 homologs in Salmonella enterica that are all validated to confer resistance to antibiotics. This work demonstrates how evidence-driven decisions are a step toward automating knowledge discovery with high confidence and accelerated pace, thereby substituting traditional time-consuming and expensive methods.

Recently a zoology of non-collinear chiral spin textures has been discovered, most of which, such as skyrmions and antiskyrmions, have integer topological charges. Here we report the experimental real-space observation of the formation and stability of fractional antiskyrmions and fractional elliptical skyrmions in a Heusler material. These fractional objects appear, over a wide range of temperature and magnetic field, at the edges of a sample, whose interior is occupied by an array of nano-objects with integer topological charges, in agreement with our simulations. We explore the evolution of these objects in the presence of magnetic fields and show their interconversion to objects with integer topological charges. This means the topological charge can be varied continuously. These fractional spin textures are not just another type of skyrmion, but are essentially a new state of matter that emerges and lives only at the boundary of a magnetic system. The coexistence of both integer and fractionally charged spin textures in the same material makes the Heusler family of compounds unique for the manipulation of the real-space topology of spin textures and thus an exciting platform for spintronic and magnonic applications.

Wave breaking is the main mechanism that dissipates energy input into ocean waves by wind and transferred across the spectrum by nonlinearity. It determines the properties of a sea state and plays a crucial role in ocean-atmosphere interaction, ocean pollution, and rogue waves. Owing to its turbulent nature, wave breaking remains too computationally demanding to solve using direct numerical simulations except in simple, short-duration circumstances. To overcome this challenge, we present a blended machine learning framework in which a physics-based nonlinear evolution model for deep-water, non-breaking waves and a recurrent neural network are combined to predict the evolution of breaking waves. We use wave tank measurements rather than simulations to provide training data and use a long short-term memory neural network to apply a finite-domain correction to the evolution model. Our blended machine learning framework gives excellent predictions of breaking and its effects on wave evolution, including for external data.

Paenibacillus larvae, the causative agent of the devastating honey-bee disease American Foulbrood, produces the cationic polyketide-peptide hybrid paenilamicin that displays antibacterial and antifungal activity. Its biosynthetic gene cluster contains a gene coding for the N-acetyltransferase PamZ. We show that PamZ acts as self-resistance factor in Paenibacillus larvae by deactivation of paenilamicin. Using tandem mass spectrometry, nuclear magnetic resonance spectroscopy and synthetic diastereomers, we identified the N-terminal amino group of the agmatinamic acid as the N-acetylation site. These findings highlight the pharmacophore region of paenilamicin, which we very recently identified as a ribosome inhibitor. Here, we further determined the crystal structure of PamZ:acetyl-CoA complex at 1.34 Å resolution. An unusual tandem-domain architecture provides a well-defined substrate-binding groove decorated with negatively-charged residues to specifically attract the cationic paenilamicin. Our results will help to understand the mode of action of paenilamicin and its role in pathogenicity of Paenibacillus larvae to fight American Foulbrood.

Talin-induced integrin binding to extracellular matrix ligands (integrin activation) is the key step to trigger many fundamental cellular processes including cell adhesion, cell migration, and spreading. Talin is widely known to use its N-terminal head domain (talin-H) to bind and activate integrin, but how talin-H operates in the context of full-length talin and its surrounding remains unknown. Here we show that while being capable of inducing integrin activation, talin-H alone exhibits unexpectedly low potency versus a constitutively activated full-length talin. We find that the large C-terminal rod domain of talin (talin-R), which otherwise masks the integrin binding site on talin-H in inactive talin, dramatically enhances the talin-H potency by dimerizing activated talin and bridging it to the integrin co-activator kindlin-2 via the adaptor protein paxillin. These data provide crucial insight into the mechanism of talin and its cooperation with kindlin to promote potent integrin activation, cell adhesion, and signaling.

Organic semiconductors offer a tunable platform for photocatalysis, yet the more difficult exciton dissociation, compared to that in inorganic semiconductors, lowers their photocatalytic activities. In this work, we report that the charge carrier lifetime is dramatically prolonged by incorporating a suitable donor-acceptor (β-ketene-cyano) pair into a covalent organic framework nanosheet. These nanosheets show an apparent quantum efficiency up to 82.6% at 450 nm using platinum as co-catalyst for photocatalytic H2 evolution. Charge carrier kinetic analysis and femtosecond transient absorption spectroscopy characterizations verify that these modified covalent organic framework nanosheets have intrinsically lower exciton binding energies and longer-lived charge carriers than the corresponding nanosheets without the donor-acceptor unit. This work provides a model for gaining insight into the nature of short-lived active species in polymeric organic photocatalysts.

Electromechanical phonon-cavity systems are man-made micro-structures, in which vibrational energy can be coherently transferred between different degrees of freedom. In such devices, the energy transfer direction and coupling strength can be parametrically controlled, offering great opportunities for both fundamental studies and practical applications such as phonon manipulation and sensing. However, to date the investigation of such systems has largely been limited to linear vibrations, while their responses in the nonlinear regime remain yet to be explored. Here, we demonstrate nonlinear operation of electromechanical phonon-cavity systems, and show that the resonant response differs drastically from that in the linear regime. We further demonstrate that by controlling the parametric pump, one can achieve nonlinearity-mediated digitization and amplification in the frequency domain, which can be exploited to build high-performance MEMS sensing devices based on phonon-cavity systems. Our findings offer intriguing opportunities for creating frequency-shift-based sensors and transducers.

Approximately 10% of cystic fibrosis patients harbor nonsense mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which can generate nonsense codons in the CFTR mRNA and subsequently activate the nonsense-mediated decay (NMD) pathway resulting in rapid mRNA degradation. However, it is not known which NMD branches govern the decay of CFTR mRNAs containing nonsense codons. Here we utilize antisense oligonucleotides targeting NMD factors to evaluate the regulation of nonsense codon-containing CFTR mRNAs by the NMD pathway. We observe that CFTR mRNAs with nonsense codons G542X, R1162X, and W1282X, but not Y122X, require UPF2 and UPF3 for NMD. Furthermore, we demonstrate that all evaluated CFTR mRNAs harboring nonsense codons are degraded by the SMG6-mediated endonucleolytic pathway rather than the SMG5-SMG7-mediated exonucleolytic pathway. Finally, we show that upregulation of all evaluated CFTR mRNAs with nonsense codons by NMD pathway inhibition improves outcomes of translational readthrough therapy.

The electrochemical nitrate reduction reaction (NO3RR) to ammonia is an essential step toward restoring the globally disrupted nitrogen cycle. In search of highly efficient electrocatalysts, tailoring catalytic sites with ligand and strain effects in random alloys is a common approach but remains limited due to the ubiquitous energy-scaling relations. With interpretable machine learning, we unravel a mechanism of breaking adsorption-energy scaling relations through the site-specific Pauli repulsion interactions of the metal d-states with adsorbate frontier orbitals. The non-scaling behavior can be realized on (100)-type sites of ordered B2 intermetallics, in which the orbital overlap between the hollow *N and subsurface metal atoms is significant while the bridge-bidentate *NO3 is not directly affected. Among those intermetallics predicted, we synthesize monodisperse ordered B2 CuPd nanocubes that demonstrate high performance for NO3RR to ammonia with a Faradaic efficiency of 92.5% at -0.5 VRHE and a yield rate of 6.25 mol h-1 g-1 at -0.6 VRHE. This study provides machine-learned design rules besides the d-band center metrics, paving the path toward data-driven discovery of catalytic materials beyond linear scaling limitations.

We describe a precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 378 UC patients we map the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. With unsupervised clustering algorithms we group these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. The pathway analysis identifies calcium homeostasis, wound healing and cell motility as key processes in UC pathogenesis. Using transcriptomic data from an independent patient cohort, with three complementary validation approaches focusing on the SNP-affected genes, the patient specific modules and affected functions, we confirm the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, we propose a systems-level way to stratify patients.

The microscopic origins of emergent behaviours in condensed matter systems are encoded in their excitations. In ordinary magnetic materials, single spin-flips give rise to collective dipolar magnetic excitations called magnons. Likewise, multiple spin-flips can give rise to multipolar magnetic excitations in magnetic materials with spin S ≥ 1. Unfortunately, since most experimental probes are governed by dipolar selection rules, collective multipolar excitations have generally remained elusive. For instance, only dipolar magnetic excitations have been observed in isotropic S = 1 Haldane spin systems. Here, we unveil a hidden quadrupolar constituent of the spin dynamics in antiferromagnetic S = 1 Haldane chain material Y2BaNiO5 using Ni L3-edge resonant inelastic x-ray scattering. Our results demonstrate that pure quadrupolar magnetic excitations can be probed without direct interactions with dipolar excitations or anisotropic perturbations. Originating from on-site double spin-flip processes, the quadrupolar magnetic excitations in Y2BaNiO5 show a remarkable dual nature of collective dispersion. While one component propagates as non-interacting entities, the other behaves as a bound quadrupolar magnetic wave. This result highlights the rich and largely unexplored physics of higher-order magnetic excitations.

Patients with type 2 diabetes (T2D) are characterized by blunted immune responses, which are affected by glycaemic control. Whether glycaemic control influences the response to COVID-19 vaccines and the incidence of SARS-CoV-2 breakthrough infections is unknown. Here we show that poor glycaemic control, assessed as mean HbA1c in the post-vaccination period, is associated with lower immune responses and an increased incidence of SARS-CoV-2 breakthrough infections in T2D patients vaccinated with mRNA-BNT162b2. We report data from a prospective observational study enroling healthcare and educator workers with T2D receiving the mRNA-BNT162b2 vaccine in Campania (Italy) and followed for one year (5 visits, follow-up 346 ± 49 days) after one full vaccination cycle. Considering the 494 subjects completing the study, patients with good glycaemic control (HbA1c one-year mean < 7%) show a higher virus-neutralizing antibody capacity and a better CD4 + T/cytokine response, compared with those with poor control (HbA1c one-year mean ≥ 7%). The one-year mean of HbA1c is linearly associated with the incidence of breakthrough infections (Beta = 0.068; 95% confidence interval [CI], 0.032-0.103; p < 0.001). The comparison of patients with poor and good glycaemic control through Cox regression also show an increased risk for patients with poor control (adjusted hazard ratio [HR], 0.261; 95% CI, 0.097-0.700; p = 0.008). Among other factors, only smoking (HR = 0.290, CI 0.146-0.576 for non-smokers; p < 0.001) and sex (HR = 0.105, CI 0.035-0.317 for females; p < 0.001) are significantly associated with the incidence of breakthrough infections.

One of the greatest obstacles to the real application of solid-state refrigeration is the huge driving fields. Here, we report a giant barocaloric effect in inorganic NH4I with reversible entropy changes of [Formula: see text] ∼71 J K-1 kg-1 around room temperature, associated with a structural phase transition. The phase transition temperature, Tt, varies dramatically with pressure at a rate of dTt/dP ∼0.79 K MPa-1, which leads to a very small saturation driving pressure of ΔP ∼40 MPa, an extremely large barocaloric strength of [Formula: see text] ∼1.78 J K-1 kg-1 MPa-1, as well as a broad temperature span of ∼41 K under 80 MPa. Comprehensive characterizations of the crystal structures and atomic dynamics by neutron scattering reveal that a strong reorientation-vibration coupling is responsible for the large pressure sensitivity of Tt. This work is expected to advance the practical application of barocaloric refrigeration.

The emergence and spread of antimicrobial resistance (AMR) represent an ever-growing healthcare challenge worldwide. Nevertheless, the mechanisms and timescales shaping this resistome remain elusive. Using an antibiotic cocktail administered to a murine model along with a longitudinal sampling strategy, we identify the mechanisms by which gut commensals acquire antimicrobial resistance genes (ARGs) after a single antibiotic course. While most of the resident bacterial populations are depleted due to the treatment, Akkermansia muciniphila and members of the Enterobacteriaceae, Enterococcaceae, and Lactobacillaceae families acquire resistance and remain recalcitrant. We identify specific genes conferring resistance against the antibiotics in the corresponding metagenome-assembled genomes (MAGs) and trace their origins within each genome. Here we show that, while mobile genetic elements (MGEs), including bacteriophages and plasmids, contribute to the spread of ARGs, integrons represent key factors mediating AMR in the antibiotic-treated mice. Our findings suggest that a single course of antibiotics alone may act as the selective sweep driving ARG acquisition and incidence in gut commensals over a single mammalian lifespan.

The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR = 2.05 per change in body size category, 95% CI = 1.20 to 3.50, P = 0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR = 2.32, 95% CI = 1.21 to 4.42, P = 0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n = 15,573 cases and n = 158,408 controls (OR = 1.94, 95% CI = 1.21 to 3.12, P = 0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggested that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.

Hydrogen can be used as an anti-cancer treatment. However, the continuous generation of H2 molecules within the tumor is challenging. Magnesium (Mg) and its alloys have been extensively used in the clinic as implantable metals. Here we develop, by decorating platinum on the surface of Mg rods, a Mg-based galvanic cell (MgG), which allows the continuous generation of H2 in an aqueous environment due to galvanic-cell-accelerated water etching of Mg. By implanting MgG rods into a tumor, H2 molecules can be generated within the tumor, which induces mitochondrial dysfunction and intracellular redox homeostasis destruction. Meanwhile, the Mg(OH)2 residue can neutralize the acidic tumor microenvironment (TME). Such MgG rods with the micro-galvanic cell structure enable hydrogen therapy to inhibit the growth of tumors, including murine tumor models, patient-derived xenografts (PDX), as well as VX2 tumors in rabbits. Our research suggests that the galvanic cells for hydrogen therapy based on implantable metals may be a safe and effective cancer treatment.

The cerebral cortex receives multiple afferents from the thalamus that segregate by stimulus modality forming cortical maps for each sense. In vision, the primary visual cortex maps the multiple dimensions of the visual stimulus in patterns that vary across species for reasons unknown. Here we introduce a general theory of cortical map formation, which proposes that map diversity emerges from species variations in the thalamic afferent density sampling sensory space. In the theory, increasing afferent sampling density enlarges the cortical domains representing the same visual point, allowing the segregation of afferents and cortical targets by multiple stimulus dimensions. We illustrate the theory with an afferent-density model that accurately replicates the maps of different species through afferent segregation followed by thalamocortical convergence pruned by visual experience. Because thalamocortical pathways use similar mechanisms for axon segregation and pruning, the theory may extend to other sensory areas of the mammalian brain.

Bloodstream infections (BSIs) cause >500,000 infections and >80,000 deaths per year in North America. The length of time between the onset of symptoms and administration of appropriate antimicrobials is directly linked to mortality rates. It currently takes 2-5 days to identify BSI pathogens and measure their susceptibility to antimicrobials - a timeline that directly contributes to preventable deaths. To address this, we demonstrate a rapid metabolic preference assay (MPA) that uses the pattern of metabolic fluxes observed in ex-vivo microbial cultures to identify common pathogens and determine their antimicrobial susceptibility profiles. In a head-to-head race with a leading platform (VITEK 2, BioMérieux) used in diagnostic laboratories, MPA decreases testing timelines from 40 hours to under 20. If put into practice, this assay could reduce septic shock mortality and reduce the use of broad spectrum antibiotics.

Evanescent illumination has been widely used to detect single biological macromolecules because it can notably enhance light-analyte interaction. However, the current evanescent single-molecule detection system usually requires specially designed microspheres or nanomaterials. Here we show that single protein detection and imaging can be realized on a plain glass surface by imaging the interference between the evanescent lights scattered by the single proteins and by the natural roughness of the cover glass. This allows us to quantify the sizes of single proteins, characterize the protein-antibody interactions at the single-molecule level, and analyze the heterogeneity of single protein binding behaviors. In addition, owing to the exponential distribution of evanescent field intensity, the evanescent imaging system can track the analyte axial movement with high resolution, which can be used to analyze the DNA conformation changes, providing one solution for detecting small molecules, such as microRNA. This work demonstrates a label-free single protein imaging method with ordinary consumables and may pave a road for detecting small biological molecules.

Rotational motion lies at the heart of intermolecular, molecule-surface chemistry and cold molecule science, motivating the development of methods to excite and de-excite rotations. Existing schemes involve perturbing the molecules with photons or electrons which supply or remove energy comparable to the rotational level spacing. Here, we study the possibility of de-exciting the molecular rotation of a D2 molecule, from J = 2 to the non-rotating J = 0 state, without using an energy-matched perturbation. We show that passing the beam through a 1 m long magnetic field, which splits the rotational projection states by only 10-12 eV, can change the probability that a molecule-surface collision will stop a molecule from rotating and lose rotational energy which is 9 orders larger than that of the magnetic manipulation. Calculations confirm that different rotational orientations have different de-excitation probabilities but underestimate rotational flips (∆mJ[Formula: see text]0), highlighting the importance of the results as a sensitive benchmark for further developing theoretical models of molecule-surface interactions.

The 2-dimensional layered oxide material SrCu2(BO3)2, long studied as a realization of the Shastry-Sutherland spin topology, exhibits a range of intriguing physics as a function of both hydrostatic pressure and magnetic field, with a still debated intermediate plaquette phase appearing at approximately 20 kbar and a possible deconfined critical point at higher pressure. Here, we employ a tunnel diode oscillator (TDO) technique to probe the behavior in the combined extreme conditions of high pressure, high magnetic field, and low temperature. We reveal an extensive phase space consisting of multiple magnetic analogs of the elusive supersolid phase and a magnetization plateau. In particular, a 10 × 2 supersolid and a 1/5 plateau, identified by infinite Projected Entangled Pair States (iPEPS) calculations, are found to rely on the presence of both magnetic and non-magnetic particles in the sea of dimer singlets. These states are best understood as descendants of the full-plaquette phase, the leading candidate for the intermediate phase of SrCu2(BO3)2.

Elastic organic crystals are the materials foundation of future lightweight flexible electronic, optical and sensing devices, yet precise control over their deformation has not been accomplished. Here, we report a general non-destructive approach to remote bending of organic crystals. Flexible organic crystals are coupled to magnetic nanoparticles to prepare hybrid actuating elements whose shape can be arbitrarily and precisely controlled simply by using magnetic field. The crystals are mechanically and chemically robust, and can be flexed precisely to a predetermined curvature with complete retention of their macroscopic integrity at least several thousand times in contactless mode, in air or in a liquid medium. These crystals are used as optical waveguides whose light output can be precisely and remotely controlled by using a permanent magnet. This approach expands the range of applications of flexible organic crystals beyond the known limitations with other methods for control of their shape, and opens prospects for their direct implementation in flexible devices such as sensors, emitters, and other (opto)electronics.

Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5' end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3' end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging.

Transient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2. Additionally, electrophysiological experiments show that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation, and cryo-EM structures demonstrate that both drugs were able to bind simultaneously. Together, our cryo-EM structures represent multiple functional states of the channel, providing a native picture of TRPV2 activation by small molecules and a structural framework for the development of TRPV2-specific activators.

The COVID-19 pandemic has highlighted the importance of understanding and managing information seeking behavior. Information-seeking in humans is often viewed as irrational rather than utility maximizing. Here, we hypothesized that this apparent disconnect between utility and information-seeking is due to a latent third variable, motivation. We quantified information-seeking, learning, and COVID-19-related concern (which we used as a proxy for motivation regarding COVID-19 and the changes in circumstance it caused) in a US-based sample (n = 5376) during spring 2020. We found that self-reported levels of COVID-19 concern were associated with directed seeking of COVID-19-related content and better memory for such information. Interestingly, this specific motivational state was also associated with a general enhancement of information-seeking for content unrelated to COVID-19. These effects were associated with commensurate changes to utility expectations and were dissociable from the influence of non-specific anxiety. Thus, motivation both directs and energizes epistemic behavior, linking together utility and curiosity.

In the developing mouse forebrain, temporally distinct waves of oligodendrocyte progenitor cells (OPCs) arise from different germinal zones and eventually populate either dorsal or ventral regions, where they present as transcriptionally and functionally equivalent cells. Despite that, developmental heterogeneity influences adult OPC responses upon demyelination. Here we show that accumulation of DNA damage due to ablation of citron-kinase or cisplatin treatment cell-autonomously disrupts OPC fate, resulting in cell death and senescence in the dorsal and ventral subsets, respectively. Such alternative fates are associated with distinct developmental origins of OPCs, and with a different activation of NRF2-mediated anti-oxidant responses. These data indicate that, upon injury, dorsal and ventral OPC subsets show functional and molecular diversity that can make them differentially vulnerable to pathological conditions associated with DNA damage.

