Ultrahigh-mobility semiconducting epitaxial graphene on silicon carbide.

Semiconducting graphene plays an important part in graphene nanoelectronics because of the lack of an intrinsic bandgap in graphene1. In the past two decades, attempts to modify the bandgap either by quantum confinement or by chemical functionalization failed to produce viable semiconducting graphene. Here we demonstrate that semiconducting epigraphene (SEG) on single-crystal silicon carbide substrates has a band gap of 0.6 eV and room temperature mobilities exceeding 5,000 cm2 V-1 s-1, which is 10 times larger than that of silicon and 20 times larger than that of the other two-dimensional semiconductors. It is well known that when silicon evaporates from silicon carbide crystal surfaces, the carbon-rich surface crystallizes to produce graphene multilayers2. The first graphitic layer to form on the silicon-terminated face of SiC is an insulating epigraphene layer that is partially covalently bonded to the SiC surface3. Spectroscopic measurements of this buffer layer4 demonstrated semiconducting signatures4, but the mobilities of this layer were limited because of disorder5. Here we demonstrate a quasi-equilibrium annealing method that produces SEG (that is, a well-ordered buffer layer) on macroscopic atomically flat terraces. The SEG lattice is aligned with the SiC substrate. It is chemically, mechanically and thermally robust and can be patterned and seamlessly connected to semimetallic epigraphene using conventional semiconductor fabrication techniques. These essential properties make SEG suitable for nanoelectronics.

The demise of the giant ape Gigantopithecus blacki.

The largest ever primate and one of the largest of the southeast Asian megafauna, Gigantopithecus blacki1, persisted in China from about 2.0 million years until the late middle Pleistocene when it became extinct2-4. Its demise is enigmatic considering that it was one of the few Asian great apes to go extinct in the last 2.6 million years, whereas others, including orangutan, survived until the present5. The cause of the disappearance of G. blacki remains unresolved but could shed light on primate resilience and the fate of megafauna in this region6. Here we applied three multidisciplinary analyses-timing, past environments and behaviour-to 22 caves in southern China. We used 157 radiometric ages from six dating techniques to establish a timeline for the demise of G. blacki. We show that from 2.3 million years ago the environment was a mosaic of forests and grasses, providing ideal conditions for thriving G. blacki populations. However, just before and during the extinction window between 295,000 and 215,000 years ago there was enhanced environmental variability from increased seasonality, which caused changes in plant communities and an increase in open forest environments. Although its close relative Pongo weidenreichi managed to adapt its dietary preferences and behaviour to this variability, G. blacki showed signs of chronic stress and dwindling populations. Ultimately its struggle to adapt led to the extinction of the greatest primate to ever inhabit the Earth.

Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy.

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.

Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2.

Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative pathogen of the COVID-19 pandemic, exerts a massive health and socioeconomic crisis. The virus infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange, but the mechanisms driving infection and pathology are unclear. We performed a quantitative phosphoproteomic survey of induced pluripotent stem cell-derived AT2s (iAT2s) infected with SARS-CoV-2 at air-liquid interface (ALI). Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity. Comparison to analogous data from transformed cell lines revealed respiratory-specific processes hijacked by SARS-CoV-2, highlighting potential novel therapeutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2 ALI system.

Crystal-Phase Engineering in Heterogeneous Catalysis.

The performance of a chemical reaction is critically dependent on the electronic and/or geometric structures of a material in heterogeneous catalysis. Over the past century, the Sabatier principle has already provided a conceptual framework for optimal catalyst design by adjusting the electronic structure of the catalytic material via a change in composition. Beyond composition, it is essential to recognize that the geometric atomic structures of a catalyst, encompassing terraces, edges, steps, kinks, and corners, have a substantial impact on the activity and selectivity of a chemical reaction. Crystal-phase engineering has the capacity to bring about substantial alterations in the electronic and geometric configurations of a catalyst, enabling control over coordination numbers, morphological features, and the arrangement of surface atoms. Modulating the crystallographic phase is therefore an important strategy for improving the stability, activity, and selectivity of catalytic materials. Nonetheless, a complete understanding of how the performance depends on the crystal phase of a catalyst remains elusive, primarily due to the absence of a molecular-level view of active sites across various crystal phases. In this review, we primarily focus on assessing the dependence of catalytic performance on crystal phases to elucidate the challenges and complexities inherent in heterogeneous catalysis, ultimately aiming for improved catalyst design.