Understanding the hybrid charge-storage mechanisms of pseudocapacitive nanomaterials holds promising keys to further improve the performance of energy storage devices. Based on the dependence of the light scattering intensity of single Prussian blue nanoparticles (PBNPs) on their oxidation state during sinusoidal potential modulation at varying frequencies, we present an electro-optical microscopic imaging approach to optically acquire the Faradaic electrochemical impedance spectroscopy (oEIS) of single PBNPs. Here we reveal typical pseudocapacitive behavior with hybrid charge-storage mechanisms depending on the modulation frequency. In the low-frequency range, the optical amplitude is inversely proportional to the square root of the frequency (∆I ∝ f-0.5; diffusion-limited process), while in the high-frequency range, it is inversely proportional to the frequency (∆I ∝ f-1; surface charging process). Because the geometry of single cuboid-shaped PBNPs can be precisely determined by scanning electron microscopy and atomic force microscopy, oEIS of single PBNPs allows the determination of the depth of the surface charging layer, revealing it to be ~2 unit cells regardless of the nanoparticle size.

This paper describes the fabrication of digital logic circuits comprising resistors and diodes made from protein complexes and wired together using printed liquid metal electrodes. These resistors and diodes exhibit temperature-independent charge-transport over a distance of approximately 10 nm and require no encapsulation or special handling. The function of the protein complexes is determined entirely by self-assembly. When induced to self-assembly into anisotropic monolayers, the collective action of the aligned dipole moments increases the electrical conductivity of the ensemble in one direction and decreases it in the other. When induced to self-assemble into isotropic monolayers, the dipole moments are randomized and the electrical conductivity is approximately equal in both directions. We demonstrate the robustness and utility of these all-protein logic circuits by constructing pulse modulators based on AND and OR logic gates that function nearly identically to simulated circuits. These results show that digital circuits with useful functionality can be derived from readily obtainable biomolecules using simple, straightforward fabrication techniques that exploit molecular self-assembly, realizing one of the primary goals of molecular electronics.

During embryonic development, epithelial cell blocks called somites are periodically formed according to the segmentation clock, becoming the foundation for the segmental pattern of the vertebral column. The process of somitogenesis has recently been recapitulated with murine and human pluripotent stem cells. However, an in vitro model for human somitogenesis coupled with the segmentation clock and epithelialization is still missing. Here, we report the generation of human somitoids, organoids that periodically form pairs of epithelial somite-like structures. Somitoids display clear oscillations of the segmentation clock that coincide with the segmentation of the presomitic mesoderm. The resulting somites show anterior-posterior and apical-basal polarities. Matrigel is essential for epithelialization but dispensable for the differentiation into somite cells. The size of somites is rather constant, irrespective of the initial cell number. The amount of WNT signaling instructs the proportion of mesodermal lineages in somitoids. Somitoids provide a novel platform to study human somitogenesis.

Controlled transport of biomolecules across lipid bilayer membranes is of profound significance in biological processes. In cells, cargo exchange is mediated by dedicated channels that respond to triggers, undergo a nanomechanical change to reversibly open, and thus regulate cargo flux. Replicating these processes with simple yet programmable chemical means is of fundamental scientific interest. Artificial systems that go beyond nature's remit in transport control and cargo are also of considerable interest for biotechnological applications but challenging to build. Here, we describe a synthetic channel that allows precisely timed, stimulus-controlled transport of folded and functional proteins across bilayer membranes. The channel is made via DNA nanotechnology design principles and features a 416 nm2 opening cross-section and a nanomechanical lid which can be controllably closed and re-opened via a lock-and-key mechanism. We envision that the functional DNA device may be used in highly sensitive biosensing, drug delivery of proteins, and the creation of artificial cell networks.

Metagenomic binning is the step in building metagenome-assembled genomes (MAGs) when sequences predicted to originate from the same genome are automatically grouped together. The most widely-used methods for binning are reference-independent, operating de novo and enable the recovery of genomes from previously unsampled clades. However, they do not leverage the knowledge in existing databases. Here, we introduce SemiBin, an open source tool that uses deep siamese neural networks to implement a semi-supervised approach, i.e. SemiBin exploits the information in reference genomes, while retaining the capability of reconstructing high-quality bins that are outside the reference dataset. Using simulated and real microbiome datasets from several different habitats from GMGCv1 (Global Microbial Gene Catalog), including the human gut, non-human guts, and environmental habitats (ocean and soil), we show that SemiBin outperforms existing state-of-the-art binning methods. In particular, compared to other methods, SemiBin returns more high-quality bins with larger taxonomic diversity, including more distinct genera and species.

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett's esophagus compared to 40 Barrett's patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett's tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett's versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett's esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.

Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Hematopoietic stem cells can be distinguished from LSCs by an array of cell surface antigens such as CD123, thus a candidate to eliminate LSCs using a variety of approaches, including CAR T cells. Here, we evaluate the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123). UCART123 cells are TCRαβneg T cells generated from healthy donors using TALEN® gene-editing technology, decreasing the likelihood of graft vs host disease. As safety feature, cells express RQR8 to allow elimination with Rituximab. UCART123 effectively eliminates AML cells in vitro and in vivo with significant benefits in overall survival of AML-patient derived xenograft mice. Furthermore, UCART123 preferentially target AML over normal cells with modest toxicity to normal hematopoietic stem/progenitor cells. Together these results suggest that UCART123 represents an off-the shelf therapeutic approach for AML.

Development of regulated cellular processes and signaling methods in synthetic cells is essential for their integration with living materials. Light is an attractive tool to achieve this, but the limited penetration depth into tissue of visible light restricts its usability for in-vivo applications. Here, we describe the design and implementation of bioluminescent intercellular and intracellular signaling mechanisms in synthetic cells, dismissing the need for an external light source. First, we engineer light generating SCs with an optimized lipid membrane and internal composition, to maximize luciferase expression levels and enable high-intensity emission. Next, we show these cells' capacity to trigger bioprocesses in natural cells by initiating asexual sporulation of dark-grown mycelial cells of the fungus Trichoderma atroviride. Finally, we demonstrate regulated transcription and membrane recruitment in synthetic cells using bioluminescent intracellular signaling with self-activating fusion proteins. These functionalities pave the way for deploying synthetic cells as embeddable microscale light sources that are capable of controlling engineered processes inside tissues.

Native mass spectrometry (MS) is increasingly used to provide complementary data to electron microscopy (EM) for protein structure characterization. Beyond the ability to provide mass measurements of gas-phase biomolecular ions, MS instruments offer the ability to purify, select, and precisely control the spatial location of these ions. Here we present a modified Orbitrap MS system capable of depositing a native MS ion beam onto EM grids. We further describe the use of a chemical landing matrix that preserves the structural integrity of the deposited particles. With this system we obtain a three-dimensional reconstruction of the 800 kDa protein complex GroEL from gas-phase deposited GroEL ions. These data provide direct evidence that non-covalent protein complexes can indeed retain their condensed-phase structures following ionization and vaporization. Finally, we describe how further developments of this technology could pave the way to an integrated MS-EM technology with promise to provide improved cryo-EM sample preparation over conventional plunge-freezing techniques.

Maintenance of bacterial cell shape and resistance to osmotic stress by the peptidoglycan (PG) renders PG biosynthetic enzymes and precursors attractive targets for combating bacterial infections. Here, by applying native mass spectrometry, we elucidate the effects of lipid substrates on the PG membrane enzymes MraY, MurG, and MurJ. We show that dimerization of MraY is coupled with binding of the carrier lipid substrate undecaprenyl phosphate (C55-P). Further, we demonstrate the use of native MS for biosynthetic reaction monitoring and find that the passage of substrates and products is controlled by the relative binding affinities of the different membrane enzymes. Overall, we provide a molecular view of how PG membrane enzymes convey lipid precursors through favourable binding events and highlight possible opportunities for intervention.

Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and differentiation toward neuroendocrine lineage. Here, we find that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identify the proneuronal transcription factor ASCL1 motif to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 through UHRF1/AMPK axis and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPIs, governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs.

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (αS) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of αS aggregation. However, the bottleneck towards achieving this goal is the identification of αS domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified αS sequences-based targets that are essential for aggregation and will have significant therapeutic implications. An extensive array of in vitro, ex vivo, and in vivo assays is utilized to validate αS sequences and their structural characteristics that are essential for aggregation and propagation of PD phenotypes. The study aids in developing significant mechanistic and therapeutic insights into various facets of αS aggregation, which will pave the way for effective treatments for PD.

A long-standing crucial question with atomic nuclei is whether or not α clustering occurs there. An α particle (helium-4 nucleus) comprises two protons and two neutrons, and may be the building block of some nuclei. This is a very beautiful and fascinating idea, and is indeed plausible because the α particle is particularly stable with a large binding energy. However, direct experimental evidence has never been provided. Here, we show whether and how α(-like) objects emerge in atomic nuclei, by means of state-of-the-art quantum many-body simulations formulated from first principles, utilizing supercomputers including K/Fugaku. The obtained physical quantities exhibit agreement with experimental data. The appearance and variation of the α clustering are shown by utilizing density profiles for the nuclei beryllium-8, -10 and carbon-12. With additional insight by statistical learning, an unexpected crossover picture is presented for the Hoyle state, a critical gateway to the birth of life.

Ligaments are flexible and stiff tissues around joints to support body movements, showing superior toughness and fatigue-resistance. Such a combination of mechanical properties is rarely seen in synthetic elastomers because stretchability, stiffness, toughness, and fatigue resistance are seemingly incompatible in materials design. Here we resolve this long-standing mismatch through a hierarchical crosslinking design. The obtained elastomer can endure 30,000% stretch and exhibit a Young's modulus of 18 MPa and toughness of 228 MJ m-3, outperforming all the reported synthetic elastomers. Furthermore, the fatigue threshold is as high as 2,682 J m-2, the same order of magnitude as the ligaments (~1,000 J m-2). We reveal that the dynamic double-crosslinking network composed of Li+-O interactions and PMMA nanoaggregates allows for a hierarchical energy dissipation, enabling the elastomers as artificial ligaments in soft robotics.

In colonies of the filamentous multicellular bacterium Streptomyces coelicolor, a subpopulation of cells arises that hyperproduces metabolically costly antibiotics, resulting in a division of labor that increases colony fitness. Because these cells contain large genomic deletions that cause massive reductions to individual fitness, their behavior is similar to altruistic worker castes in social insects or somatic cells in multicellular organisms. To understand these mutant cells' reproductive and genomic fate after their emergence, we use experimental evolution by serially transferring populations via spore-to-spore transfer for 25 cycles, reflective of the natural mode of bottlenecked transmission for these spore-forming bacteria. We show that in contrast to wild-type cells, putatively altruistic mutant cells continue to decline in fitness during transfer while they lose more fragments from their chromosome ends. In addition, the base-substitution rate in mutants increases roughly 10-fold, possibly due to mutations in genes for DNA replication and repair. Ecological damage, caused by reduced sporulation, coupled with DNA damage due to point mutations and deletions, leads to an inevitable and irreversible type of mutational meltdown in these cells. Taken together, these results suggest the cells arising in the S. coelicolor division of labor are analogous to altruistic reproductively sterile castes of social insects.

The "marine ice-sheet instability" hypothesis continues to be used to interpret the observed mass loss from the Antarctic and Greenland ice sheets. This hypothesis has been developed for conditions that do not account for feedbacks between ice sheets and environmental conditions. However, snow accumulation and the ice-sheet surface melting depend on the surface temperature, which is a strong function of elevation. Consequently, there is a feedback between precipitation, atmospheric surface temperature and ice-sheet surface elevation. Here, we investigate stability conditions of a marine-based ice sheet in the presence of such a feedback. Our results show that no general stability condition similar to one associated with the "marine ice-sheet instability" hypothesis can be determined. Stability of individual configurations can be established only on a case-by-case basis. These results apply to a wide range of feedbacks between marine ice sheets and atmosphere, ocean and lithosphere.

Class B1 of G protein-coupled receptors (GPCRs) comprises 15 members activated by physiologically important peptide hormones. Among them, vasoactive intestinal polypeptide receptor 2 (VIP2R) is expressed in the central and peripheral nervous systems and involved in a number of pathophysiological conditions, including pulmonary arterial hypertension, autoimmune and psychiatric disorders, in which it is thus a valuable drug target. Here, we report the cryo-electron microscopy structure of the human VIP2R bound to its endogenous ligand PACAP27 and the stimulatory G protein. Different from all reported peptide-bound class B1 GPCR structures, the N-terminal α-helix of VIP2R adopts a unique conformation that deeply inserts into a cleft between PACAP27 and the extracellular loop 1, thereby stabilizing the peptide-receptor interface. Its truncation or extension significantly decreased VIP2R-mediated cAMP accumulation. Our results provide additional information on peptide recognition and receptor activation among class B1 GPCRs and may facilitate the design of better therapeutics.

Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying and exploiting these pockets remains challenging. Here, we apply a general pipeline for identifying cryptic pockets to the interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola's replication cycle but lacks pockets that present obvious utility for drug design. Using adaptive sampling simulations and machine learning algorithms, we predict VP35 harbors a cryptic pocket that is allosterically coupled to a key dsRNA-binding interface. Thiol labeling experiments corroborate the predicted pocket and mutating the predicted allosteric network supports our model of allostery. Finally, covalent modifications that mimic drug binding allosterically disrupt dsRNA binding that is essential for immune evasion. Based on these results, we expect this pipeline will be applicable to other proteins.

Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

Photosystem II is crucial for life on Earth as it provides oxygen as a result of photoinduced electron transfer and water splitting reactions. The excited state dynamics of the photosystem II-reaction center (PSII-RC) has been a matter of vivid debate because the absorption spectra of the embedded chromophores significantly overlap and hence it is extremely difficult to distinguish transients. Here, we report the two-dimensional electronic-vibrational spectroscopic study of the PSII-RC. The simultaneous resolution along both the visible excitation and infrared detection axis is crucial in allowing for the character of the excitonic states and interplay between them to be clearly distinguished. In particular, this work demonstrates that the mixed exciton-charge transfer state, previously proposed to be responsible for the far-red light operation of photosynthesis, is characterized by the ChlD1+Phe radical pair and can be directly prepared upon photoexcitation. Further, we find that the initial electron acceptor in the PSII-RC is Phe, rather than PD1, regardless of excitation wavelength.

There is growing evidence for the importance of 3' untranslated region (3'UTR) dependent regulatory processes. However, our current human 3'UTR catalogue is incomplete. Here, we develop a machine learning-based framework, leveraging both genomic and tissue-specific transcriptomic features to predict previously unannotated 3'UTRs. We identify unannotated 3'UTRs associated with 1,563 genes across 39 human tissues, with the greatest abundance found in the brain. These unannotated 3'UTRs are significantly enriched for RNA binding protein (RBP) motifs and exhibit high human lineage-specificity. We find that brain-specific unannotated 3'UTRs are enriched for the binding motifs of important neuronal RBPs such as TARDBP and RBFOX1, and their associated genes are involved in synaptic function. Our data is shared through an online resource F3UTER ( https://astx.shinyapps.io/F3UTER/ ). Overall, our data improves 3'UTR annotation and provides additional insights into the mRNA-RBP interactome in the human brain, with implications for our understanding of neurological and neurodevelopmental diseases.

Dozens of families of asteroids in the asteroid belt have similar orbits and compositions because they formed through a collision. However, the icy debris beyond the orbit of Neptune, called the Kuiper Belt, contains only one known family, the Haumea family. So far, no self-consistent explanation for the formation of the Haumea family can match all geophysical and orbital characteristics of the family without invoking extremely improbable events. Here, we show that the family is adequately explained as the product of a merging binary near the end of Neptune's orbital migration. The unique orbital signature of a merging binary, which was not found in extensive searches, is effectively erased during the final stages of migration, providing an explanation for all aspects of the Haumea family. By placing the formation of the Haumea family in the broader context of solar system formation, we demonstrate a proof-of-concept model for the formation of Haumea.

Electrical switching based data center networks have an intrinsic bandwidth bottleneck and, require inefficient and power-consuming multi-tier switching layers to cope with the rapid growing traffic in data centers. With the benefits of ultra-large bandwidth, high-efficient cost and power consumption, switching traffic in the optical domain has been investigated to replace the electrical switches inside data center networks. However, the deployment of nanosecond optical switches remains a challenge due to the lack of corresponding nanosecond switch control, the lack of optical buffers for packet contention, and the requirement of nanosecond clock and data recovery. In this work, a nanosecond optical switching and control system has been experimentally demonstrated to enable an optically switched data center network with 43.4 nanosecond switching and control capability and with packet contention resolution as well as 3.1 nanosecond clock and data recovery.

Living systems have evolved to efficiently consume available energy sources using an elaborate circuitry of chemical reactions which, puzzlingly, bear a strict restriction to asymmetric chiral configurations. While autocatalysis is known to promote such chiral symmetry breaking, whether a similar phenomenon may also be induced in a more general class of configurable chemical systems-via energy exploitation-is a sensible yet underappreciated possibility. This work examines this question within a model of randomly generated complex chemical networks. We show that chiral symmetry breaking may occur spontaneously and generically by harnessing energy sources from external environmental drives. Key to this transition are intrinsic fluctuations of achiral-to-chiral reactions and tight matching of system configurations to the environmental drives, which together amplify and sustain diverged enantiomer distributions. These asymmetric states emerge through steep energetic transitions from the corresponding symmetric states and sharply cluster as highly-dissipating states. The results thus demonstrate a generic mechanism in which energetic drives may give rise to homochirality in an otherwise totally symmetrical environment, and from an early-life perspective, might emerge as a competitive, energy-harvesting advantage.

Mechanistic understanding of large molecule conversion and the discovery of suitable heterogeneous catalysts have been lagging due to the combinatorial inventory of intermediates and the inability of humans to enumerate all structures. Here, we introduce an automated framework to predict stable configurations on transition metal surfaces and demonstrate its validity for adsorbates with up to 6 carbon and oxygen atoms on 11 metals, enabling the exploration of ~108 potential configurations. It combines a graph enumeration platform, force field, multi-fidelity DFT calculations, and first-principles trained machine learning. Clusters in the data reveal groups of catalysts stabilizing different structures and expose selective catalysts for showcase transformations, such as the ethylene epoxidation on Ag and Cu and the lack of C-C scission chemistry on Au. Deviations from the commonly assumed atom valency rule of small adsorbates are also manifested. This library can be leveraged to identify catalysts for converting large molecules computationally.

Neuromorphic hardware that emulates biological computations is a key driver of progress in AI. For example, memristive technologies, including chalcogenide-based in-memory computing concepts, have been employed to dramatically accelerate and increase the efficiency of basic neural operations. However, powerful mechanisms such as reinforcement learning and dendritic computation require more advanced device operations involving multiple interacting signals. Here we show that nano-scaled films of chalcogenide semiconductors can perform such multi-factor in-memory computation where their tunable electronic and optical properties are jointly exploited. We demonstrate that ultrathin photoactive cavities of Ge-doped Selenide can emulate synapses with three-factor neo-Hebbian plasticity and dendrites with shunting inhibition. We apply these properties to solve a maze game through on-device reinforcement learning, as well as to provide a single-neuron solution to linearly inseparable XOR implementation.

Bloom syndrome (BS) is associated with a profoundly increased cancer risk and is caused by mutations in the Bloom helicase (BLM). BLM is involved in the nucleolytic processing of the ends of DNA double-strand breaks (DSBs), to yield long 3' ssDNA tails that serve as the substrate for break repair by homologous recombination (HR). Here, we use single-molecule imaging to demonstrate that BLM mediates formation of large ssDNA loops during DNA end processing. A BLM mutant lacking the N-terminal domain (NTD) retains vigorous in vitro end processing activity but fails to generate ssDNA loops. This same mutant supports DSB end processing in cells, however, these cells do not form RAD51 DNA repair foci and the processed DSBs are channeled into synthesis-dependent strand annealing (SSA) instead of HR-mediated repair, consistent with a defect in RAD51 filament formation. Together, our results provide insights into BLM functions during homologous recombination.

Ebola virus (EBOV), one of the deadliest viruses, is the cause of fatal Ebola virus disease (EVD). The underlying mechanism of viral replication and EBOV-related hemorrhage is not fully understood. Here, we show that EBOV VP35, a cofactor of viral RNA-dependent RNA polymerase, binds human A kinase interacting protein (AKIP1), which consequently activates protein kinase A (PKA) and the PKA-downstream transcription factor CREB1. During EBOV infection, CREB1 is recruited into EBOV ribonucleoprotein complexes in viral inclusion bodies (VIBs) and employed for viral replication. AKIP1 depletion or PKA-CREB1 inhibition dramatically impairs EBOV replication. Meanwhile, the transcription of several coagulation-related genes, including THBD and SERPINB2, is substantially upregulated by VP35-dependent CREB1 activation, which may contribute to EBOV-related hemorrhage. The finding that EBOV VP35 hijacks the host PKA-CREB1 signal axis for viral replication and pathogenesis provides novel potential therapeutic approaches against EVD.

Tumor-infiltrating lymphocytes (TILs) are critical in the elimination of cancer cells, a concept highlighted by recent advances in cancer immunotherapy. Significant evidence reveals that their organization in tertiary lymphoid structures together with specific subpopulation composition/balances stimulates cellular crosstalk and anti-tumor immunity in patients.

The lack of pyrimidine diversity in meteorites remains a mystery since prebiotic chemical models and laboratory experiments have predicted that these compounds can also be produced from chemical precursors found in meteorites. Here we report the detection of nucleobases in three carbonaceous meteorites using state-of-the-art analytical techniques optimized for small-scale quantification of nucleobases down to the range of parts per trillion (ppt). In addition to previously detected purine nucleobases in meteorites such as guanine and adenine, we identify various pyrimidine nucleobases such as cytosine, uracil, and thymine, and their structural isomers such as isocytosine, imidazole-4-carboxylic acid, and 6-methyluracil, respectively. Given the similarity in the molecular distribution of pyrimidines in meteorites and those in photon-processed interstellar ice analogues, some of these derivatives could have been generated by photochemical reactions prevailing in the interstellar medium and later incorporated into asteroids during solar system formation. This study demonstrates that a diversity of meteoritic nucleobases could serve as building blocks of DNA and RNA on the early Earth.

Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, we show that knockdown of the α3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta (1.5-4 Hz) oscillations which are implicated in many health-promoting effects of sleep. Inhibitory synaptic currents in thalamic reticular parvalbumin neurons were strongly reduced in vitro. Further analysis revealed that delta power in long NREM bouts prior to NREM-REM transitions was preferentially affected by deletion of α3 subunits. Our results identify a role for GABAA receptors on thalamic reticular nucleus neurons and suggest antagonism of α3 subunits as a strategy to enhance delta activity during sleep.

There is ample support for developmental regulation of glioblastoma stem cells. To examine how cell lineage controls glioblastoma stem cell function, we present a cross-species epigenome analysis of mouse and human glioblastoma stem cells. We analyze and compare the chromatin-accessibility landscape of nine mouse glioblastoma stem cell cultures of three defined origins and 60 patient-derived glioblastoma stem cell cultures by assay for transposase-accessible chromatin using sequencing. This separates the mouse cultures according to cell of origin and identifies three human glioblastoma stem cell clusters that show overlapping characteristics with each of the mouse groups, and a distribution along an axis of proneural to mesenchymal phenotypes. The epigenetic-based human glioblastoma stem cell clusters display distinct functional properties and can separate patient survival. Cross-species analyses reveals conserved epigenetic regulation of mouse and human glioblastoma stem cells. We conclude that epigenetic control of glioblastoma stem cells primarily is dictated by developmental origin which impacts clinically relevant glioblastoma stem cell properties and patient survival.

The global spread of SARS-CoV-2 led to major economic and health challenges worldwide. Revealing host genes essential for infection by multiple variants of SARS-CoV-2 can provide insights into the virus pathogenesis, and facilitate the development of novel therapeutics. Here, employing a genome-scale CRISPR screen, we provide a comprehensive data-set of cellular factors that are exploited by wild type SARS-CoV-2 as well as two additional recently emerged variants of concerns (VOCs), Alpha and Beta. We identified several host factors critical for SARS-CoV-2 infection, including various components belonging to the Clathrin-dependent transport pathway, ubiquitination, Heparan sulfate biogenesis and host phosphatidylglycerol biosynthesis. Comparative analysis of the different VOCs revealed the host factors KREMEN2 and SETDB1 as potential unique candidates required only to the Alpha variant. Furthermore, the analysis identified GATA6, a zinc finger transcription factor, as an essential proviral gene for all variants inspected. We show that GATA6 directly regulates ACE2 transcription and accordingly, is critical for SARS-CoV-2 cell entry. Analysis of clinical samples collected from SARS-CoV-2 infected individuals shows elevated levels of GATA6, suggesting a role in COVID-19 pathogenesis. Finally, pharmacological inhibition of GATA6 resulted in down-modulation of ACE2 and inhibition of viral infectivity. Overall, we show GATA6 may represent a target for the development of anti-SARS-CoV-2 therapeutic strategies and reaffirm the value of the CRISPR loss-of-function screens in providing a list of potential new targets for therapeutic interventions.

Erratum in Nat Commun. 2022 May 6;13(1):2619.

Erratum in Nat Commun. 2022 May 17;13(1):2849.

A Brillouin zone is the unit for the momentum space of a crystal. It is topologically a torus, and distinguishing whether a set of wave functions over the Brillouin torus can be smoothly deformed to another leads to the classification of various topological states of matter. Here, we show that under [Formula: see text] gauge fields, i.e., hopping amplitudes with phases ±1, the fundamental domain of momentum space can assume the topology of a Klein bottle. This drastic change of the Brillouin zone theory is due to the projective symmetry algebra enforced by the gauge field. Remarkably, the non-orientability of the Brillouin Klein bottle corresponds to the topological classification by a [Formula: see text] invariant, in contrast to the Chern number valued in [Formula: see text] for the usual Brillouin torus. The result is a novel Klein bottle insulator featuring topological modes at two edges related by a nonlocal twist, radically distinct from all previous topological insulators. Our prediction can be readily achieved in various artificial crystals, and the discovery opens a new direction to explore topological physics by gauge-field-modified fundamental structures of physics.

Afterglow luminescence is an internal luminescence pathway that occurs after photo-excitation, holds great promise for non-background molecular imaging in vivo, but suffer from poor quantitative ability owing to luminescent attenuation over time. Moreover, the inert structure and insufficient reactive sites of current afterglow materials make it hard to design activatable afterglow probes for specific detection. Here, we report a ratiometric afterglow luminescent nanoplatform to customize various activatable afterglow probes for reliable quantification and molecular imaging of specific analytes, such as NO, ONOO- or pH. Notably, these afterglow probes can not only address the attenuation of afterglow intensity and eliminate the interference of factors (e.g., laser power, irradiation time, and exposure time), but also significantly improve the imaging reliability in vivo and signal-to-background ratios (~1200-fold), both of which enable more reliable quantitative analysis in biological systems. Moreover, as a proof-of-concept, we successfully design an NO-responsive ratiometric afterglow nanoprobe, RAN1. This nanoprobe can monitor the fluctuations of intratumoral NO, as a biomarker of macrophage polarization, making it possible to real-time dynamically evaluate the degree cancer immunotherapy, which provides a reliable parameter to predict the immunotherapeutic effect.

Structural snapshots of protein/ligand complexes are a prerequisite for gaining atomic level insight into enzymatic reaction mechanisms. An important group of enzymes has been deprived of this analytical privilege: members of the protein tyrosine phosphatase (PTP) superfamily with catalytic WPD-loops lacking the indispensable general-acid/base within a tryptophan-proline-aspartate/glutamate context. Here, we provide the ligand/enzyme crystal complexes for one such PTP outlier: Arabidopsis thaliana Plant and Fungi Atypical Dual Specificity Phosphatase 1 (AtPFA-DSP1), herein unveiled as a regioselective and efficient phosphatase towards inositol pyrophosphate (PP-InsP) signaling molecules. Although the WPD loop is missing its canonical tripeptide motif, this structural element contributes to catalysis by assisting PP-InsP delivery into the catalytic pocket, for a choreographed exchange with phosphate reaction product. Subsequently, an intramolecular proton donation by PP-InsP substrate is posited to substitute functionally for the absent aspartate/glutamate general-acid. Overall, we expand mechanistic insight into adaptability of the conserved PTP structural elements.

Understanding nanostructure ripening mechanisms is desirable for gaining insight on the growth and potential applications of nanoscale materials. However, the atomic pathways of nanostructure ripening in solution have rarely been observed directly. Here, we report defect-mediated ripening of Cd-CdCl2 core-shell nanoparticles (CSN) revealed by in-situ atomic resolution imaging with liquid cell transmission electron microscopy. We find that ripening is initiated by dissolution of the nanoparticle with an incomplete CdCl2 shell, and that the areas of the Cd core that are exposed to the solution are etched first. The growth of the other nanoparticles is achieved by generating crack defects in the shell, followed by ion diffusion through the cracks. Subsequent healing of crack defects leads to a highly crystalline CSN. The formation and annihilation of crack defects in the CdCl2 shell, accompanied by disordering and crystallization of the shell structure, mediate the ripening of Cd-CdCl2 CSN in the solution.

Plant pathogens degrade cell wall through secreted polygalacturonases (PGs) during infection. Plants counteract the PGs by producing PG-inhibiting proteins (PGIPs) for protection, reversibly binding fungal PGs, and mitigating their hydrolytic activities. To date, how fungal pathogens specifically overcome PGIP inhibition is unknown. Here, we report an effector, Sclerotinia sclerotiorum PGIP-INactivating Effector 1 (SsPINE1), which directly interacts with and functionally inactivates PGIP. S. sclerotiorum is a necrotrophic fungus that causes stem rot diseases on more than 600 plant species with tissue maceration being the most prominent symptom. SsPINE1 enhances S. sclerotiorum necrotrophic virulence by specifically interacting with host PGIPs to negate their polygalacturonase-inhibiting function via enhanced dissociation of PGIPs from PGs. Targeted deletion of SsPINE1 reduces the fungal virulence. Ectopic expression of SsPINE1 in plant reduces its resistance against S. sclerotiorum. Functional and genomic analyses reveal a conserved virulence mechanism of cognate PINE1 proteins in broad host range necrotrophic fungal pathogens.

Construction of internal electric fields (IEFs) is crucial to realize efficient charge separation for charge-induced redox reactions, such as water splitting and CO2 reduction. However, a quantitative understanding of the charge transfer dynamics modulated by IEFs remains elusive. Here, electron microscopy study unveils that the non-equilibrium photo-excited electrons are collectively steered by two contiguous IEFs within binary (001)/(200) facet junctions of BiOBr platelets, and they exhibit characteristic Gaussian distribution profiles on reduction facets by using metal co-catalysts as probes. An analytical model justifies the Gaussian curve and allows us to measure the diffusion length and drift distance of electrons. The charge separation efficiency, as well as photocatalytic performances, are maximized when the platelet size is about twice the drift distance, either by tailoring particle dimensions or tuning IEF-dependent drift distances. The work offers great flexibility for precisely constructing high-performance particulate photocatalysts by understanding charge transfer dynamics.

The recently discovered layered kagome metals AV3Sb5 (A = K, Rb, Cs) exhibit diverse correlated phenomena, which are intertwined with a topological electronic structure with multiple van Hove singularities (VHSs) in the vicinity of the Fermi level. As the VHSs with their large density of states enhance correlation effects, it is of crucial importance to determine their nature and properties. Here, we combine polarization-dependent angle-resolved photoemission spectroscopy with density functional theory to directly reveal the sublattice properties of 3d-orbital VHSs in CsV3Sb5. Four VHSs are identified around the M point and three of them are close to the Fermi level, with two having sublattice-pure and one sublattice-mixed nature. Remarkably, the VHS just below the Fermi level displays an extremely flat dispersion along MK, establishing the experimental discovery of higher-order VHS. The characteristic intensity modulation of Dirac cones around K further demonstrates the sublattice interference embedded in the kagome Fermiology. The crucial insights into the electronic structure, revealed by our work, provide a solid starting point for the understanding of the intriguing correlation phenomena in the kagome metals AV3Sb5.

The electrosynthesis of formate from CO2 can mitigate environmental issues while providing an economically valuable product. Although stannic oxide is a good catalytic material for formate production, a metallic phase is formed under high reduction overpotentials, reducing its activity. Here, using a fluorine-doped tin oxide catalyst, a high Faradaic efficiency for formate (95% at 100 mA cm-2) and a maximum partial current density of 330 mA cm-2 (at 400 mA cm-2) is achieved for the electroreduction of CO2. Furthermore, the formate selectivity (≈90%) is nearly constant over 7 days of operation at a current density of 100 mA cm-2. In-situ/operando spectroscopies reveal that the fluorine dopant plays a critical role in maintaining the high oxidation state of Sn, leading to enhanced durability at high current densities. First-principle calculation also suggests that the fluorine-doped tin oxide surface could provide a thermodynamically stable environment to form HCOO* intermediate than tin oxide surface. These findings suggest a simple and efficient approach for designing active and durable electrocatalysts for the electrosynthesis of formate from CO2.

Reversible protonic ceramic electrochemical cells (R-PCECs) are ideally suited for efficient energy storage and conversion; however, one of the limiting factors to high performance is the poor stability and insufficient electrocatalytic activity for oxygen reduction and evolution of the air electrode exposed to the high concentration of steam. Here we report our findings in enhancing the electrochemical activity and durability of a perovskite-type air electrode, Ba0.9Co0.7Fe0.2Nb0.1O3-δ (BCFN), via a water-promoted surface restructuring process. Under properly-controlled operating conditions, the BCFN electrode is naturally restructured to an Nb-rich BCFN electrode covered with Nb-deficient BCFN nanoparticles. When used as the air electrode for a fuel-electrode-supported R-PCEC, good performances are demonstrated at 650 °C, achieving a peak power density of 1.70 W cm-2 in the fuel cell mode and a current density of 2.8 A cm-2 at 1.3 V in the electrolysis mode while maintaining reasonable Faradaic efficiencies and promising durability.

Transfer of information across membranes is fundamental to the function of all organisms and is primarily initiated by transmembrane receptors. For many receptors, how ligand sensitivity is fine-tuned and how disease associated mutations modulate receptor conformation to allosterically affect receptor sensitivity are unknown. Here we map the activation of the calcium-sensing receptor (CaSR) - a dimeric class C G protein-coupled receptor (GPCR) and responsible for maintaining extracellular calcium in vertebrates. We show that CaSR undergoes unique conformational rearrangements compared to other class C GPCRs owing to specific structural features. Moreover, by analyzing disease associated mutations, we uncover a large permissiveness in the architecture of the extracellular domain of CaSR, with dynamics- and not specific receptor topology- determining the effect of a mutation. We show a structural hub at the dimer interface allosterically controls CaSR activation via focused electrostatic repulsion. Changes in the surface charge distribution of this hub, which is highly variable between organisms, finely tune CaSR sensitivity. This is potentially a general tuning mechanism for other dimeric receptors.

Erratum in Nat Commun. 2023 Jan 24;14(1):389.

The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we define the Mtb protein CinA as a major determinant of drug tolerance and as a potential target to shorten TB chemotherapy. By reducing the fraction of drug-tolerant persisters, genetic inactivation of cinA accelerated killing of Mtb by four antibiotics in clinical use: isoniazid, ethionamide, delamanid and pretomanid. Mtb ΔcinA was killed rapidly in conditions known to impede the efficacy of isoniazid, such as during nutrient starvation, during persistence in a caseum mimetic, in activated macrophages and during chronic mouse infection. Deletion of CinA also increased in vivo killing of Mtb by BPaL, a combination of pretomanid, bedaquiline and linezolid that is used to treat highly drug-resistant TB. Genetic and drug metabolism studies suggest that CinA mediates drug tolerance via cleavage of NAD-drug adducts.

Skeletal muscle mass is regulated through coordinated activation of multiple signaling pathways. TAK1 signalosome has been found to be activated in various conditions of muscle atrophy and hypertrophy. However, the role and mechanisms by which TAK1 regulates skeletal muscle mass remain less understood. Here, we demonstrate that supraphysiological activation of TAK1 in skeletal muscle of adult mice stimulates translational machinery, protein synthesis, and myofiber growth. TAK1 causes phosphorylation of elongation initiation factor 4E (eIF4E) independent of mTOR. Inactivation of TAK1 disrupts neuromuscular junction morphology and causes deregulation of Smad signaling. Using genetic approaches, we demonstrate that TAK1 prevents excessive loss of muscle mass during denervation. TAK1 favors the nuclear translocation of Smad4 and cytoplasmic retention of Smad6. TAK1 is also required for the phosphorylation of eIF4E in denervated skeletal muscle. Collectively, our results demonstrate that TAK1 supports skeletal muscle growth and prevents neurogenic muscle atrophy in adult mice.

Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers.

Bifunctional catalysts with tandem processes have achieved great success in a wide range of important catalytic processes, however, this concept has hardly been applied in the elimination of volatile organic compounds. Herein, we designed a tandem bifunctional Zeolites-Silver catalyst that enormously boosted formaldehyde oxidation at low temperatures, and formaldehyde conversion increased by 50 times (100% versus 2%) at 70 °C compared to that of monofunctional supported silver catalyst. This is enabled by designing a bifunctional catalyst composed of acidic ZSM-5 zeolite and silver component, which provides two types of active sites with complementary functions. Detached acidic ZSM-5 activates formaldehyde to generate gaseous intermediates of methyl formate, which is more easily oxidized by subsequent silver component. We anticipate that the findings here will open up a new avenue for the development of formaldehyde oxidation technologies, and also provide guidance for designing efficient catalysts in a series of oxidation reactions.

Defect engineering is an effective strategy to improve the activity of two-dimensional molybdenum disulfide base planes toward electrocatalytic hydrogen evolution reaction. Here, we report a Frenkel-defected monolayer MoS2 catalyst, in which a fraction of Mo atoms in MoS2 spontaneously leave their places in the lattice, creating vacancies and becoming interstitials by lodging in nearby locations. Unique charge distributions are introduced in the MoS2 surface planes, and those interstitial Mo atoms are more conducive to H adsorption, thus greatly promoting the HER activity of monolayer MoS2 base planes. At the current density of 10 mA cm-2, the optimal Frenkel-defected monolayer MoS2 exhibits a lower overpotential (164 mV) than either pristine monolayer MoS2 surface plane (358 mV) or Pt-single-atom doped MoS2 (211 mV). This work provides insights into the structure-property relationship of point-defected MoS2 and highlights the advantages of Frenkel defects in tuning the catalytic performance of MoS2 materials.

The rational design of disordered frameworks is an appealing route to target functional materials. However, intentional realisation of such materials relies on our ability to readily characterise and quantify structural disorder. Here, we use multivariate analysis of pair distribution functions to fingerprint and quantify the disorder within a series of compositionally identical metal-organic frameworks, possessing different crystalline, disordered, and amorphous structures. We find this approach can provide powerful insight into the kinetics and mechanism of structural collapse that links these materials. Our methodology is also extended to a very different system, namely the melting of a zeolitic imidazolate framework, to demonstrate the potential generality of this approach across many areas of disordered structural chemistry.

The app-based COVID Symptom Study was launched in Sweden in April 2020 to contribute to real-time COVID-19 surveillance. We enrolled 143,531 study participants (≥18 years) who contributed 10.6 million daily symptom reports between April 29, 2020 and February 10, 2021. Here, we include data from 19,161 self-reported PCR tests to create a symptom-based model to estimate the individual probability of symptomatic COVID-19, with an AUC of 0.78 (95% CI 0.74-0.83) in an external dataset. These individual probabilities are employed to estimate daily regional COVID-19 prevalence, which are in turn used together with current hospital data to predict next week COVID-19 hospital admissions. We show that this hospital prediction model demonstrates a lower median absolute percentage error (MdAPE: 25.9%) across the five most populated regions in Sweden during the first pandemic wave than a model based on case notifications (MdAPE: 30.3%). During the second wave, the error rates are similar. When we apply the same model to an English dataset, not including local COVID-19 test data, we observe MdAPEs of 22.3% and 19.0% during the first and second pandemic waves, respectively, highlighting the transferability of the prediction model.