Last appearance of Homo erectus at Ngandong, Java, 117,000-108,000 years ago.

Homo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago1,2. Twelve H. erectus calvaria (skull caps) and two tibiae (lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 19333,4, and are of the youngest, most-advanced form of H. erectus5-8. Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated9-14. Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish-to our knowledge-the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence, 40argon/39argon (40Ar/39Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series-electron-spin resonance (US-ESR) dating to non-human fossils to directly date our re-excavation of Ngandong5,15. We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum)16 and 134 and 118 ka (US-ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions3,17. These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species.

Novel insecticidal proteins from ferns resemble insecticidal proteins from Bacillus thuringiensis.

Lepidopterans affect crop production worldwide. The use of transgenes encoding insecticidal proteins from Bacillus thuringiensis (Bt) in crop plants is a well-established technology that enhances protection against lepidopteran larvae. Concern about widespread field-evolved resistance to Bt proteins has highlighted an urgent need for new insecticidal proteins with different modes or sites of action. We discovered a new family of insecticidal proteins from ferns. The prototype protein from Pteris species (Order Polypodiales) and variants from two other orders of ferns, Schizaeales and Ophioglossales, were effective against important lepidopteran pests of maize and soybean in diet-based assays. Transgenic maize and soybean plants producing these proteins were more resistant to insect damage than controls. We report here the crystal structure of a variant of the prototype protein to 1.98 Å resolution. Remarkably, despite being derived from plants, the structure resembles the 3-domain Cry proteins from Bt but has only two out of three of their characteristic domains, lacking the C-terminal domain which is typically required for their activities. Two of the fern proteins were effective against strains of fall armyworm that were resistant to Bt 3-domain Cry proteins Cry1Fa or Cry2A.127. This therefore represents a novel family of insecticidal proteins that have the potential to provide future tools for pest control.

scGMAAE: Gaussian mixture adversarial autoencoders for diversification analysis of scRNA-seq data.

The progress of single-cell RNA sequencing (scRNA-seq) has led to a large number of scRNA-seq data, which are widely used in biomedical research. The noise in the raw data and tens of thousands of genes pose a challenge to capture the real structure and effective information of scRNA-seq data. Most of the existing single-cell analysis methods assume that the low-dimensional embedding of the raw data belongs to a Gaussian distribution or a low-dimensional nonlinear space without any prior information, which limits the flexibility and controllability of the model to a great extent. In addition, many existing methods need high computational cost, which makes them difficult to be used to deal with large-scale datasets. Here, we design and develop a depth generation model named Gaussian mixture adversarial autoencoders (scGMAAE), assuming that the low-dimensional embedding of different types of cells follows different Gaussian distributions, integrating Bayesian variational inference and adversarial training, as to give the interpretable latent representation of complex data and discover the statistical distribution of different types of cells. The scGMAAE is provided with good controllability, interpretability and scalability. Therefore, it can process large-scale datasets in a short time and give competitive results. scGMAAE outperforms existing methods in several ways, including dimensionality reduction visualization, cell clustering, differential expression analysis and batch effect removal. Importantly, compared with most deep learning methods, scGMAAE requires less iterations to generate the best results.

Exosomes derived from umbilical cord-derived mesenchymal stem cells exposed to diabetic microenvironment enhance M2 macrophage polarization and protect against diabetic nephropathy.