The lack of innovative standards for biosafety in synthetic biology is an unresolved policy gap that limits many potential applications in synthetic biology. We argue that a massive support for standardization in biosafety is required for synthetic biology to flourish.

Electronic textiles capable of sensing, powering, and communication can be used to non-intrusively monitor human health during daily life. However, achieving these functionalities with clothing is challenging because of limitations in the electronic performance, flexibility and robustness of the underlying materials, which must endure repeated mechanical, thermal and chemical stresses during daily use. Here, we demonstrate electronic textile systems with functionalities in near-field powering and communication created by digital embroidery of liquid metal fibers. Owing to the unique electrical and mechanical properties of the liquid metal fibers, these electronic textiles can conform to body surfaces and establish robust wireless connectivity with nearby wearable or implantable devices, even during strenuous exercise. By transferring optimized electromagnetic patterns onto clothing in this way, we demonstrate a washable electronic shirt that can be wirelessly powered by a smartphone and continuously monitor axillary temperature without interfering with daily activities.

Photodynamic therapy (PDT) offers several advantages for treating cancers, but its efficacy is highly dependent on light delivery to activate a photosensitizer. Advances in wireless technologies enable remote delivery of light to tumors, but suffer from key limitations, including low levels of tissue penetration and photosensitizer activation. Here, we introduce DeepLabCut (DLC)-informed low-power wireless telemetry with an integrated thermal/light simulation platform that overcomes the above constraints. The simulator produces an optimized combination of wavelengths and light sources, and DLC-assisted wireless telemetry uses the parameters from the simulator to enable adequate illumination of tumors through high-throughput (<20 mice) and multi-wavelength operation. Together, they establish a range of guidelines for effective PDT regimen design. In vivo Hypericin and Foscan mediated PDT, using cancer xenograft models, demonstrates substantial suppression of tumor growth, warranting further investigation in research and/or clinical settings.

Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and there are contradictory data about their roles in regulatory T cell (Treg) function. Here we show activated Tregs and CD4 effector T cells (Teffs) use PD-1/PD-L1 and CD80/PD-L1, respectively, to regulate transendothelial migration across lymphatic endothelial cells (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative ligand for PD-L1), or LEC PD-L1 impairs Treg or Teff migration in vitro and in vivo. PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate zipper junctional VE-cadherin, and through NFκB-p65 to up-regulate VCAM-1 expression on LECs. CD80/PD-L1 signaling up-regulates VCAM-1 through ERK and NFκB-p65. PD-1 and CD80 blockade reduces tumor egress of PD-1high fragile Tregs and Teffs into draining lymph nodes, respectively, and promotes tumor regression. These data provide roles for PD-L1 in cell migration and immune regulation.

Chromoselective photocatalysis offers an intriguing opportunity to enable a specific reaction pathway out of a potentially possible multiplicity for a given substrate by using a sensitizer that converts the energy of incident photon into the redox potential of the corresponding magnitude. Several sensitizers possessing different discrete redox potentials (high/low) upon excitation with photons of specific wavelength (short/long) have been reported. Herein, we report design of molecular structures of two-dimensional amorphous covalent triazine-based frameworks (CTFs) possessing intraband states close to the valence band with strong red edge effect (REE). REE enables generation of a continuum of excited sites characterized by their own redox potentials, with the magnitude proportional to the wavelength of incident photons. Separation of charge carriers in such materials depends strongly on the wavelength of incident light and is the primary parameter that defines efficacy of the materials in photocatalytic bromination of electron rich aromatic compounds. In dual Ni-photocatalysis, excitation of electrons from the intraband states to the conduction band of the CTF with 625 nm photons enables selective formation of C‒N cross-coupling products from arylhalides and pyrrolidine, while an undesirable dehalogenation process is completely suppressed.

Cardiac excitation-contraction coupling requires dyads, the nanoscopic microdomains formed adjacent to Z-lines by apposition of transverse tubules and junctional sarcoplasmic reticulum. Disruption of dyad architecture and function are common features of diseased cardiomyocytes. However, little is known about the mechanisms that modulate dyad organization during cardiac development, homeostasis, and disease. Here, we use proximity proteomics in intact, living hearts to identify proteins enriched near dyads. Among these proteins is CMYA5, an under-studied striated muscle protein that co-localizes with Z-lines, junctional sarcoplasmic reticulum proteins, and transverse tubules in mature cardiomyocytes. During cardiac development, CMYA5 positioning adjacent to Z-lines precedes junctional sarcoplasmic reticulum positioning or transverse tubule formation. CMYA5 ablation disrupts dyad architecture, dyad positioning at Z-lines, and junctional sarcoplasmic reticulum Ca2+ release, leading to cardiac dysfunction and inability to tolerate pressure overload. These data provide mechanistic insights into cardiomyopathy pathogenesis by demonstrating that CMYA5 anchors junctional sarcoplasmic reticulum to Z-lines, establishes dyad architecture, and regulates dyad Ca2+ release.

Anchoring single metal atoms on enzymes has great potential to generate hybrid catalysts with high activity and selectivity for reactions that cannot be driven by traditional metal catalysts. Herein, we develop a photochemical method to construct a stable single-atom enzyme-metal complex by binding single metal atoms to the carbon radicals generated on an enzyme-polymer conjugate. The metal mass loading of Pd-anchored enzyme is up to 4.0% while maintaining the atomic dispersion of Pd. The cooperative catalysis between lipase-active site and single Pd atom accelerates alkyl-alkyl cross-coupling reaction between 1-bromohexane and B-n-hexyl-9-BBN with high efficiency (TOF is 540 h-1), exceeding that of the traditional catalyst Pd(OAc)2 by a factor of 300 under ambient conditions.

Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPARγ, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Quorum sensing (QS) is a ubiquitous cell-cell communication mechanism that can be employed to autonomously and dynamically control metabolic fluxes. However, since the functions of genetic components in the circuits are not fully understood, the developed QS circuits are still less sophisticated for regulating multiple sets of genes or operons in metabolic engineering applications. Here, we discover the regulatory roles of a CRP-binding site and the lux box to -10 region within luxR-luxI intergenic sequence in controlling the lux-type QS promoters. By varying the numbers of the CRP-binding site and redesigning the lux box to -10 site sequence, we create a library of QS variants that possess both high dynamic ranges and low leakiness. These circuits are successfully applied to achieve diverse metabolic control in salicylic acid and 4-hydroxycoumarin biosynthetic pathways in Escherichia coli. This work expands the toolbox for dynamic control of multiple metabolic fluxes under complex metabolic background and presents paradigms to engineer metabolic pathways for high-level synthesis of target products.

Coleoid cephalopods (squid, cuttlefish, octopus) have the largest nervous system among invertebrates that together with many lineage-specific morphological traits enables complex behaviors. The genomic basis underlying these innovations remains unknown. Using comparative and functional genomics in the model squid Euprymna scolopes, we reveal the unique genomic, topological, and regulatory organization of cephalopod genomes. We show that coleoid cephalopod genomes have been extensively restructured compared to other animals, leading to the emergence of hundreds of tightly linked and evolutionary unique gene clusters (microsyntenies). Such novel microsyntenies correspond to topological compartments with a distinct regulatory structure and contribute to complex expression patterns. In particular, we identify a set of microsyntenies associated with cephalopod innovations (MACIs) broadly enriched in cephalopod nervous system expression. We posit that the emergence of MACIs was instrumental to cephalopod nervous system evolution and propose that microsyntenic profiling will be central to understanding cephalopod innovations.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

The neutron inelastic scattering of carbon-12, populating the Hoyle state, is a reaction of interest for the triple-alpha process. The inverse process (neutron upscattering) can enhance the Hoyle state's decay rate to the bound states of 12C, effectively increasing the overall triple-alpha reaction rate. The cross section of this reaction is impossible to measure experimentally but has been determined here at astrophysically-relevant energies using detailed balance. Using a highly-collimated monoenergetic beam, here we measure neutrons incident on the Texas Active Target Time Projection Chamber (TexAT TPC) filled with CO2 gas, we measure the 3α-particles (arising from the decay of the Hoyle state following inelastic scattering) and a cross section is extracted. Here we show the neutron-upscattering enhancement is observed to be much smaller than previously expected. The importance of the neutron-upscattering enhancement may therefore not be significant aside from in very particular astrophysical sites (e.g. neutron star mergers).

In glacier-fed streams, ecological windows of opportunity allow complex microbial biofilms to develop and transiently form the basis of the food web, thereby controlling key ecosystem processes. Using metagenome-assembled genomes, we unravel strategies that allow biofilms to seize this opportunity in an ecosystem otherwise characterized by harsh environmental conditions. We observe a diverse microbiome spanning the entire tree of life including a rich virome. Various co-existing energy acquisition pathways point to diverse niches and the exploitation of available resources, likely fostering the establishment of complex biofilms during windows of opportunity. The wide occurrence of rhodopsins, besides chlorophyll, highlights the role of solar energy capture in these biofilms while internal carbon and nutrient cycling between photoautotrophs and heterotrophs may help overcome constraints imposed by oligotrophy in these habitats. Mechanisms potentially protecting bacteria against low temperatures and high UV-radiation are also revealed and the selective pressure of this environment is further highlighted by a phylogenomic analysis differentiating important components of the glacier-fed stream microbiome from other ecosystems. Our findings reveal key genomic underpinnings of adaptive traits contributing to the success of complex biofilms to exploit environmental opportunities in glacier-fed streams, which are now rapidly changing owing to global warming.

Groundwater comprises 95% of the liquid fresh water on Earth and contains a diverse mix of dissolved organic matter (DOM) molecules which play a significant role in the global carbon cycle. Currently, the storage times and degradation pathways of groundwater DOM are unclear, preventing an accurate estimate of groundwater carbon sources and sinks for global carbon budgets. Here we reveal the transformations of DOM in aging groundwater using ultra-high resolution mass spectrometry combined with radiocarbon dating. Long-term anoxia and a lack of photodegradation leads to the removal of oxidised DOM and a build-up of both reduced photodegradable formulae and aerobically biolabile formulae with a strong microbial signal. This contrasts with the degradation pathway of DOM in oxic marine, river, and lake systems. Our findings suggest that processes such as groundwater extraction and subterranean groundwater discharge to oceans could result in up to 13 Tg of highly photolabile and aerobically biolabile groundwater dissolved organic carbon released to surface environments per year, where it can be rapidly degraded. These findings highlight the importance of considering groundwater DOM in global carbon budgets.

Although the single-impurity Kondo physics has already been well understood, the understanding of the Kondo lattice where a dense array of local moments couples to the conduction electrons is still far from complete. The ability of creating and tuning the Kondo lattice in non-f-electron systems will be great helpful for further understanding the Kondo lattice behavior. Here we show that the Pb intercalation in the charge-density-wave-driven narrow-electronic-band system 1T-TaS2 induces a transition from the insulating gap to a sharp Kondo resonance in the scanning tunneling microscopy measurements. It results from the Kondo screening of the localized moments in the 13-site Star-of-David clusters of 1T-TaS2. As increasing the Pb concentration, the narrow electronic band derived from the localized electrons shifts away from the Fermi level and the Kondo resonance peak is gradually suppressed. Our results pave the way for creating and tuning many-body electronic states in layered narrow-electronic-band materials.

Bottom-up synthesis of prototissues helps us to understand the internal cellular communications in the natural tissues and their functions, as well as to improve or repair the damaged tissues. The existed prototissues are rarely used to improve the function of living tissues. We demonstrate a methodology to produce spatially programmable prototissues based on the magneto-Archimedes effect in a high-throughput manner. More than 2000 prototissues are produced once within 2 h. Two-component and three-component spatial coded prototissues are fabricated by varying the addition giant unilamellar vesicles order/number, and the magnetic field distributions. Two-step and three-step signal communications in the prototissues are realized using cascade enzyme reactions. More importantly, the two-component prototissues capable of producing nitric oxide cause vasodilation of rat blood vessels in the presence of glucose and hydroxyurea. The tension force decreases 2.59 g, meanwhile the blood vessel relaxation is of 31.2%. Our works pave the path to fabricate complicated programmable prototissues, and hold great potential in the biomedical field.

Organisms have the capacity to alter their physiological response to warming through acclimation or adaptation, but the consequence of this metabolic plasticity for energy flow through food webs is currently unknown, and a generalisable framework does not exist for modelling its ecosystem-level effects. Here, using temperature-controlled experiments on stream invertebrates from a natural thermal gradient, we show that the ability of organisms to raise their metabolic rate following chronic exposure to warming decreases with increasing body size. Chronic exposure to higher temperatures also increases the acute thermal sensitivity of whole-organismal metabolic rate, independent of body size. A mathematical model parameterised with these findings shows that metabolic plasticity could account for 60% higher ecosystem energy flux with just +2 °C of warming than a traditional model based on ecological metabolic theory. This could explain why long-term warming amplifies ecosystem respiration rates through time in recent mesocosm experiments, and highlights the need to embed metabolic plasticity in predictive models of global warming impacts on ecosystems.

Supramolecular polymers are composed of monomers that self-assemble non-covalently, generating distributions of monodimensional fibres in continuous communication with each other and with the surrounding solution. Fibres, exchanging molecular species, and external environment constitute a sole complex system, which intrinsic dynamics is hard to elucidate. Here we report coarse-grained molecular simulations that allow studying supramolecular polymers at the thermodynamic equilibrium, explicitly showing the complex nature of these systems, which are composed of exquisitely dynamic molecular entities. Detailed studies of molecular exchange provide insights into key factors controlling how assemblies communicate with each other, defining the equilibrium dynamics of the system. Using minimalistic and finer chemically relevant molecular models, we observe that a rich concerted complexity is intrinsic in such self-assembling systems. This offers a new dynamic and probabilistic (rather than structural) picture of supramolecular polymer systems, where the travelling molecular species continuously shape the assemblies that statistically emerge at the equilibrium.

Although morphologic progression coupled with expression of specific molecular markers has been characterized along the esophageal squamous differentiation gradient, the molecular heterogeneity within cell types along this trajectory has yet to be classified at the single cell level. To address this knowledge gap, we perform single cell RNA-sequencing of 44,679 murine esophageal epithelial, to identify 11 distinct cell populations as well as pathways alterations along the basal-superficial axis and in each individual population. We evaluate the impact of aging upon esophageal epithelial cell populations and demonstrate age-associated mitochondrial dysfunction. We compare single cell transcriptomic profiles in 3D murine organoids and human esophageal biopsies with that of murine esophageal epithelium. Finally, we employ pseudotemporal trajectory analysis to develop a working model of cell fate determination in murine esophageal epithelium. These studies provide comprehensive molecular perspective on the cellular heterogeneity of murine esophageal epithelium in the context of homeostasis and aging.

Author information: (1)PARCC, INSERM, Université de Paris, F-750015, Paris, France. (2)Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. (3)Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA. (4)Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands. (5)Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, 55902, USA. (6)Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7)Centre National de Recherche en Génomique Humaine, Institut de Génomique, CEA and Fondation Jean Dausset-CEPH, Evry, France. (8)Hypertension Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015, Paris, France. (9)Department of Anesthesiology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. (10)Vascular Surgery Section, Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA. (11)Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12)Department of Internal Medicine, Division of General Internal Medicine, Section Vascular Medicine, Maastricht University Medical Centre, Maastricht University, Maastricht, the Netherlands. (13)CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht University, Maastricht, the Netherlands. (14)Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. (15)Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R, Kravis Center for Cardiovascular Health Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16)Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200, Brussels, Belgium. (17)Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Turin, Turin, Italy. (18)Department of Hypertension, National Institute of Cardiology, Warsaw, Poland. (19)Department of Demography, University of Lodz, Lodz, Poland. (20)Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA. (21)Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Labex DISTALZ - Risk Factors and Molecular Determinants of Aging-Related Disease, F-59000, Lille, France. (22)Department of Cardiovascular Diseases, Ghent University and Ghent University Hospital, Ghent, Belgium. (23)Department of Neurology, Bordeaux University Hospital, Inserm U1219, Bordeaux, France. (24)Department of Epidemiology, Cardiovascular Disease Prevention, and Health Promotion, National Institute of Cardiology, Warsaw, Poland. (25)Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200, Brussels, Belgium. (26)Gonda Vascular Center, Mayo Clinic, Rochester, MN, 55902, USA. (27)Université de Paris, Inserm, Centre d'Investigation Clinique 1418, F-75006, Paris, France. (28)Department of Genetics, Assistance-Publiques-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015, Paris, France. (29)Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200, Brussels, Belgium. (30)Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia. (31)St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia. (32)Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. sganesh@med.umich.edu. (33)Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA. sganesh@med.umich.edu. (34)PARCC, INSERM, Université de Paris, F-750015, Paris, France. nabila.bouatia-naji@inserm.fr. (#)Contributed equally

Chromosome segregation requires sister kinetochores to attach microtubules emanating from opposite spindle poles. Proper attachments come under tension and are stabilized, but defective attachments lacking tension are released, giving another chance for correct attachments to form. This error correction process depends on Aurora B kinase, which phosphorylates kinetochores to destabilize their microtubule attachments. However, the mechanism by which Aurora B distinguishes tense versus relaxed kinetochores remains unclear because it is difficult to detect kinase-triggered detachment and to manipulate kinetochore tension in vivo. To address these challenges, we apply an optical trapping-based assay using soluble Aurora B and reconstituted kinetochore-microtubule attachments. Strikingly, the tension on these attachments suppresses their Aurora B-triggered release, suggesting that tension-dependent changes in the conformation of kinetochores can regulate Aurora B activity or its outcome. Our work uncovers the basis for a key mechano-regulatory event that ensures accurate segregation and may inform studies of other mechanically regulated enzymes.

Photothermal sensing is crucial for the creation of smart wearable devices. However, the discovery of luminescent materials with suitable dual-wavelength emissions is a great challenge for the construction of stable wearable optical fibre temperature sensors. Benefiting from the Mn2+-Mn2+ superexchange interactions, a dual-wavelength (530/650 nm)-emitting material Li2ZnSiO4:Mn2+ is presented via simple increasing the Mn2+ concentration, wherein the two emission bands have different temperature-dependent emission behaviours, but exhibit quite similar excitation spectra. Density functional theory calculations, coupled with extended X-ray absorption fine structure and electron-diffraction analyses reveal the origins of the two emission bands in this material. A wearable optical temperature sensor is fabricated by incorporating Li2ZnSiO4:Mn2+ in stretchable elastomer-based optical fibres, which can provide thermal-sensitive emissions at dual- wavelengths for stable ratiometric temperature sensing with good precision and repeatability. More importantly, a wearable mask integrated with this stretchable fibre sensor is demonstrated for the detection of physiological thermal changes, showing great potential for use as a wearable health monitor. This study also provides a framework for creating transition-metal-activated luminescence materials.

Ultrathin two-dimensional (2D) metal oxyhalides exhibit outstanding photocatalytic properties with unique electronic and interfacial structures. Compared with monometallic oxyhalides, bimetallic oxyhalides are less explored. In this work, we have developed a novel top-down wet-chemistry desalination approach to remove the alkali-halide salt layer within the complicated precursor bulk structural matrix Pb0.6Bi1.4Cs0.6O2Cl2, and successfully fabricate a new 2D ultrathin bimetallic oxyhalide Pb0.6Bi1.4O2Cl1.4. The unlocked larger surface area, rich bimetallic active sites, and faster carrier dynamics within Pb0.6Bi1.4O2Cl1.4 layers significantly enhance the photocatalytic efficiency for atmospheric CO2 reduction. It outperforms the corresponding parental matrix phase and other state-of-the-art bismuth-based monometallic oxyhalides photocatalysts. This work reports a top-down desalination strategy to engineering ultrathin bimetallic 2D material for photocatalytic atmospheric CO2 reduction, which sheds light on further constructing other ultrathin 2D catalysts for environmental and energy applications from similar complicate structure matrixes.

Sex differences exist in many neurological and psychiatric diseases, but these have not always been addressed adequately in research. In order to address this, it is necessary to consider how sex is incorporated into the design (e.g. using a balanced design) and into the analyses (e.g. using sex as a covariate) in the published literature. We surveyed papers published in 2009 and 2019 across six journals in neuroscience and psychiatry. In this sample, we find a 30% increase in the percentage of papers reporting studies that included both sexes in 2019 compared with 2009. Despite this increase, in 2019 only 19% of papers in the sample reported using an optimal design for discovery of possible sex differences, and only 5% of the papers reported studies that analysed sex as a discovery variable. We conclude that progress to date has not been sufficient to address the importance of sex differences in research for discovery and therapeutic potential for neurological and psychiatric disease.

It is generally expected that a solvent has only marginal effect on the stability of a covalent bond. In this work, we present a combined computational and experimental study showing a surprising stabilization of the covalent/dative bond in Me3NBH3 complex with increasing solvent polarity. The results show that for a given complex, its stability correlates with the strength of the bond. Notably, the trends in calculated changes of binding (free) energies, observed with increasing solvent polarity, match the differences in the solvation energies (ΔEsolv) of the complex and isolated fragments. Furthermore, the studies performed on the set of the dative complexes, with different atoms involved in the bond, show a linear correlation between the changes of binding free energies and ΔEsolv. The observed data indicate that the ionic part of the combined ionic-covalent character of the bond is responsible for the stabilizing effects of solvents.

The relaxation behavior of glass formers exhibits spatial heterogeneity and dramatically changes upon cooling towards the glass transition. However, the underlying mechanisms of the dynamics at different microscopic length scales are not fully understood. Employing the recently developed wide-angle neutron spin-echo spectroscopy technique, we measured the Q-dependent coherent intermediate scattering function of a prototypical ionic glass former Ca0.4K0.6(NO3)1.4, in the highly viscous liquid state. In contrast to the structure modulated dynamics for Q < 2.4 Å-1, i.e., at and below the structure factor main peak, for Q > 2.4 Å-1, beyond the first minimum above the structure factor main peak, the stretching exponent exhibits no temperature dependence and concomitantly the relaxation time shows smaller deviations from Arrhenius behavior. This finding indicates a change in the dominant relaxation mechanisms around a characteristic length of 2π/(2.4 Å-1) ≈ 2.6 Å, below which the relaxation process exhibits a temperature independent distribution and more Arrhenius-like behavior.

Intermetallic compounds containing f-electron elements have been prototypical materials for investigating strong electron correlations and quantum criticality (QC). Their heavy fermion ground state evoked by the magnetic f-electrons is susceptible to the onset of quantum phases, such as magnetism or superconductivity, due to the enhanced effective mass (m*) and a corresponding decrease of the Fermi temperature. However, the presence of f-electron valence fluctuations to a non-magnetic state is regarded an anathema to QC, as it usually generates a paramagnetic Fermi-liquid state with quasiparticles of moderate m*. Such systems are typically isotropic, with a characteristic energy scale T0 of the order of hundreds of kelvins that require large magnetic fields or pressures to promote a valence or magnetic instability. Here we show the discovery of a quantum critical behaviour and a Lifshitz transition under low magnetic field in an intermediate valence compound α-YbAlB4. The QC origin is attributed to the anisotropic hybridization between the conduction and localized f-electrons. These findings suggest a new route to bypass the large valence energy scale in developing the QC.

Exceptional points (EPs) are degeneracies at which two or more eigenvalues and eigenstates of a physical system coalesce. Dynamically encircling EPs by varying the parameters of a non-Hermitian system enables chiral mode switching, that is, the final state of the system upon a closed loop in parameter space depends on the encircling handedness. In conventional schemes, the parametric evolution during the encircling process has to be sufficiently slow to ensure adiabaticity. Here, we show that fast parametric evolution along the parameter space boundary of the system Hamiltonian can relax this constraint. The proposed scheme enables highly efficient transmission and more compact footprint for asymmetric mode converters. We experimentally demonstrate these principles in a 57 μm-long double-coupled silicon waveguide system, enabling chiral mode switching with near-unity transmission efficiency at 1550 nm. This demonstration paves the way towards high-efficiency and highly integrated chiral mode switching for a wide range of practical applications.

We demonstrate a carbon capture system based on pH swing cycles driven through proton-coupled electron transfer of sodium (3,3'-(phenazine-2,3-diylbis(oxy))bis(propane-1-sulfonate)) (DSPZ) molecules. Electrochemical reduction of DSPZ causes an increase of hydroxide concentration, which absorbs CO2; subsequent electrochemical oxidation of the reduced DSPZ consumes the hydroxide, causing CO2 outgassing. The measured electrical work of separating CO2 from a binary mixture with N2, at CO2 inlet partial pressures ranging from 0.1 to 0.5 bar, and releasing to a pure CO2 exit stream at 1.0 bar, was measured for electrical current densities of 20-150 mA cm-2. The work for separating CO2 from a 0.1 bar inlet and concentrating into a 1 bar exit is 61.3 kJ molCO2-1 at a current density of 20 mA cm-2. Depending on the initial composition of the electrolyte, the molar cycle work for capture from 0.4 mbar extrapolates to 121-237 kJ molCO2-1 at 20 mA cm-2. We also introduce an electrochemical rebalancing method that extends cell lifetime by recovering the initial electrolyte composition after it is perturbed by side reactions. We discuss the implications of these results for future low-energy electrochemical carbon capture devices.

From the motion of fish and birds, to migrating herds of ungulates, collective motion has attracted people for centuries. Active soft matter exhibits a plethora of emergent dynamic behaviors that mimic those of biological systems. Here we introduce an active system composed of dynamic dissipative solitons, i.e. directrons, which mimics the collective motion of living systems. Although the directrons are inanimate, artificial particle-like solitonic field configurations, they locally align their motions like their biological counterparts. Driven by external electric fields, hundreds of directrons are generated in a chiral nematic film. They start with random motions but self-organize into flocks and synchronize their motions. The directron flocks exhibit rich dynamic behaviors and induce population density fluctuations far larger than those in thermal equilibrium systems. They exhibit "turbulent" swimming patterns manifested by transient vortices and jets. They even distinguish topological defects, heading towards defects of positive topological strength and avoiding negative ones.

Federated learning is a privacy-preserving machine learning technique to train intelligent models from decentralized data, which enables exploiting private data by communicating local model updates in each iteration of model learning rather than the raw data. However, model updates can be extremely large if they contain numerous parameters, and many rounds of communication are needed for model training. The huge communication cost in federated learning leads to heavy overheads on clients and high environmental burdens. Here, we present a federated learning method named FedKD that is both communication-efficient and effective, based on adaptive mutual knowledge distillation and dynamic gradient compression techniques. FedKD is validated on three different scenarios that need privacy protection, showing that it maximally can reduce 94.89% of communication cost and achieve competitive results with centralized model learning. FedKD provides a potential to efficiently deploy privacy-preserving intelligent systems in many scenarios, such as intelligent healthcare and personalization.

The generation of a two-octave supercontinuum from the visible to mid-infrared (700-2800 nm) in a non-silica graded-index multimode fiber is reported. The fiber design is based on a nanostructured core comprised of two types of drawn lead-bismuth-gallate glass rods with different refractive indices. This yields an effective parabolic index profile and ten times increased nonlinearity when compared to silica fibers. Using femtosecond pulse pumping at wavelengths in both normal and anomalous dispersion regimes, a detailed study is carried out into the supercontinuum generating mechanisms and instabilities seeded by periodic self-imaging. Significantly, suitable injection conditions in the high power regime are found to result in the output beam profile showing clear signatures of beam self-cleaning from nonlinear mode mixing. Experimental observations are interpreted using spatio-temporal 3+1D numerical simulations of the generalized nonlinear Schrödinger equation, and simulated spectra are in excellent agreement with experiment over the full two-octave spectral bandwidth. Experimental comparison with the generation of supercontinuum in a silica graded-index multimode fiber shows that the enhanced nonlinear refractive index of the lead-bismuth-gallate fiber yields a spectrum with a significantly larger bandwidth. These results demonstrate a new pathway towards the generation of bright, ultrabroadband light sources in the mid-infrared.

Honeybees are highly social insects with a rich behavioral repertoire and are a versatile model for neurobiological research. Their gut microbiota comprises a limited number of host-restricted bacterial phylotypes that are important for honeybee health. However, it remains unclear how specific gut members affect honeybee behaviors. Here, we find that antibiotic exposure disturbs the gut community and influences honeybee phenotypes under field conditions. Using laboratory-generated gnotobiotic bees, we show that a normal gut microbiota is required for olfactory learning and memory abilities. Brain transcriptomic profiling reveals distinct brain gene expression patterns between microbiota-free and conventional bees. Subsequent metabolomic analyses of both hemolymph and gut samples show that the microbiota mainly regulates tryptophan metabolism. Our results indicate that host-specific Lactobacillus strains promote memory behavior by transforming tryptophan to indole derivatives that activate the host aryl hydrocarbon receptor. Our findings highlight the contributions of specific gut members to honeybee neurological processes, thus providing a promising model to understand host-microbe interactions.

The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type CaV3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. CaV3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type CaV channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the CaV3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.

Transcriptionally active loci are particularly prone to breakage and mounting evidence suggests that DNA Double-Strand Breaks arising in active genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loop accumulation and dissolution. Here, we uncover a function for the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in an R-loop dissolution-deficient background, we find that BLM promotes cell death. We report that upon excessive RNA:DNA hybrid accumulation, DNA synthesis is enhanced at DSBs, in a manner that depends on BLM and POLD3. Altogether our work unveils a role for BLM at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at transcription-associated DSBs.

The Indonesian Throughflow plays an important role in the global ocean circulation and climate. Existing studies of the Indonesian Throughflow have focused on the Makassar Strait and the exit straits, where the upper thermocline currents carry North Pacific waters to the Indian Ocean. Here we show, using mooring observations, that a previous unknown intermediate western boundary current (with the core at ~1000 m depth) exists in the Maluku Sea, which transports intermediate waters (primarily the Antarctic Intermediate Water) from the Pacific into the Seram-Banda Seas through the Lifamatola Passage above the bottom overflow. Our results suggest the importance of the western boundary current in global ocean intermediate circulation and overturn. We anticipate that our study is the beginning of more extensive investigations of the intermediate circulation of the Indo-Pacific ocean in global overturn, which shall improve our understanding of ocean heat and CO2 storages significantly.

Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated by cohesin and CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale and to what extent fine-scale regulatory interactions depend on loop extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, which has enabled us to generate the most detailed local interaction data to date (20 bp resolution) and precisely investigate the effects of cohesin and CTCF depletion on chromatin architecture. Our data reveal that cis-regulatory elements have distinct internal nano-scale structures, within which local insulation is dependent on CTCF, but which are independent of cohesin. In contrast, we find that depletion of cohesin causes a subtle reduction in longer-range enhancer-promoter interactions and that CTCF depletion can cause rewiring of regulatory contacts. Together, our data show that loop extrusion is not essential for enhancer-promoter interactions, but contributes to their robustness and specificity and to precise regulation of gene expression.

Magnetic sensors are widely used in our daily life for assessing the position and orientation of objects. Recently, the magnetic sensing modality has been introduced to electronic skins (e-skins), enabling remote perception of moving objects. However, the integration density of magnetic sensors is limited and the vector properties of the magnetic field cannot be fully explored since the sensors can only perceive field components in one or two dimensions. Here, we report an approach to fabricate high-density integrated active matrix magnetic sensor with three-dimensional (3D) magnetic vector field sensing capability. The 3D magnetic sensor is composed of an array of self-assembled micro-origami cubic architectures with biased anisotropic magnetoresistance (AMR) sensors manufactured in a wafer-scale process. Integrating the 3D magnetic sensors into an e-skin with embedded magnetic hairs enables real-time multidirectional tactile perception. We demonstrate a versatile approach for the fabrication of active matrix integrated 3D sensor arrays using micro-origami and pave the way for new electronic devices relying on the autonomous rearrangement of functional elements in space.

Most stored groundwater is 'fossil' in its age, having been under the ground for more than ~12 thousand years. Mapping where wells tap fossil aquifers is relevant for water quality and quantity management. Nevertheless, the prevalence of wells that tap fossil aquifers is not known. Here we show that wells that are sufficiently deep to tap fossil aquifers are widespread, though they remain outnumbered by shallower wells in most areas. Moreover, the proportion of newly drilled wells that are deep enough to tap fossil aquifers has increased over recent decades. However, this widespread and increased drilling of wells into fossil aquifers is not necessarily associated with groundwater depletion, emphasizing that the presence of fossil groundwater does not necessarily indicate a non-renewable water supply. Our results highlight the importance of safeguarding fossil groundwater quality and quantity to meet present and future water demands.

Accurate delineation of individual teeth and alveolar bones from dental cone-beam CT (CBCT) images is an essential step in digital dentistry for precision dental healthcare. In this paper, we present an AI system for efficient, precise, and fully automatic segmentation of real-patient CBCT images. Our AI system is evaluated on the largest dataset so far, i.e., using a dataset of 4,215 patients (with 4,938 CBCT scans) from 15 different centers. This fully automatic AI system achieves a segmentation accuracy comparable to experienced radiologists (e.g., 0.5% improvement in terms of average Dice similarity coefficient), while significant improvement in efficiency (i.e., 500 times faster). In addition, it consistently obtains accurate results on the challenging cases with variable dental abnormalities, with the average Dice scores of 91.5% and 93.0% for tooth and alveolar bone segmentation. These results demonstrate its potential as a powerful system to boost clinical workflows of digital dentistry.

Neural generative models can be used to learn complex probability distributions from data, to sample from them, and to produce probability density estimates. We propose a computational framework for developing neural generative models inspired by the theory of predictive processing in the brain. According to predictive processing theory, the neurons in the brain form a hierarchy in which neurons in one level form expectations about sensory inputs from another level. These neurons update their local models based on differences between their expectations and the observed signals. In a similar way, artificial neurons in our generative models predict what neighboring neurons will do, and adjust their parameters based on how well the predictions matched reality. In this work, we show that the neural generative models learned within our framework perform well in practice across several benchmark datasets and metrics and either remain competitive with or significantly outperform other generative models with similar functionality (such as the variational auto-encoder).

Recent discovery of an unusual bond between Na and B in NaBH3- motivated us to look for potentially similar bonds, which remained unnoticed among systems isoelectronic with NaBH3-. Here, we report a novel family of collective interactions and a measure called exchange-correlation interaction collectivity index (ICIXC; [Formula: see text]) to characterize the extent of collective versus pairwise bonding. Unlike conventional bonds in which ICIXC remains close to one, in collective interactions ICIXC may approach zero. We show that collective interactions are commonplace among widely used organometallics, as well as among boron and aluminum complexes with the general formula [Ma+AR3]b- (A: C, B or Al). In these species, the metal atom interacts more efficiently with the substituents (R) on the central atoms than the central atoms (A) upon forming efficient collective interactions. Furthermore, collective interactions were also found among fluorine atoms of XFn systems (X: B or C). Some of organolithium and organomagnesium species have the lowest ICIXC among the more than 100 studied systems revealing the fact that collective interactions are rather a rule than an exception among organometallic species.

Single-atom Fe-N-C catalysts has attracted widespread attentions in the oxygen reduction reaction (ORR). However, the origin of ORR activity on Fe-N-C catalysts is still unclear, which hinder the further improvement of Fe-N-C catalysts. Herein, we provide a model to understand the ORR activity of Fe-N4 site from the spatial structure and energy level of the frontier orbitals by density functional theory calculations. Taking the regulation of divacancy defects on Fe-N4 site ORR activity as examples, we demonstrate that the hybridization between Fe 3dz2, 3dyz (3dxz) and O2 π* orbitals is the origin of Fe-N4 ORR activity. We found that the Fe-O bond length, the d-band center gap of spin states, the magnetic moment of Fe site and *O2 as descriptors can accurately predict the ORR activity of Fe-N4 site. Furthermore, these descriptors and ORR activity of Fe-N4 site are mainly distributed in two regions with obvious difference, which greatly relate to the height of Fe 3d projected orbital in the Z direction. This work provides a new insight into the ORR activity of single-atom M-N-C catalysts.

Eighty percent of US oil and natural gas (O&G) production sites are low production well sites, with average site-level production ≤15 barrels of oil equivalent per day and producing only 6% of the nation's O&G output in 2019. Here, we integrate national site-level O&G production data and previously reported site-level CH4 measurement data (n = 240) and find that low production well sites are a disproportionately large source of US O&G well site CH4 emissions, emitting more than 4 (95% confidence interval: 3-6) teragrams, 50% more than the total CH4 emissions from the Permian Basin, one of the world's largest O&G producing regions. We estimate low production well sites represent roughly half (37-75%) of all O&G well site CH4 emissions, and a production-normalized CH4 loss rate of more than 10%-a factor of 6-12 times higher than the mean CH4 loss rate of 1.5% for all O&G well sites in the US. Our work suggests that achieving significant reductions in O&G CH4 emissions will require mitigation of emissions from low production well sites.

Rising emissions from wildfires over recent decades in the Pacific Northwest are known to counteract the reductions in human-produced aerosol pollution over North America. Since amplified Pacific Northwest wildfires are predicted under accelerating climate change, it is essential to understand both local and transported contributions to air pollution in North America. Here, we find corresponding increases for carbon monoxide emitted from the Pacific Northwest wildfires and observe significant impacts on both local and down-wind air pollution. Between 2002 and 2018, the Pacific Northwest atmospheric carbon monoxide abundance increased in August, while other months showed decreasing carbon monoxide, so modifying the seasonal pattern. These seasonal pattern changes extend over large regions of North America, to the Central USA and Northeast North America regions, indicating that transported wildfire pollution could potentially impact the health of millions of people.

Surface modification on Jupiter's volcanically active moon, Io, has to date been attributed almost exclusively to lava emplacement and volcanic plume deposits. Here we demonstrate that wind-blown transport of sediment may also be altering the Ionian surface. Specifically, shallow subsurface interactions between lava and Io's widespread sulfur dioxide (SO2) frost can produce localized sublimation vapor flows with sufficient gas densities to enable particle saltation. We calculate anticipated outgassing velocities from lava-SO2 frost interactions, and compare these to the saltation thresholds predicted when accounting for the tenuous nature of the sublimated vapor. We find that saltation may occur if frost temperatures surpass 155 K. Finally we make the first measurements of the dimensions of linear features in images from the Galileo probe, previously termed "ridges", which demonstrate certain similarities to dunes on other planetary bodies. Io joins a growing list of bodies with tenuous and transient atmospheres where aeolian sediment transport may be an important control on the landscape.

Tuning the local reaction environment is an important and challenging issue for determining electrochemical performances. Herein, we propose a strategy of intentionally engineering the local reaction environment to yield highly active catalysts. Taking Ptδ- nanoparticles supported on oxygen vacancy enriched MgO nanosheets as a prototypical example, we have successfully created a local acid-like environment in the alkaline medium and achieve excellent hydrogen evolution reaction performances. The local acid-like environment is evidenced by operando Raman, synchrotron radiation infrared and X-ray absorption spectroscopy that observes a key H3O+ intermediate emergence on the surface of MgO and accumulation around Ptδ- sites during electrocatalysis. Further analysis confirms that the critical factors of the forming the local acid-like environment include: the oxygen vacancy enriched MgO facilitates H2O dissociation to generate H3O+ species; the F centers of MgO transfers its unpaired electrons to Pt, leading to the formation of electron-enriched Ptδ- species; positively charged H3O+ migrates to negatively charged Ptδ- and accumulates around Ptδ- nanoparticles due to the electrostatic attraction, thus creating a local acidic environment in the alkaline medium.