The role of mesenchymal-stem-cell-derived exosomes (MSCs-Exo) in the regulation of macrophage polarization has been recognized in several diseases. There is emerging evidence that MSCs-Exo partially prevent the progression of diabetic nephropathy (DN). This study aimed to investigate whether exosomes secreted by MSCs pre-treated with a diabetic environment (Exo-pre) have a more pronounced protective effect against DN by regulating the balance of macrophages. Exo-pre and Exo-Con were isolated from the culture medium of UC-MSCs pre-treated with a diabetic mimic environment and natural UC-MSCs, respectively. Exo-pre and Exo-Con were injected into the tail veins of db/db mice three times a week for 6 weeks. Serum creatinine and serum urea nitrogen levels, the urinary protein/creatinine ratio, and histological staining were used to determine renal function and morphology. Macrophage phenotypes were analyzed by immunofluorescence, western blotting, and quantitative reverse transcription polymerase chain reaction. In vitro, lipopolysaccharide-induced M1 macrophages were incubated separately with Exo-Con and Exo-pre. We performed microRNA (miRNA) sequencing to identify candidate miRNAs and predict their target genes. An miRNA inhibitor was used to confirm the role of miRNAs in macrophage modulation. Exo-pre were more potent than Exo-Con at alleviating DN. Exo-pre administration significantly reduced the number of M1 macrophages and increased the number of M2 macrophages in the kidney compared to Exo-Con administration. Parallel outcomes were observed in the co-culture experiments. Moreover, miR-486-5p was distinctly expressed in Exo-Con and Exo-pre groups, and it played an important role in macrophage polarization by targeting PIK3R1 through the PI3K/Akt pathway. Reducing miR-486-5p levels in Exo-pre abolished macrophage polarization modulation. Exo-pre administration exhibited a superior effect on DN by remodeling the macrophage balance by shuttling miR-486-5p, which targets PIK3R1.

Earliest hunting scene in prehistoric art.

Humans seem to have an adaptive predisposition for inventing, telling and consuming stories1. Prehistoric cave art provides the most direct insight that we have into the earliest storytelling2-5, in the form of narrative compositions or 'scenes'2,5 that feature clear figurative depictions of sets of figures in spatial proximity to each other, and from which one can infer actions taking place among the figures5. The Upper Palaeolithic cave art of Europe hosts the oldest previously known images of humans and animals interacting in recognizable scenes2,5, and of therianthropes6,7-abstract beings that combine qualities of both people and animals, and which arguably communicated narrative fiction of some kind (folklore, religious myths, spiritual beliefs and so on). In this record of creative expression (spanning from about 40 thousand years ago (ka) until the beginning of the Holocene epoch at around 10 ka), scenes in cave art are generally rare and chronologically late (dating to about 21-14 ka)7, and clear representations of therianthropes are uncommon6-the oldest such image is a carved figurine from Germany of a human with a feline head (dated to about 40-39 ka)8. Here we describe an elaborate rock art panel from the limestone cave of Leang Bulu' Sipong 4 (Sulawesi, Indonesia) that portrays several figures that appear to represent therianthropes hunting wild pigs and dwarf bovids; this painting has been dated to at least 43.9 ka on the basis of uranium-series analysis of overlying speleothems. This hunting scene is-to our knowledge-currently the oldest pictorial record of storytelling and the earliest figurative artwork in the world.

A fungal effector suppresses the nuclear export of AGO1-miRNA complex to promote infection in plants.

Communication between interacting organisms via bioactive molecules is widespread in nature and plays key roles in diverse biological processes. Small RNAs (sRNAs) can travel between host plants and filamentous pathogens to trigger transkingdom RNA interference (RNAi) in recipient cells and modulate plant defense and pathogen virulence. However, how fungal pathogens counteract transkingdom antifungal RNAi has rarely been reported. Here we show that a secretory protein VdSSR1 (secretory silencing repressor 1) from Verticillium dahliae, a soil-borne phytopathogenic fungus that causes wilt diseases in a wide range of plant hosts, is required for fungal virulence in plants. VdSSR1 can translocate to plant nucleus and serve as a general suppressor of sRNA nucleocytoplasmic shuttling. We further reveal that VdSSR1 sequesters ALY family proteins, adaptors of the TREX complex, to interfere with nuclear export of the AGO1­microRNA (AGO1­miRNA) complex, leading to a great attenuation in cytoplasmic AGO1 protein and sRNA levels. With this mechanism, V. dahliae can suppress the accumulation of mobile plant miRNAs in fungal cells and succedent transkingdom silencing of virulence genes, thereby increasing its virulence in plants. Our findings reveal a mechanism by which phytopathogenic fungi antagonize antifungal RNAi-dependent plant immunity and expand the understanding on the complex interaction between host and filamentous pathogens.

Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

DNA methylation of promoter region inhibits galectin-1 expression in BMSCs of aged mice.

Senile osteoporosis increases fracture risks. Bone marrow stromal cells (BMSCs) are sensitive to aging. Deep insights into BMSCs aging are vital to elucidate the mechanisms underlying age-related bone loss. Recent advances showed that osteoporosis is associated with aberrant DNA methylation of many susceptible genes. Galectin-1 (Gal-1) has been proposed as a mediator of BMSCs functions. In our previous study, we showed that Gal-1 was downregulated in aged BMSCs and global deletion of Gal-1 in mice caused bone loss via impaired osteogenesis potential of BMSCs. Gal-1 promoter is featured by CpG islands. However, there are no reports concerning the DNA methylation status in Gal-1 promoter during osteoporosis. In the current study, we sought to investigate the role of DNA methylation in Gal-1 downregulation in aged BMSCs. The potential for anti-bone loss therapy based on modulating DNA methylation is explored. Our results showed that Dnmt3b-mediated Gal-1 promoter DNA hypermethylation plays an important role in Gal-1 downregulation in aged BMSCs, which inhibited ß-catenin binding on Gal-1 promoter. Bone loss of aged mice was alleviated in response to in vivo deletion of Dnmt3b from BMSCs. Finally, when bone marrow of young wild-type (WT) mice or young Dnmt3bPrx1-Cre mice was transplanted into aged WT mice, Gal-1 level in serum and trabecular bone mass were elevated in recipient aged WT mice. Our study will benefit for deeper insights into the regulation mechanisms of Gal-1 expression in BMSCs during osteoporosis development, and for the discovery of new therapeutic targets for osteoporosis via modulating DNA methylation status.NEW & NOTEWORTHY There is Dnmt3b-mediated DNA methylation in Gal-1 promoter in aged bone marrow stromal cell (BMSC). DNA methylation causes Gal-1 downregulation and osteogenesis attenuation of aged BMSC. DNA methylation blocks ß-catenin binding on Gal-1 promoter. Bone loss of aged mice is alleviated by in vivo deletion of Dnmt3b from BMSC.

Integrated Transcriptomics-Proteomics Analysis Identifies Molecular Phenotypic Alterations Associated with Colorectal Cancer.

Understanding the pathogenesis and finding diagnostic markers for colorectal cancer (CRC) are the key to its diagnosis and treatment. Integrated transcriptomics and proteomics analysis can be used to characterize alterations of molecular phenotypes and reveal the hidden pathogenesis of CRC. This study employed a novel strategy integrating transcriptomics and proteomics to identify pathological molecular pathways and diagnostic biomarkers of CRC. First, differentially expressed proteins and coexpressed genes generated from weighted gene coexpression network analysis (WGCNA) were intersected to obtain key genes of the CRC phenotype. In total, 63 key genes were identified, and pathway enrichment analysis showed that the process of coagulation and peptidase regulator activity could both play important roles in the development of CRC. Second, protein-protein interaction analysis was then conducted on these key genes to find the central genes involved in the metabolic pathways underpinning CRC. Finally, Itih3 and Lrg1 were further screened out as diagnostic biomarkers of CRC by applying statistical analysis on central genes combining transcriptomics and proteomics data. The deep involvement of central genes in tumorigenesis demonstrates the accuracy and reliability of this novel transcriptomics-proteomics integration strategy in biomarker discovery. The identified candidate biomarkers and enriched metabolic pathways provide insights for CRC diagnosis and treatment.