The gut microbiota represents a large community of microorganisms that play an important role in immune regulation and maintenance of homeostasis. Living bacteria receive increasing interest as potential therapeutics for gut disorders, because they inhibit the colonization of pathogens and positively regulate the composition of bacteria in gut. However, these treatments are often accompanied by antibiotic administration targeting pathogens. In these cases, the efficacy of therapeutic bacteria is compromised by their susceptibility to antibiotics. Here, we demonstrate that a single-cell coating composed of tannic acids and ferric ions, referred to as 'nanoarmor', can protect bacteria from the action of antibiotics. The nanoarmor protects both Gram-positive and Gram-negative bacteria against six clinically relevant antibiotics. The multiple interactions between the nanoarmor and antibiotic molecules allow the antibiotics to be effectively absorbed onto the nanoarmor. Armored probiotics have shown the ability to colonize inside the gastrointestinal tracts of levofloxacin-treated rats, which significantly reduced antibiotic-associated diarrhea (AAD) resulting from the levofloxacin-treatment and improved some of the pre-inflammatory symptoms caused by AAD. This nanoarmor strategy represents a robust platform to enhance the potency of therapeutic bacteria in the gastrointestinal tracts of patients receiving antibiotics and to avoid the negative effects of antibiotics in the gastrointestinal tract.

The gene regulation underlying axon formation and its exclusiveness to neurons remains elusive. TRIM46 is postulated to determine axonal fate. We show Trim46 mRNA is expressed before axonogenesis, but TRIM46 protein level is inhibited by alternative splicing of two cassette exons coupled separately to stability controls of Trim46 mRNA and proteins, effectively inducing functional knockout of TRIM46 proteins. Exon 8 inclusion causes nonsense-mediated mRNA decay of Trim46 transcripts. PTBP2-mediated exon 10 skipping produces transcripts encoding unstable TRIM46 proteins. During axonogenesis, transcriptional activation, decreased exon 8 inclusion, and enhanced exon 10 inclusion converge to increase TRIM46 proteins, leading to its neural-specific expression. Genetic deletion of these exons alters TRIM46 protein levels and shows TRIM46 is instructive though not always required for AnkG localization nor a determinant of AnkG density. Therefore, two concurrently but independently regulated alternative exons orchestrate the temporal induction and tissue-specific expression of TRIM46 proteins to mediate axon formation.

Rare earth (RE3+)-doped phosphors generally suffer from thermal quenching, in which their photoluminescence (PL) intensities decrease at high temperatures. Herein, we report a class of unique two-dimensional negative-thermal-expansion phosphor of Sc2(MoO4)3:Yb/Er. By virtue of the reduced distances between sensitizers and emitters as well as confined energy migration with increasing the temperature, a 45-fold enhancement of green upconversion (UC) luminescence and a 450-fold enhancement of near-infrared downshifting (DS) luminescence of Er3+ are achieved upon raising the temperature from 298 to 773 K. The thermally boosted UC and DS luminescence mechanism is systematically investigated through in situ temperature-dependent Raman spectroscopy, synchrotron X-ray diffraction and PL dynamics. Moreover, the luminescence lifetime of 4I13/2 of Er3+ in Sc2(MoO4)3:Yb/Er displays a strong temperature dependence, enabling luminescence thermometry with the highest relative sensitivity of 12.3%/K at 298 K and low temperature uncertainty of 0.11 K at 623 K. These findings may gain a vital insight into the design of negative-thermal-expansion RE3+-doped phosphors for versatile applications.

Access to clinically relevant small cell lung cancer (SCLC) tissue is limited because surgical resection is rare in metastatic SCLC. Patient-derived xenografts (PDX) and circulating tumor cell-derived xenografts (CDX) have emerged as valuable tools to characterize SCLC. Here, we present a resource of 46 extensively annotated PDX/CDX models derived from 33 patients with SCLC. We perform multi-omic analyses, using targeted tumor next-generation sequencing, RNA-sequencing, and immunohistochemistry to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these SCLC models. SCLC subtypes characterized by transcriptional regulators, ASCL1, NEUROD1 and POU2F3 are confirmed in this cohort. A subset of SCLC clinical specimens, including matched PDX/CDX and clinical specimen pairs, confirm that the primary features and genomic and proteomic landscapes of the tumors of origin are preserved in the derivative PDX models. This resource provides a powerful system to study SCLC biology.

Decision-making is a continuous and dynamic process with prior experience reflected in and used by the brain to guide adaptive behavior. However, most neurobiological studies constrain behavior and/or analyses to task-related variables, not accounting for the continuous internal and temporal space in which they occur. We show mice rely on information learned through recent and longer-term experience beyond just prior actions and reward - including checking behavior and the passage of time - to guide self-initiated, self-paced, and self-generated actions. These experiences are represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrates this information to bias strategy-level decision-making, and DMS projections reflect specific aspects of this recent experience to guide actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.

Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown. Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1WT/S52F mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects. Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1WT/S52F mice. Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.

Actin polymerization dynamics regulated by actin-binding proteins are essential for various cellular functions. The cofilin family of proteins are potent regulators of actin severing and filament disassembly. The structural basis for cofilin-isoform-specific severing activity is poorly understood as their high-resolution structures in complex with filamentous actin (F-actin) are lacking. Here, we present the atomic-resolution structure of the muscle-tissue-specific isoform, cofilin-2 (CFL2), assembled on ADP-F-actin, determined by magic-angle-spinning (MAS) NMR spectroscopy and data-guided molecular dynamics (MD) simulations. We observe an isoform-specific conformation for CFL2. This conformation is the result of a unique network of hydrogen bonding interactions within the α2 helix containing the non-conserved residue, Q26. Our results indicate F-site interactions that are specific between CFL2 and ADP-F-actin, revealing mechanistic insights into isoform-dependent F-actin disassembly.

The emergence of new highly pathogenic and drug-resistant influenza strains urges the development of novel therapeutics for influenza A virus (IAV). Here, we report the discovery of an anti-IAV microbial metabolite called APL-16-5 that was originally isolated from the plant endophytic fungus Aspergillus sp. CPCC 400735. APL-16-5 binds to both the E3 ligase TRIM25 and IAV polymerase subunit PA, leading to TRIM25 ubiquitination of PA and subsequent degradation of PA in the proteasome. This mode of action conforms to that of a proteolysis targeting chimera which employs the cellular ubiquitin-proteasome machinery to chemically induce the degradation of target proteins. Importantly, APL-16-5 potently inhibits IAV and protects mice from lethal IAV infection. Therefore, we have identified a natural microbial metabolite with potent in vivo anti-IAV activity and the potential of becoming a new IAV therapeutic. The antiviral mechanism of APL-16-5 opens the possibility of improving its anti-IAV potency and specificity by adjusting its affinity for TRIM25 and viral PA protein through medicinal chemistry.

The development of synthetic methodologies towards enhanced performance in biomass conversion is desirable due to the growing energy demand. Here we design two types of Ru impregnated MIL-100-Cr defect engineered metal-organic frameworks (Ru@DEMOFs) by incorporating defective ligands (DLs), aiming at highly efficient catalysts for biomass hydrogenation. Our results show that Ru@DEMOFs simultaneously exhibit boosted recyclability, selectivity and activity with the turnover frequency being about 10 times higher than the reported values of polymer supported Ru towards D-glucose hydrogenation. This work provides in-depth insights into (i) the evolution of various defects in the cationic framework upon DLs incorporation and Ru impregnation, (ii) the special effect of each type of defects on the electron density of Ru nanoparticles and activation of reactants, and (iii) the respective role of defects, confined Ru particles and metal single active sites in the catalytic performance of Ru@DEMOFs for D-glucose selective hydrogenation as well as their synergistic catalytic mechanism.

P-bodies are conserved mRNP complexes that are implicated in determining mRNA fate by affecting translation and mRNA decay. In this report, we identify RGG-motif containing translation repressor protein Sbp1 as a disassembly factor of P-bodies since disassembly of P-bodies is defective in Δsbp1. RGG-motif is necessary and sufficient to rescue the PB disassembly defect in Δsbp1. Binding studies using purified proteins revealed that Sbp1 physically interacts with Edc3 and Sbp1-Edc3 interaction competes with Edc3-Edc3 interaction. Purified Edc3 forms assemblies, promoted by the presence of RNA and NADH and the addition of purified Sbp1, but not the RGG-deletion mutant, leads to significantly decreased Edc3 assemblies. We further note that the aggregates of human EWSR1 protein, implicated in neurodegeneration, are more persistent in the absence of Sbp1 and overexpression of EWSR1 in Δsbp1 leads to a growth defect. Taken together, our observations suggest a role of Sbp1 in disassembly, which could apply to disease-relevant heterologous protein-aggregates.

Development of next-generation solid-state Li-ion batteries requires not only electrolytes with high room-temperature (RT) ionic conductivities but also a fundamental understanding of the ionic transport in solids. In spite of considerable work, only a few lithium conductors are known with the highest RT ionic conductivities ~ 0.01 S/cm and the lowest activation energies ~0.2 eV. New design strategy and novel ionic conduction mechanism are needed to expand the pool of high-performance lithium conductors as well as achieve even higher RT ionic conductivities. Here, we theoretically show that lithium conductors with RT ionic conductivity over 0.1 S/cm and low activation energies ~ 0.1 eV can be achieved by incorporating cluster-dynamics into an argyrodite structure. The extraordinary superionic metrics are supported by conduction mechanism characterized as a relay between local and long-range ionic diffusions, as well as correlational dynamics beyond the paddle-wheel effect.

A growing number of studies have used stylized network models of communication to predict brain function from structure. Most have focused on a small set of models applied globally. Here, we compare a large number of models at both global and regional levels. We find that globally most predictors perform poorly. At the regional level, performance improves but heterogeneously, both in terms of variance explained and the optimal model. Next, we expose synergies among predictors by using pairs to jointly predict FC. Finally, we assess age-related differences in global and regional coupling across the human lifespan. We find global decreases in the magnitude of structure-function coupling with age. We find that these decreases are driven by reduced coupling in sensorimotor regions, while higher-order cognitive systems preserve local coupling with age. Our results describe patterns of structure-function coupling across the cortex and how this may change with age.

The ubiquitin ligase NEDD4 promotes neural crest cell (NCC) survival and stem-cell like properties to regulate craniofacial and peripheral nervous system development. However, how ubiquitination and NEDD4 control NCC development remains unknown. Here we combine quantitative analysis of the proteome, transcriptome and ubiquitinome to identify key developmental signalling pathways that are regulated by NEDD4. We report 276 NEDD4 targets in NCCs and show that loss of NEDD4 leads to a pronounced global reduction in specific ubiquitin lysine linkages. We further show that NEDD4 contributes to the regulation of the NCC actin cytoskeleton by controlling ubiquitination and turnover of Profilin 1 to modulate filamentous actin polymerization. Taken together, our data provide insights into how NEDD4-mediated ubiquitination coordinates key regulatory processes during NCC development.

Ultrafast atomic vibrations mediate heat transport, serve as fingerprints for chemical bonds and drive phase transitions in condensed matter systems. Light pulses shorter than the atomic oscillation period can not only probe, but even stimulate and control collective excitations. In general, such interactions are performed with free-propagating pulses. Here, we demonstrate intra-cavity excitation and time-domain sampling of coherent optical phonons inside an active laser oscillator. Employing real-time spectral interferometry, we reveal that Terahertz beats of Raman-active optical phonons are the origin of soliton bound-states - also termed "Soliton molecules" - and we resolve a coherent coupling mechanism of phonon and intra-cavity soliton motion. Concurring electronic and nuclear refractive nonlinearities generate distinct soliton trajectories and, effectively, enhance the time-domain Raman signal. We utilize the intrinsic soliton motion to automatically perform highspeed Raman spectroscopy of the intra-cavity crystal. Our results pinpoint the impact of Raman-induced soliton interactions in crystalline laser media and microresonators, and offer unique perspectives toward ultrafast nonlinear phononics by exploiting the coupling of atomic motion and solitons inside a cavity.

Tissue-specific transcriptional activity is silenced in mitotic cells but it remains unclear whether the mitotic regulatory machinery interacts with tissue-specific transcriptional programs. We show that such cross-talk involves the controlled interaction between core subunits of the anaphase-promoting complex (APC) and the ID2 substrate. The N-terminus of ID2 is independently and structurally compatible with a pocket composed of core APC/C subunits that may optimally orient ID2 onto the APCCDH1 complex. Phosphorylation of serine-5 by CDK1 prevented the association of ID2 with core APC, impaired ubiquitylation and stabilized ID2 protein at the mitosis-G1 transition leading to inhibition of basic Helix-Loop-Helix (bHLH)-mediated transcription. The serine-5 phospho-mimetic mutant of ID2 that inefficiently bound core APC remained stable during mitosis, delayed exit from mitosis and reloading of bHLH transcription factors on chromatin. It also locked cells into a "mitotic stem cell" transcriptional state resembling the pluripotent program of embryonic stem cells. The substrates of APCCDH1 SKP2 and Cyclin B1 share with ID2 the phosphorylation-dependent, D-box-independent interaction with core APC. These results reveal a new layer of control of the mechanism by which substrates are recognized by APC.

Magnetic molecules known as molecular nanomagnets (MNMs) may be the key to ultra-high density data storage. Thus, novel strategies on how to design MNMs are desirable. Here, inspired by the hexagonal structure of the hardest intermetallic magnet SmCo5, we have synthesized a nanomagnetic molecule where the central lanthanide (Ln) ErIII is coordinated solely by three transition metal ions (TM) in a perfectly trigonal planar fashion. This intermetallic molecule [ErIII(ReICp2)3] (ErRe3) starts a family of molecular nanomagnets (MNM) with unsupported Ln-TM bonds and paves the way towards molecular intermetallics with strong direct magnetic exchange interactions-a promising route towards high-performance single-molecule magnets.

Dynamic polarization control is crucial for emerging highly integrated photonic systems with diverse metasurfaces being explored for its realization, but efficient, fast, and broadband operation remains a cumbersome challenge. While efficient optical metasurfaces (OMSs) involving liquid crystals suffer from inherently slow responses, other OMS realizations are limited either in the operating wavelength range (due to resonances involved) or in the range of birefringence tuning. Capitalizing on our development of piezoelectric micro-electro-mechanical system (MEMS) based dynamic OMSs, we demonstrate reflective MEMS-OMS dynamic wave plates (DWPs) with high polarization conversion efficiencies (∼75%), broadband operation (∼100 nm near the operating wavelength of 800 nm), fast responses (<0.4 milliseconds) and full-range birefringence control that enables completely encircling the Poincaré sphere along trajectories determined by the incident light polarization and DWP orientation. Demonstrated complete electrical control over light polarization opens new avenues in further integration and miniaturization of optical networks and systems.

Copper hydrides are important hydrogenation catalysts, but their poor stability hinders the practical applications. Ligand engineering is an effective strategy to tackle this issue. An amidinate ligand, N,N'-Di(5-trifluoromethyl-2-pyridyl)formamidinate (Tf-dpf) with four N-donors has been applied as a protecting agent in the synthesis of stable copper hydride clusters: Cu11H3(Tf-dpf)6(OAc)2 (Cu11) with three interfacial μ5-H and [Cu12H3(Tf-dpf)6(OAc)2]·OAc (Cu12) with three interstitial μ6-H. A solvent-triggered reversible interconversion between Cu11 and Cu12 has been observed thanks to the flexibility of Tf-dpf. Cu11 shows high activity in the reduction of 4-nitrophenol to 4-aminophenol, while Cu12 displays very low activity. Deuteration experiments prove that the type of hydride is the key in dictating the catalytic activity, for the interfacial μ5-H species in Cu11 are involved in the catalytic cycle whereas the interstitial μ6-H species in Cu12 are not. This work highlights the role of hydrides with regard to catalytic hydrogenation activity.

Herein, we report a strategy to construct highly efficient perfluorooctanoic acid (PFOA) adsorbents by installing synergistic electrostatic/hydrophobic sites onto porous organic polymers (POPs). The constructed model material of PAF-1-NDMB (NDMB = N,N-dimethyl-butylamine) demonstrates an exceptionally high PFOA uptake capacity over 2000 mg g-1, which is 14.8 times enhancement compared with its parent material of PAF-1. And it is 32.0 and 24.1 times higher than benchmark materials of DFB-CDP (β-cyclodextrin (β-CD)-based polymer network) and activated carbon under the same conditions. Furthermore, PAF-1-NDMB exhibits the highest k2 value of 24,000 g mg-1 h-1 among all reported PFOA sorbents. And it can remove 99.99% PFOA from 1000 ppb to <70 ppt within 2 min, which is lower than the advisory level of Environmental Protection Agency of United States. This work thus not only provides a generic approach for constructing PFOA adsorbents, but also develops POPs as a platform for PFOA capture.

Developing precise nanomedicines to improve the transport of anticancer drugs into tumor tissue and to the final action site remains a critical challenge. Here, we present a bioorthogonal in situ assembly strategy for prolonged retention of nanomedicines within tumor areas to act as drug depots. After extravasating into the tumor site, the slightly acidic microenvironment induces the exposure of cysteine on the nanoparticle surface, which subsequently undergoes a bioorthogonal reaction with the 2-cyanobenzothiazole group of another neighboring nanoparticle, enabling the formation of micro-sized drug depots to enhance drug retention and enrichment. This in situ nanoparticle assembly strategy remarkably improves the antimetastatic efficacy of extracellular-targeted drug batimastat, and also leads to the simultaneous enhanced retention and sustained release of multiple agents for combined cocktail chemoimmunotherapy to finally elicit a potent antitumor immune response. Such in situ assembly of nanomedicines represents a generalizable strategy towards extracellular drug delivery and cocktail chemoimmunotherapy.

AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.

Considerable uncertainty and debate exist in projecting the future capacity of forests to sequester atmospheric CO2. Here we estimate spatially explicit patterns of biomass loss by tree mortality (LOSS) from largely unmanaged forest plots to constrain projected (2015-2099) net primary productivity (NPP), heterotrophic respiration (HR) and net carbon sink in six dynamic global vegetation models (DGVMs) across continents. This approach relies on a strong relationship among LOSS, NPP, and HR at continental or biome scales. The DGVMs overestimated historical LOSS, particularly in tropical regions and eastern North America by as much as 5 Mg ha-1 y-1. The modeled spread of DGVM-projected NPP and HR uncertainties was substantially reduced in tropical regions after incorporating the field-based mortality constraint. The observation-constrained models show a decrease in the tropical forest carbon sink by the end of the century, particularly across South America (from 2 to 1.4 PgC y-1), and an increase in the sink in North America (from 0.8 to 1.1 PgC y-1). These results highlight the feasibility of using forest demographic data to empirically constrain forest carbon sink projections and the potential overestimation of projected tropical forest carbon sinks.

Neurovascular coupling is a fundamental brain mechanism that regulates local cerebral blood flow (CBF) in response to changes in neuronal activity. Functional imaging techniques are commonly used to record these changes in CBF as a proxy of neuronal activity to study the human brain. However, the mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models (laboratory rats and mice) that the neuronal activity-dependent increases in local CBF in the somatosensory cortex are prevented by saturation of the CO2-sensitive vasodilatory brain mechanism with surplus of exogenous CO2 or disruption of brain CO2/HCO3- transport by genetic knockdown of electrogenic sodium-bicarbonate cotransporter 1 (NBCe1) expression in astrocytes. A systematic review of the literature data shows that CO2 and increased neuronal activity recruit the same vasodilatory signaling pathways. These results and analysis suggest that CO2 mediates signaling between neurons and the cerebral vasculature to regulate brain blood flow in accord with changes in the neuronal activity.

Electrically actuated optomechanical resonators provide a route to quantum-coherent, bidirectional conversion of microwave and optical photons. Such devices could enable optical interconnection of quantum computers based on qubits operating at microwave frequencies. Here we present a platform for microwave-to-optical conversion comprising a photonic crystal cavity made of single-crystal, piezoelectric gallium phosphide integrated on pre-fabricated niobium circuits on an intrinsic silicon substrate. The devices exploit spatially extended, sideband-resolved mechanical breathing modes at ~3.2 GHz, with vacuum optomechanical coupling rates of up to g0/2π ≈ 300 kHz. The mechanical modes are driven by integrated microwave electrodes via the inverse piezoelectric effect. We estimate that the system could achieve an electromechanical coupling rate to a superconducting transmon qubit of ~200 kHz. Our work represents a decisive step towards integration of piezoelectro-optomechanical interfaces with superconducting quantum processors.

Material elements - which are lines, surfaces, or volumes behaving as passive, non-diffusive markers - provide an inherently geometric window into the intricate dynamics of chaotic flows. Their stretching and folding dynamics has immediate implications for mixing in the oceans or the atmosphere, as well as the emergence of self-sustained dynamos in astrophysical settings. Here, we uncover robust statistical properties of an ensemble of material loops in a turbulent environment. Our approach combines high-resolution direct numerical simulations of Navier-Stokes turbulence, stochastic models, and dynamical systems techniques to reveal predictable, universal features of these complex objects. We show that the loop curvature statistics become stationary through a dynamical formation process of high-curvature folds, leading to distributions with power-law tails whose exponents are determined by the large-deviations statistics of finite-time Lyapunov exponents of the flow. This prediction applies to advected material lines in a broad range of chaotic flows. To complement this dynamical picture, we confirm our theory in the analytically tractable Kraichnan model with an exact Fokker-Planck approach.

Erratum in Nat Commun. 2022 Apr 27;13(1):2410.

The epithelial to mesenchymal transition (EMT) has been proposed to contribute to the metastatic spread of breast cancer cells. EMT-promoting transcription factors determine a continuum of different EMT states. In contrast, estrogen receptor α (ERα) helps to maintain the epithelial phenotype of breast cancer cells and its expression is crucial for effective endocrine therapies. Determining whether and how EMT-associated transcription factors such as ZEB1 modulate ERα signaling during early stages of EMT could promote the discovery of therapeutic approaches to suppress metastasis. Here we show that, shortly after induction of EMT and while cells are still epithelial, ZEB1 modulates ERα-mediated transcription induced by estrogen or cAMP signaling in breast cancer cells. Based on these findings and our ex vivo and xenograft results, we suggest that the functional interaction between ZEB1 and ERα may alter the tissue tropism of metastatic breast cancer cells towards bone.

Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.

In the transition to decarbonized energy systems, Power-to-Gas (PtG) processes have the potential to connect the existing markets for electricity and hydrogen. Specifically, reversible PtG systems can convert electricity to hydrogen at times of ample power supply, yet they can also operate in the reverse direction to deliver electricity during times when power is relatively scarce. Here we develop a model for determining when reversible PtG systems are economically viable. We apply the model to the current market environment in both Germany and Texas and find that the reversibility feature of unitized regenerative fuel cells (solid oxide) makes them already cost-competitive at current hydrogen prices, provided the fluctuations in electricity prices are as pronounced as currently observed in Texas. We further project that, due to their inherent flexibility, reversible PtG systems would remain economically viable at substantially lower hydrogen prices in the future, provided recent technological trends continue over the coming decade.

Miniaturized image classifiers are potential for revolutionizing their applications in optical communication, autonomous vehicles, and healthcare. With subwavelength structure enabled directional diffraction and dispersion engineering, the light propagation through multi-layer metasurfaces achieves wavelength-selective image recognitions on a silicon photonic platform at telecommunication wavelength. The metasystems implement high-throughput vector-by-matrix multiplications, enabled by near 103 nanoscale phase shifters as weight elements within 0.135 mm2 footprints. The diffraction manifested computing capability incorporates the fabrication and measurement related phase fluctuations, and thus the pre-trained metasystem can handle uncertainties in inputs without post-tuning. Here we demonstrate three functional metasystems: a 15-pixel spatial pattern classifier that reaches near 90% accuracy with femtosecond inputs, a multi-channel wavelength demultiplexer, and a hyperspectral image classifier. The diffractive metasystem provides an alternative machine learning architecture for photonic integrated circuits, with densely integrated phase shifters, spatially multiplexed throughput, and data processing capabilities.

Combination therapy is preferred over single-targeted monotherapies for cancer treatment due to its efficiency and safety. However, identifying effective drug combinations costs time and resources. We propose a method for identifying potential drug combinations by bipartite network modelling of patient-related drug response data, specifically the Beat AML dataset. The median of cell viability is used as a drug potency measurement to reconstruct a weighted bipartite network, model drug-biological sample interactions, and find the clusters of nodes inside two projected networks. Then, the clustering results are leveraged to discover effective multi-targeted drug combinations, which are also supported by more evidence using GDSC and ALMANAC databases. The potency and synergy levels of selective drug combinations are corroborated against monotherapy in three cell lines for acute myeloid leukaemia in vitro. In this study, we introduce a nominal data mining approach to improving acute myeloid leukaemia treatment through combinatorial therapy.

Boron neutron capture therapy (BNCT) is an attractive approach to treat invasive malignant tumours due to binary heavy-particle irradiation, but its clinical applications have been hindered by boron delivery agents with low in vivo stability, poor biocompatibility, and limited application of combinational modalities. Here, we report boronsome, a carboranyl-phosphatidylcholine based liposome for combinational BNCT and chemotherapy. Theoretical simulations and experimental approaches illustrate high stability of boronsome. Then positron emission tomography (PET) imaging with Cu-64 labelled boronsome reveals high-specific tumour accumulation and long retention with a clear irradiation background. In particular, we show the suppression of tumour growth treated with boronsome with neutron irradiation and therapeutic outcomes are further improved by encapsulation of chemotherapy drugs, especially with PARP1 inhibitors. In sum, boronsome may be an efficient agent for concurrent chemoradiotherapy with theranostic properties against malignancies.

Staphylococcus aureus frequently causes infections that are challenging to treat, leading to high rates of persistent and relapsing infection. Here, to understand how the host environment influences treatment outcomes, we study the impact of human serum on staphylococcal antibiotic susceptibility. We show that serum triggers a high degree of tolerance to the lipopeptide antibiotic daptomycin and several other classes of antibiotic. Serum-induced daptomycin tolerance is due to two independent mechanisms. Firstly, the host defence peptide LL-37 induces tolerance by triggering the staphylococcal GraRS two-component system, leading to increased peptidoglycan accumulation. Secondly, GraRS-independent increases in membrane cardiolipin abundance are required for full tolerance. When both mechanisms are blocked, S. aureus incubated in serum is as susceptible to daptomycin as when grown in laboratory media. Our work demonstrates that host factors can significantly modulate antibiotic susceptibility via diverse mechanisms, and combination therapy may provide a way to mitigate this.

The resolution of chromatin conformation capture technologies keeps increasing, and the recent nucleosome resolution chromatin contact maps allow us to explore how fine-scale 3D chromatin organization is related to epigenomic states in human cells. Using publicly available Micro-C datasets, we develop a deep learning model, CAESAR, to learn a mapping function from epigenomic features to 3D chromatin organization. The model accurately predicts fine-scale structures, such as short-range chromatin loops and stripes, that Hi-C fails to detect. With existing epigenomic datasets from ENCODE and Roadmap Epigenomics Project, we successfully impute high-resolution 3D chromatin contact maps for 91 human tissues and cell lines. In the imputed high-resolution contact maps, we identify the spatial interactions between genes and their experimentally validated regulatory elements, demonstrating CAESAR's potential in coupling transcriptional regulation with 3D chromatin organization at high resolution.

Energy level alignment (ELA) at donor (D) -acceptor (A) heterojunctions is essential for understanding the charge generation and recombination process in organic photovoltaic devices. However, the ELA at the D-A interfaces is largely underdetermined, resulting in debates on the fundamental operating mechanisms of high-efficiency non-fullerene organic solar cells. Here, we systematically investigate ELA and its depth-dependent variation of a range of donor/non-fullerene-acceptor interfaces by fabricating and characterizing D-A quasi bilayers and planar bilayers. In contrast to previous assumptions, we observe significant vacuum level (VL) shifts existing at the D-A interfaces, which are demonstrated to be abrupt, extending over only 1-2 layers at the heterojunctions, and are attributed to interface dipoles induced by D-A electrostatic potential differences. The VL shifts result in reduced interfacial energetic offsets and increased charge transfer (CT) state energies which reconcile the conflicting observations of large energy level offsets inferred from neat films and large CT energies of donor - non-fullerene-acceptor systems.

Comment in Sci Signal. 2022 Jun 14;15(738):eabq5594.

The mechanistic pathways connecting ocean-atmosphere variability and terrestrial productivity are well-established theoretically, but remain challenging to quantify empirically. Such quantification will greatly improve the assessment and prediction of changes in terrestrial carbon sequestration in response to dynamically induced climatic extremes. The jet stream latitude (JSL) over the North Atlantic-European domain provides a synthetic and robust physical framework that integrates climate variability not accounted for by atmospheric circulation patterns alone. Surface climate impacts of north-south summer JSL displacements are not uniform across Europe, but rather create a northwestern-southeastern dipole in forest productivity and radial-growth anomalies. Summer JSL variability over the eastern North Atlantic-European domain (5-40E) exerts the strongest impact on European beech, inducing anomalies of up to 30% in modelled gross primary productivity and 50% in radial tree growth. The net effects of JSL movements on terrestrial carbon fluxes depend on forest density, carbon stocks, and productivity imbalances across biogeographic regions.

Interactions of the RNA polymerase II (Pol II) preinitiation complex (PIC) and paused early elongation complexes with the first downstream (+1) nucleosome are thought to be functionally important. However, current methods are limited for investigating these relationships, both for cellular chromatin and the human cytomegalovirus (HCMV) genome. Digestion with human DNA fragmentation factor (DFF) before immunoprecipitation (DFF-ChIP) precisely revealed both similarities and major differences in PICs driven by TBP on the host genome in comparison with PICs driven by TBP or the viral-specific, late initiation factor UL87 on the viral genome. Host PICs and paused Pol II complexes are frequently found in contact with the +1 nucleosome and paused Pol II can also be found in a complex involved in the initial invasion of the +1 nucleosome. In contrast, viral transcription complexes have very limited nucleosomal interactions, reflecting a relative lack of chromatinization of transcriptionally active regions of HCMV genomes.

Although Ru(II)-based agents are expected to be promising candidates for substituting Pt-drug, their in vivo biomedical applications are still limited by the short excitation/emission wavelengths and unsatisfactory therapeutic efficiency. Herein, we rationally design a Ru(II) metallacycle with excitation at 808 nm and emission over 1000 nm, namely Ru1085, which holds deep optical penetration (up to 6 mm) and enhanced chemo-phototherapy activity. In vitro studies indicate that Ru1085 exhibits prominent cell uptake and desirable anticancer capability against various cancer cell lines, especially for cisplatin-resistant A549 cells. Further studies reveal Ru1085 induces mitochondria-mediated apoptosis along with S and G2/M phase cell cycle arrest. Finally, Ru1085 shows precise NIR-II fluorescence imaging guided and long-term monitored chemo-phototherapy against A549 tumor with minimal side effects. We envision that the design of long-wavelength emissive metallacycle will offer emerging opportunities of metal-based agents for in vivo biomedical applications.

Methods that assay protein foldedness with proteomics have generated censuses of apparent protein folding stabilities in biological milieu. However, different censuses poorly correlate with each other. Here, we show that the reason for this is that methods targeting foldedness through monitoring amino acid sidechain reactivity also detect changes in conformation and ligand binding, which can be a substantial fraction of the data. We show that the reactivity of only one quarter of cysteine or methionine sidechains in proteins in a urea denaturation curve of mammalian cell lysate can be confidently explained by a two-state unfolding isotherm. Contrary to that expected from unfolding, up to one third of the cysteines decreased reactivity. These cysteines were enriched in proteins with functions relating to unfolded protein stress. One protein, chaperone HSPA8, displayed changes arising from ligand and cofactor binding. Unmasking this hidden information using the approaches outlined here should improve efforts to understand both folding and the remodeling of protein function directly in complex biological settings.

Efficient delivery of payload to intracellular targets has been identified as the central principle for nanomedicine development, while the extracellular targets are equally important for cancer treatment. Notably, the contribution of extracellularly distributed nanoparticles to therapeutic outcome is far from being understood. Herein, we develop a pH/light dual-responsive monochromatic ratiometric imaging nanoparticle (MRIN), which functions through sequentially lighting up the intracellular and extracellular fluorescence signals by acidic endocytic pH and near-infrared light. Enabled by MRIN nanotechnology, we accurately quantify the extracellular and intracellular distribution of nanoparticles in several tumor models, which account for 65-80% and 20-35% of total tumor exposure, respectively. Given that the majority of nanoparticles are trapped in extracellular regions, we successfully dissect the contribution of extracellularly distributed nanophotosensitizer to therapeutic efficacy, thereby maximize the treatment outcome. Our study provides key strategies to precisely quantify nanocarrier microdistribtion and engineer multifunctional nanomedicines for efficient theranostics.

The nutrient-rich tubers of the greater yam, Dioscorea alata L., provide food and income security for millions of people around the world. Despite its global importance, however, greater yam remains an orphan crop. Here, we address this resource gap by presenting a highly contiguous chromosome-scale genome assembly of D. alata combined with a dense genetic map derived from African breeding populations. The genome sequence reveals an ancient allotetraploidization in the Dioscorea lineage, followed by extensive genome-wide reorganization. Using the genomic tools, we find quantitative trait loci for resistance to anthracnose, a damaging fungal pathogen of yam, and several tuber quality traits. Genomic analysis of breeding lines reveals both extensive inbreeding as well as regions of extensive heterozygosity that may represent interspecific introgression during domestication. These tools and insights will enable yam breeders to unlock the potential of this staple crop and take full advantage of its adaptability to varied environments.

Cell type assignment is a major challenge for all types of high throughput single cell data. In many cases such assignment requires the repeated manual use of external and complementary data sources. To improve the ability to uniformly assign cell types across large consortia, platforms and modalities, we developed Cellar, a software tool that provides interactive support to all the different steps involved in the assignment and dataset comparison process. We discuss the different methods implemented by Cellar, how these can be used with different data types, how to combine complementary data types and how to analyze and visualize spatial data. We demonstrate the advantages of Cellar by using it to annotate several HuBMAP datasets from multi-omics single-cell sequencing and spatial proteomics studies. Cellar is open-source and includes several annotated HuBMAP datasets.

Erratum in Nat Commun. 2022 Apr 26;13(1):2385.

Scarce dissolved surface ocean concentrations of the essential algal micronutrient zinc suggest that Zn may influence the growth of phytoplankton such as diatoms, which are major contributors to marine primary productivity. However, the specific mechanisms by which diatoms acclimate to Zn deficiency are poorly understood. Using global proteomic analysis, we identified two proteins (ZCRP-A/B, Zn/Co Responsive Protein A/B) among four diatom species that became abundant under Zn/Co limitation. Characterization using reverse genetic techniques and homology data suggests putative Zn/Co chaperone and membrane-bound transport complex component roles for ZCRP-A (a COG0523 domain protein) and ZCRP-B, respectively. Metaproteomic detection of ZCRPs along a Pacific Ocean transect revealed increased abundances at the surface (<200 m) where dZn and dCo were scarcest, implying Zn nutritional stress in marine algae is more prevalent than previously recognized. These results demonstrate multiple adaptive responses to Zn scarcity in marine diatoms that are deployed in low Zn regions of the Pacific Ocean.

Maize unilateral cross-incompatibility (UCI) that causes non-Mendelian segregation ratios has been documented for more than a century. Ga1, Ga2, and Tcb1 are three major UCI systems, described but not fully understood. Here, we report comprehensive genetic studies on the Ga2 locus and map-based cloning of the tightly linked male determinant ZmGa2P and female determinant ZmGa2F that govern pollen-silk compatibility among different maize genotypes. Both determinants encode putative pectin methylesterases (PME). A significantly higher degree of methyl esterification is detected in the apical region of pollen tubes growing in incompatible silks. No direct interaction between ZmGa2P and ZmGa2F is detected in the yeast two-hybrid system implying a distinct mechanism from that of self-incompatibility (SI). We also demonstrate the feasibility of Ga2 as a reproductive barrier in commercial breeding programs and stacking Ga2 with Ga1 could strengthen the UCI market potentials.

Israel began administering a BNT162b2 booster dose to restore protection following the waning of the 2-dose vaccine. Biological studies have shown that a "fresh" booster dose leads to increased antibody levels compared to a fresh 2-dose vaccine, which may suggest increased effectiveness. To compare the real-world effectiveness of a fresh (up to 60 days) booster dose with that of a fresh 2-dose vaccine, we took advantage of a quasi-experimental study that compares populations that were eligible to receive the vaccine at different times due to age-dependent policies. Specifically, we compared the confirmed infection rates in adolescents aged 12-14 (215,653 individuals) who received the 2-dose vaccine and in adolescents aged 16-18 (103,454 individuals) who received the booster dose. Our analysis shows that the confirmed infection rate was lower by a factor of 3.7 (95% CI: 2.7 to 5.2) in the booster group.

Developing drugs increasingly relies on mechanistic modeling and simulation. Models that capture causal relations among genetic drivers of oncogenesis, functional plasticity, and host immunity complement wet experiments. Unfortunately, formulating such mechanistic cell-level models currently relies on hand curation, which can bias how data is interpreted or the priority of drug targets. In modeling molecular-level networks, rules and algorithms are employed to limit a priori biases in formulating mechanistic models. Here we combine digital cytometry with Bayesian network inference to generate causal models of cell-level networks linking an increase in gene expression associated with oncogenesis with alterations in stromal and immune cell subsets from bulk transcriptomic datasets. We predict how increased Cell Communication Network factor 4, a secreted matricellular protein, alters the tumor microenvironment using data from patients diagnosed with breast cancer and melanoma. Predictions are then tested using two immunocompetent mouse models for melanoma, which provide consistent experimental results.

Dendritic cells (DC) are traditionally classified according to their ontogeny and their ability to induce T cell response to antigens, however, the phenotypic and functional state of these cells in cancer does not necessarily align to the conventional categories. Here we show, by using 16 different stimuli in vitro that activated DCs in human blood are phenotypically and functionally dichotomous, and pure cultures of type 2 conventional dendritic cells acquire these states (termed Secretory and Helper) upon appropriate stimuli. PD-L1highICOSLlow Secretory DCs produce large amounts of inflammatory cytokines and chemokines but induce very low levels of T helper (Th) cytokines following co-culturing with T cells. Conversely, PD-L1lowICOSLhigh Helper DCs produce low levels of secreted factors but induce high levels and a broad range of Th cytokines. Secretory DCs bear a single-cell transcriptomic signature indicative of mature migratory LAMP3+ DCs associated with cancer and inflammation. Secretory DCs are linked to good prognosis in head and neck squamous cell carcinoma, and to response to checkpoint blockade in Melanoma. Hence, the functional dichotomy of DCs we describe has both fundamental and translational implications in inflammation and immunotherapy.

Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163+ macrophage numbers, which contribute to the worse outcome. Altogether, our findings provide insights into the mechanisms by which the sympathetic nervous system exerts cancer-protective properties in a mouse model of PDAC.

Structure determination of pharmaceutical compounds is invaluable for drug development but remains challenging for those that form as small crystals with defects. Bismuth subsalicylate, among the most commercially significant bismuth compounds, is an active ingredient in over-the-counter medications such as Pepto-Bismol, used to treat dyspepsia and H. pylori infections. Despite its century-long history, the structure of bismuth subsalicylate is still under debate. Here we show that advanced electron microscopy techniques, namely three-dimensional electron diffraction and scanning transmission electron microscopy, can give insight into the structure of active pharmaceutical ingredients that are difficult to characterize using conventional methods due to their small size or intricate structural features. Hierarchical clustering analysis of three-dimensional electron diffraction data from ordered crystals of bismuth subsalicylate revealed a layered structure. A detailed investigation using high-resolution scanning transmission electron microscopy showed variations in the stacking of layers, the presence of which has likely hindered structure solution by other means. Together, these modern electron crystallography techniques provide a toolbox for structure determination of active pharmaceutical ingredients and drug discovery, demonstrated by this study of bismuth subsalicylate.

Respiratory disease trials are profoundly affected by non-pharmaceutical interventions (NPIs) against COVID-19 because they perturb existing regular patterns of all seasonal viral epidemics. To address trial design with such uncertainty, we developed an epidemiological model of respiratory tract infection (RTI) coupled to a mechanistic description of viral RTI episodes. We explored the impact of reduced viral transmission (mimicking NPIs) using a virtual population and in silico trials for the bacterial lysate OM-85 as prophylaxis for RTI. Ratio-based efficacy metrics are only impacted under strict lockdown whereas absolute benefit already is with intermediate NPIs (eg. mask-wearing). Consequently, despite NPI, trials may meet their relative efficacy endpoints (provided recruitment hurdles can be overcome) but are difficult to assess with respect to clinical relevance. These results advocate to report a variety of metrics for benefit assessment, to use adaptive trial design and adapted statistical analyses. They also question eligibility criteria misaligned with the actual disease burden.