CsMYBL2 homologs modulate the light and temperature stress-regulated anthocyanin and catechins biosynthesis in tea plants (Camellia sinensis).

Anthocyanin and catechin production in tea (Camellia sinensis) leaves can positively affect tea quality; however, their regulatory mechanisms are not fully understood. Here we report that, while the CsMYB75- or CsMYB86-directed MYB-bHLH-WD40 (MBW) complexes differentially activate anthocyanin or catechin biosynthesis in tea leaves, respectively, CsMYBL2a and CsMYBL2b homologs negatively modified the light- and temperature-induced anthocyanin and catechin production in both Arabidopsis and tea plants. The MBW complexes activated both anthocyanin synthesis genes and the downstream repressor genes CsMYBL2a and CsMYBL2b. Overexpression of CsMYBL2b, but not CsMYBL2a, repressed Arabidopsis leaf anthocyanin accumulation and seed coat proanthocyanin production. CsMYBL2b strongly and CsMYBL2a weakly repressed the activating effects of CsMYB75/CsMYB86 on CsDFR and CsANS, due to their different EAR and TLLLFR domains and interactions with CsTT8/CsGL3, interfering with the functions of activating MBW complexes. CsMYBL2b and CsMYBL2a in tea leaves play different roles in fine-tuning CsMYB75/CsMYB86-MBW activation of biosynthesis of anthocyanins and catechins, respectively. The CsbZIP1-CsmiR858a-CsMYBL2 module mediated the UV-B- or cold-activated CsMYB75/CsMYB86 regulation of anthocyanin/catechin biosynthesis by repressing CsMYBL2a and CsMYBL2b. Similarly, the CsCOP1-CsbZIP1-CsPIF3 module, and BR signaling as well, mediated the high temperature repression of anthocyanin and catechin biosynthesis through differentially upregulating CsMYBL2b and CsMYBL2a, respectively. The present study provides new insights into the complex regulatory networks in environmental stress-modified flavonoid production in tea plant leaves.

Bayesian network-based Mendelian randomization for variant prioritization and phenotypic causal inference.

Mendelian randomization is a powerful method for inferring causal relationships. However, obtaining suitable genetic instrumental variables is often challenging due to gene interaction, linkage, and pleiotropy. We propose Bayesian network-based Mendelian randomization (BNMR), a Bayesian causal learning and inference framework using individual-level data. BNMR employs the random graph forest, an ensemble Bayesian network structural learning process, to prioritize candidate genetic variants and select appropriate instrumental variables, and then obtains a pleiotropy-robust estimate by incorporating a shrinkage prior in the Bayesian framework. Simulations demonstrate BNMR can efficiently reduce the false-positive discoveries in variant selection, and outperforms existing MR methods in terms of accuracy and statistical power in effect estimation. With application to the UK Biobank, BNMR exhibits its capacity in handling modern genomic data, and reveals the causal relationships from hematological traits to blood pressures and psychiatric disorders. Its effectiveness in handling complex genetic structures and modern genomic data highlights the potential to facilitate real-world evidence studies, making it a promising tool for advancing our understanding of causal mechanisms.

Impaired STING Activation Due to a Variant in the E3 Ubiquitin Ligase AMFR in a Patient with Severe VZV Infection and Hemophagocytic Lymphohistiocytosis.

Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, causing two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy with stroke. Here, we describe a 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, hemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. Hemophagocytic lymphohistiocytosis (HLH) was strongly suspected and as the condition deteriorated, HLH therapy was initiated. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy. We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor (AMFR), encoding a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-ß reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans. In conclusion, we describe a novel genetic etiology of severe VZV disease in childhood, also representing the first inborn error of immunity related to a defect in the cGAS-STING pathway.

A Self-Assembly-Induced Exciton Delocalization Strategy for Converting a Perylene Diimide Derivative from a Type-II to Type-I Photosensitizer.

Type-I photosensitizers have shown advantages in addressing the shortcomings of traditional oxygen-dependent type-II photosensitizers for the photodynamic therapy (PDT) of hypoxic tumors. However, developing type-I photosensitizers is yet a huge challenge because the type-II energy transfer process is much faster than the type-I electron transfer process. Herein, from the fundamental point of view, an effective approach is proposed to improve the electron transfer efficiency of the photosensitizer by lowering the internal reorganization energy and exciton binding energy via self-assembly-induced exciton delocalization. An example proof is presented by the design of a perylene diimide (PDI)-based photosensitizer (PDIMp) that can generate singlet oxygen (1O2) via a type-II energy transfer process in the monomeric state, but induce the generation of superoxide anion (O2˙-) via a type-I electron transfer process in the aggregated state. Significantly, with the addition ofcucurbit[6]uril (CB[6]), the self-assembled PDIMp can convert back to the monomeric state via host-guest complexation and consequently recover the generation of 1O2. The biological evaluations reveal that supramolecular nanoparticles (PDIMp-NPs) derived from PDIMp show superior phototherapeutic performance via synergistic type-I PDT and mild photothermal therapy (PTT) against cancer under either normoxia or hypoxia conditions.

Oxygen Vacancy-Enhanced Centrosymmetric Breaking of SrFeO3- x for Piezoelectric-Catalyzed Synthesis of H2O2.

Normally, only noncentrosymmetric structure of the materials can potentially be piezoelectric. Thus, it is limited in the field of piezoelectricity for the centrosymmetric structure of the material. In this work, the performance of piezoelectricity is successfully achieved from centrosymmetric SrFeO3- x by modulating oxygen vacancies, which have a surface piezoelectric potential up to 93 mV by using Kelvin-probe force microscopy (KPFM). Moreover, the piezoelectric effects of SrFeO3- x are also evaluated by piezoelectric catalytic effect and density functional theory calculations (DFT). The results show that the piezo-catalytic degradation of tetracycline reaches 96% after 75 min by ultrasonic mechanical vibration and the production of H2O2 by SrFeO3- x piezoelectric synthesis could reach 1821 µmol L-1. In addition, the DFT results indicate that the intrinsic effect of oxygen vacancies effectively promotes the adsorption and activation of O2 and H2O as well as intermediates and improves the piezoelectric catalytic activity. This work provides an effective basis for realizing the piezoelectricity of centrosymmetric materials and regulating the development of piezoelectric catalytic properties.

csORF-finder: an effective ensemble learning framework for accurate identification of multi-species coding short open reading frames.

Short open reading frames (sORFs) refer to the small nucleic fragments no longer than 303 nt in length that probably encode small peptides. To date, translatable sORFs have been found in both untranslated regions of messenger ribonucleic acids (RNAs; mRNAs) and long non-coding RNAs (lncRNAs), playing vital roles in a myriad of biological processes. As not all sORFs are translated or essentially translatable, it is important to develop a highly accurate computational tool for characterizing the coding potential of sORFs, thereby facilitating discovery of novel functional peptides. In light of this, we designed a series of ensemble models by integrating Efficient-CapsNet and LightGBM, collectively termed csORF-finder, to differentiate the coding sORFs (csORFs) from non-coding sORFs in Homo sapiens, Mus musculus and Drosophila melanogaster, respectively. To improve the performance of csORF-finder, we introduced a novel feature encoding scheme named trinucleotide deviation from expected mean (TDE) and computed all types of in-frame sequence-based features, such as i-framed-3mer, i-framed-CKSNAP and i-framed-TDE. Benchmarking results showed that these features could significantly boost the performance compared to the original 3-mer, CKSNAP and TDE features. Our performance comparisons showed that csORF-finder achieved a superior performance than the state-of-the-art methods for csORF prediction on multi-species and non-ATG initiation independent test datasets. Furthermore, we applied csORF-finder to screen the lncRNA datasets for identifying potential csORFs. The resulting data serve as an important computational repository for further experimental validation. We hope that csORF-finder can be exploited as a powerful platform for high-throughput identification of csORFs and functional characterization of these csORFs encoded peptides.