Robust underwater adhesion is challenging because a hydration layer impedes the interaction between substrates and adhesives. Phenolic adhesives inspired by marine creatures such as mussels were extensively studied, but these adhesives have not reached the adhesion strength and substrate diversity of Man-made dry adhesives. Here, we report a class of ultrastrong underwater adhesives with molecular phenolic designs extending beyond what nature has produced. These non-canonical phenolic polymers show versatile adhesion on various materials, with adhesion strengths exceeding 10 MPa on metal. Incorporating even just a small amount (<10%) of non-canonical phenolic groups into a polymer is sufficient for dramatically enhancing underwater adhesion, suggesting that this new class of phenolic materials will be incorporated into various industrial polymer systems in the future.

The ComFC protein is essential for natural transformation, a process that plays a major role in the spread of antibiotic resistance genes and virulence factors across bacteria. However, its role remains largely unknown. Here, we show that Helicobacter pylori ComFC is involved in DNA transport through the cell membrane, and is required for the handling of the single-stranded DNA once it is delivered into the cytoplasm. The crystal structure of ComFC includes a zinc-finger motif and a putative phosphoribosyl transferase domain, both necessary for the protein's in vivo activity. Furthermore, we show that ComFC is a membrane-associated protein with affinity for single-stranded DNA. Our results suggest that ComFC provides the link between the transport of the transforming DNA into the cytoplasm and its handling by the recombination machinery.

Author information: (1)Ministry of Health, Singapore, Singapore. rachael.pung@lshtm.ac.uk. (2)Centre for the Mathematical Modelling of infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK. rachael.pung@lshtm.ac.uk. (3)Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. rachael.pung@lshtm.ac.uk. (4)Department of Zoology, University of Oxford, Oxford, UK. (5)Merton College, University of Oxford, Oxford, UK. (6)School of Biological Sciences, University of East Anglia, Norwich, UK. (7)Ministry of Health, Singapore, Singapore. (8)Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. (9)Centre for the Mathematical Modelling of infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK. (10)Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

High quality reference genomes are crucial to understanding genome function, structure and evolution. The availability of reference genomes has allowed us to start inferring the role of genetic variation in biology, disease, and biodiversity conservation. However, analyses across organisms demonstrate that a single reference genome is not enough to capture the global genetic diversity present in populations. In this work, we generate 32 high-quality reference genomes for the well-known model species D. melanogaster and focus on the identification and analysis of transposable element variation as they are the most common type of structural variant. We show that integrating the genetic variation across natural populations from five climatic regions increases the number of detected insertions by 58%. Moreover, 26% to 57% of the insertions identified using long-reads were missed by short-reads methods. We also identify hundreds of transposable elements associated with gene expression variation and new TE variants likely to contribute to adaptive evolution in this species. Our results highlight the importance of incorporating the genetic variation present in natural populations to genomic studies, which is essential if we are to understand how genomes function and evolve.

Erratum in Nat Commun. 2022 Jul 7;13(1):3930.

Challenges to the widespread application of gene therapy with adeno-associated viral (AAV) vectors include dominant conditions due to gain-of-function mutations which require allele-specific knockout, as well as long-term transgene expression from proliferating tissues, which is hampered by AAV DNA episomal status. To overcome these challenges, we used CRISPR/Cas9-mediated homology-independent targeted integration (HITI) in retina and liver as paradigmatic target tissues. We show that AAV-HITI targets photoreceptors of both mouse and pig retina, and this results in significant improvements to retinal morphology and function in mice with autosomal dominant retinitis pigmentosa. In addition, we show that neonatal systemic AAV-HITI delivery achieves stable liver transgene expression and phenotypic improvement in a mouse model of a severe lysosomal storage disease. We also show that HITI applications predominantly result in on-target editing. These results lay the groundwork for the application of AAV-HITI for the treatment of diseases affecting various organs.

RNA modifications, including N6-methyladenosine (m6A), have been reported to regulate fundamental RNA processes and properties, and directly linked to various human diseases. Methods enabling temporal and transcript/locus-specific editing of specific RNA modifications are essential, but still limited, to dissect the dynamic and context-dependent functions of these epigenetic modifications. Here, we develop a chemically inducible and reversible RNA m6A modification editing platform integrating chemically induced proximity (CIP) and CRISPR methods. We show that m6A editing can be temporally controlled at specific sites of individual RNA transcripts by the addition or removal of the CIP inducer, abscisic acid (ABA), in the system. By incorporating a photo-caged ABA, a light-controlled version of m6A editing platform can be developed. We expect that this platform and strategy can be generally applied to edit other RNA modifications in addition to m6A.

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.

T cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of mature, clonally expanded T cells, where somatic-activating STAT3 mutations are common. Although T-LGLL has been described as a chronic T cell response to an antigen, the function of the non-leukemic immune system in this response is largely uncharacterized. Here, by utilizing single-cell RNA and T cell receptor profiling (scRNA+TCRαβ-seq), we show that irrespective of STAT3 mutation status, T-LGLL clonotypes are more cytotoxic and exhausted than healthy reactive clonotypes. In addition, T-LGLL clonotypes show more active cell communication than reactive clones with non-leukemic immune cells via costimulatory cell-cell interactions, monocyte-secreted proinflammatory cytokines, and T-LGLL-clone-secreted IFNγ. Besides the leukemic repertoire, the non-leukemic T cell repertoire in T-LGLL is also more mature, cytotoxic, and clonally restricted than in other cancers and autoimmune disorders. Finally, 72% of the leukemic T-LGLL clonotypes share T cell receptor similarities with their non-leukemic repertoire, linking the leukemic and non-leukemic repertoires together via possible common target antigens. Our results provide a rationale to prioritize therapies that target the entire immune repertoire and not only the T-LGLL clonotype.

Paramagnetic complexes containing gadolinium ions have been widely used for magnetic resonance imaging (MRI) in clinic. However, these paramagnetic complexes pose some safety concerns. There is still a demand for the development of stable MRI contrast agents that exhibit higher sensitivity and superior functionality to existing contrast agents. Here, we develop carbonized paramagnetic complexes of manganese (II) (Mn@CCs) to encapsulate Mn2+ in sealed carbonized shells with superhigh r1 relaxivity. Compared to the most common clinical contrast agent Magnevist, investigations in vivo demonstrate that the Mn@CCs cross the intact blood-brain barrier of normal health mice with minor metal deposition; preferentially target the glioma tissues distribute homogeneously with high penetration in an intracranial mouse model; delineate clear tumor margins in MRIs of ultrasmall single-nodule brain tumors, and multi-nodular liver tumors. The sensitivity, accuracy and low toxicity offer by Mn@CCs provides new opportunities for early molecular diagnostics and imaging-guided biomedical applications.

Intestinal inflammation fuels the transmission of Salmonella Typhimurium (S.Tm). However, a substantial fitness cost is associated with virulence expression. Mutations inactivating transcriptional virulence regulators generate attenuated variants profiting from inflammation without enduring virulence cost. Such variants interfere with the transmission of fully virulent clones. Horizontal transfer of functional regulatory genes (HGT) into attenuated variants could nevertheless favor virulence evolution. To address this hypothesis, we cloned hilD, coding for the master regulator of virulence, into a conjugative plasmid that is highly transferrable during intestinal colonization. The resulting mobile hilD allele allows virulence to emerge from avirulent populations, and to be restored in attenuated mutants competing against virulent clones within-host. However, mutations inactivating the mobile hilD allele quickly arise. The stability of virulence mediated by HGT is strongly limited by its cost, which depends on the hilD expression level, and by the timing of transmission. We conclude that robust evolution of costly virulence expression requires additional selective forces such as narrow population bottlenecks during transmission.

The pancreas is a central organ for human diseases. Most alleles uncovered by genome-wide association studies of pancreatic dysfunction traits overlap with non-coding sequences of DNA. Many contain epigenetic marks of cis-regulatory elements active in pancreatic cells, suggesting that alterations in these sequences contribute to pancreatic diseases. Animal models greatly help to understand the role of non-coding alterations in disease. However, interspecies identification of equivalent cis-regulatory elements faces fundamental challenges, including lack of sequence conservation. Here we combine epigenetic assays with reporter assays in zebrafish and human pancreatic cells to identify interspecies functionally equivalent cis-regulatory elements, regardless of sequence conservation. Among other potential disease-relevant enhancers, we identify a zebrafish ptf1a distal-enhancer whose deletion causes pancreatic agenesis, a phenotype previously found to be induced by mutations in a distal-enhancer of PTF1A in humans, further supporting the causality of this condition in vivo. This approach helps to uncover interspecies functionally equivalent cis-regulatory elements and their potential role in human disease.

In type II CRISPR systems, the guide RNA (gRNA) comprises a CRISPR RNA (crRNA) and a hybridized trans-acting CRISPR RNA (tracrRNA), both being essential in guided DNA targeting functions. Although tracrRNAs are diverse in sequence and structure across type II CRISPR systems, the programmability of crRNA-tracrRNA hybridization for Cas9 is not fully understood. Here, we reveal the programmability of crRNA-tracrRNA hybridization for Streptococcus pyogenes Cas9, and in doing so, redefine the capabilities of Cas9 proteins and the sources of crRNAs, providing new biosensing applications for type II CRISPR systems. By reprogramming the crRNA-tracrRNA hybridized sequence, we show that engineered crRNA-tracrRNA interactions can not only enable the design of orthogonal cellular computing devices but also facilitate the hijacking of endogenous small RNAs/mRNAs as crRNAs. We subsequently describe how these re-engineered gRNA pairings can be implemented as RNA sensors, capable of monitoring the transcriptional activity of various environment-responsive genomic genes, or detecting SARS-CoV-2 RNA in vitro, as an Atypical gRNA-activated Transcription Halting Alarm (AGATHA) biosensor.

Perovskite microcells have a great potential to be applied to diverse types of optoelectronic devices including light-emitting diodes, photodetectors, and solar cells. Although several perovskite fabrication methods have been researched, perovskite microcells without a significant efficiency drop during the patterning and fabrication process could not be developed yet. We herein report the fabrication of high-efficiency perovskite microcells using swelling-induced crack propagation and the application of the microcells to colored solar windows. The key procedure is a swelling-induced lift-off process that leads to patterned perovskite films with high-quality interfaces. Thus, a power conversion efficiency (PCE) of 20.1 % could be achieved with the perovskite microcell, which is nearly same as the PCE of our unpatterned perovskite photovoltaic device (PV). The semi-transparent PV based on microcells exhibited a light utilization efficiency of 4.67 and a color rendering index of 97.5 %. The metal-insulator-metal structure deposited on the semi-transparent PV enabled to fabricate solar windows with vivid colors and high color purity.

The MARCH E3 ubiquitin (Ub) ligase MARCH1 regulates trafficking of major histocompatibility complex class II (MHC II) and CD86, molecules of critical importance to immunity. Here we show, using a genome-wide CRISPR knockout screen, that ubiquitin-like protein 3 (UBL3) is a necessary component of ubiquitination-mediated trafficking of these molecules in mice and in humans. Ubl3-deficient mice have elevated MHC II and CD86 expression on the surface of professional and atypical antigen presenting cells. UBL3 also regulates MHC II and CD86 in human dendritic cells (DCs) and macrophages. UBL3 impacts ubiquitination of MARCH1 substrates, a mechanism that requires UBL3 plasma membrane anchoring via prenylation. Loss of UBL3 alters adaptive immunity with impaired development of thymic regulatory T cells, loss of conventional type 1 DCs, increased number of trogocytic marginal zone B cells, and defective in vivo MHC II and MHC I antigen presentation. In summary, we identify UBL3 as a conserved, critical factor in MARCH1-mediated ubiquitination with important roles in immune responses.

A catalytic method for the enantioselective and C4-selective functionalization of pyridine derivatives is yet to be developed. Herein, we report an efficient method for the asymmetric β-pyridylations of enals that involve N-heterocyclic carbene (NHC) catalysis with excellent control over enantioselectivity and pyridyl C4-selectivity. The key strategy for precise stereocontrol involves enhancing interactions between the chiral NHC-bound homoenolate and pyridinium salt in the presence of hexafluorobenzene, which effectively differentiates the two faces of the homoenolate radical. Room temperature is sufficient for this transformation, and reaction efficiency is further accelerated by photo-mediation. This methodology exhibits broad functional group tolerance and enables facile access to a diverse range of enantioenriched β-pyridyl carbonyl compounds under mild and metal-free conditions.

The evolutionarily conserved serine/threonine kinase mTORC1 is a central regulator of cell growth and proliferation. mTORC1 is activated on the lysosome surface. However, once mTORC1 is activated, it is unclear whether mTORC1 phosphorylates local lysosomal proteins to regulate specific aspects of lysosomal biology. Through cross-reference analyses of the lysosome proteome with the mTORC1-regulated phosphoproteome, we identify STK11IP as a lysosome-specific substrate of mTORC1. mTORC1 phosphorylates STK11IP at Ser404. Knockout of STK11IP leads to a robust increase of autophagy flux. Dephosphorylation of STK11IP at Ser404 represses the role of STK11IP as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase, and regulates the activity of V-ATPase. Knockout of STK11IP protects mice from fasting or Methionine/Choline-Deficient Diet (MCD)-induced fatty liver. Thus, our study demonstrates that STK11IP phosphorylation represents a mechanism for mTORC1 to regulate lysosomal acidification and autophagy, and points to STK11IP as a promising therapeutic target for the amelioration of diseases with aberrant autophagy signaling.

Comment in Nat Commun. 2022 Aug 26;13(1):5025.

Sexual plant reproduction depends on the attraction of sperm-cell delivering pollen tubes (PT) by two synergids, followed by their programmed cell death (PCD) in Arabidopsis. Disruption of the mitogen-activated protein kinase 4 (MPK4) by pathogenic effectors activates the resistance protein (R) SUMM2-mediated immunity and cell death. Here we show that synergid preservation and reactive oxygen species (ROS) homeostasis are intimately linked and maintained by MPK4. In mpk4, ROS levels are increased and synergids prematurely undergo PCD before PT-reception. However, ROS scavengers and the disruption of SUMM2, in mpk4, restore ROS homeostasis, synergid maintenance and PT perception, demonstrating that the guardian of MPK4, SUMM2, triggers synergid-PCD. In mpk4/summ2, PTs show a feronia-like overgrowth phenotype. Our results show that immunity-associated PCD and synergid cell death during plant reproduction are regulated by MPK4 underscoring an underlying molecular mechanism for the suppression of plant reproduction during systemic R-mediated immunity.

Flexible pressure sensors usually require functional materials with both mechanical compliance and appropriate electrical performance. Most sensors based on materials with limited compressibility can hardly balance between high sensitivity and broad pressure range. Here, we prepare a heterophasic ionogel with shape and stiffness memory for adaptive pressure sensors. By combining the microstructure alignment for stiffness changing and shape memory micro-inclusions for stiffness fixing, the heterophasic ionogels reveal tunable compressibility. This controllable pressure-deformation property of the ionogels results in the pressure sensors' programmable pressure-resistance behavior with tunable pressure ranges, varied detection limits, and good resolution at high pressure. Broad pressure ranges to 220 and 380 kPa, and tunable detection limit from 120 to 330 and 950 Pa are realized by the stiffness memory ionogel sensors. Adaptive detection is also brought out to monitor tiny pressure changes at low stiffness and distinguish different human motions at high stiffness. Using shape and stiffness memory materials in pressure sensors is a general design to achieve programmable performance for more complex application scenarios.

Immunization is expected to confer protection against infection and severe disease for vaccines while reducing risks to unimmunized populations by inhibiting transmission. Here, based on serial serological studies of an observational cohort of healthcare workers, we show that during a Severe Acute Respiratory Syndrome -Coronavirus 2 Delta-variant outbreak in Delhi, 25.3% (95% Confidence Interval 16.9-35.2) of previously uninfected, ChAdOx1-nCoV19 double vaccinated, healthcare workers were infected within less than two months, based on serology. Induction of anti-spike response was similar between groups with breakthrough infection (541 U/ml, Inter Quartile Range 374) and without (342 U/ml, Inter Quartile Range 497), as was the induction of neutralization activity to wildtype. This was not vaccine failure since vaccine effectiveness estimate based on infection rates in an unvaccinated cohort were about 70% and most infections were asymptomatic. We find that while ChAdOx1-nCoV19 vaccination remains effective in preventing severe infections, it is unlikely to be completely able to block transmission and provide herd immunity.

Cooperative motion in biological microswimmers is crucial for their survival as it facilitates adhesion to surfaces, formation of hierarchical colonies, efficient motion, and enhanced access to nutrients. Here, we confine synthetic, catalytic microswimmers along one-dimensional paths and demonstrate that they too show a variety of cooperative behaviours. We find that their speed increases with the number of swimmers, and that the activity induces a preferred distance between swimmers. Using a minimal model, we ascribe this behavior to an effective activity-induced potential that stems from a competition between chemical and hydrodynamic coupling. These interactions further induce active self-assembly into trains where swimmers move at a well-separated, stable distance with respect to each other, as well as compact chains that can elongate, break-up, become immobilized and remobilized. We identify the crucial role that environment morphology and swimmer directionality play on these highly dynamic chain behaviors. These activity-induced interactions open the door toward exploiting cooperation for increasing the efficiency of microswimmer motion, with temporal and spatial control, thereby enabling them to perform intricate tasks inside complex environments.

Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP+ fibroblasts and SPP1+ macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP+ fibroblasts and SPP1+ macrophages interaction to improve immunotherapy.

Electrically interfacing atomically thin transition metal dichalcogenide semiconductors (TMDSCs) with metal leads is challenging because of undesired interface barriers, which have drastically constrained the electrical performance of TMDSC devices for exploring their unconventional physical properties and realizing potential electronic applications. Here we demonstrate a strategy to achieve nearly barrier-free electrical contacts with few-layer TMDSCs by engineering interfacial bonding distortion. The carrier-injection efficiency of such electrical junction is substantially increased with robust ohmic behaviors from room to cryogenic temperatures. The performance enhancements of TMDSC field-effect transistors are well reflected by the low contact resistance (down to 90 Ωµm in MoS2, towards the quantum limit), the high field-effect mobility (up to 358,000 cm2V-1s-1 in WSe2), and the prominent transport characteristics at cryogenic temperatures. This method also offers possibilities of the local manipulation of atomic structures and electronic properties for TMDSC device design.

Micrarchaeota is a distinctive lineage assigned to the DPANN archaea, which includes poorly characterised microorganisms with reduced genomes that likely depend on interactions with hosts for growth and survival. Here, we report the enrichment of a stable co-culture of a member of the Micrarchaeota (Ca. Micrarchaeum harzensis) together with its Thermoplasmatales host (Ca. Scheffleriplasma hospitalis), as well as the isolation of the latter. We show that symbiont-host interactions depend on biofilm formation as evidenced by growth experiments, comparative transcriptomic analyses and electron microscopy. In addition, genomic, metabolomic, extracellular polymeric substances and lipid content analyses indicate that the Micrarchaeon symbiont relies on the acquisition of metabolites from its host. Our study of the cell biology and physiology of a Micrarchaeon and its host adds to our limited knowledge of archaeal symbioses.

As wildfires across the world increase in number, size, and intensity, exposure to wildfire smoke (WFS) is a growing health problem. To date, however, little is known for any species on what might be the behavioral or physiological consequences of prenatal exposure to WFS. Here we show that infant rhesus monkeys exposed to WFS in the first third of gestation (n = 52) from the Camp Fire (California, November, 2018) show greater inflammation, blunted cortisol, more passive behavior, and memory impairment compared to animals conceived after smoke had dissipated (n = 37). Parallel analyses, performed on a historical control cohort (n = 2490), did not support the alternative hypothesis that conception timing alone could explain the results. We conclude that WFS may have a teratogenic effect on the developing fetus and speculate on mechanisms by which WFS might affect neural development.