A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry.

It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.

The Making of a Flight Feather: Bio-architectural Principles and Adaptation.

The evolution of flight in feathered dinosaurs and early birds over millions of years required flight feathers whose architecture features hierarchical branches. While barb-based feather forms were investigated, feather shafts and vanes are understudied. Here, we take a multi-disciplinary approach to study their molecular control and bio-architectural organizations. In rachidial ridges, epidermal progenitors generate cortex and medullary keratinocytes, guided by Bmp and transforming growth factor ß (TGF-ß) signaling that convert rachides into adaptable bilayer composite beams. In barb ridges, epidermal progenitors generate cylindrical, plate-, or hooklet-shaped barbule cells that form fluffy branches or pennaceous vanes, mediated by asymmetric cell junction and keratin expression. Transcriptome analyses and functional studies show anterior-posterior Wnt2b signaling within the dermal papilla controls barbule cell fates with spatiotemporal collinearity. Quantitative bio-physical analyses of feathers from birds with different flight characteristics and feathers in Burmese amber reveal how multi-dimensional functionality can be achieved and may inspire future composite material designs. VIDEO ABSTRACT.

SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.

A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.

Nitrogen-doped amorphous monolayer carbon.

Monoatomic-layered carbon materials, such as graphene1 and amorphous monolayer carbon2,3, have stimulated intense fundamental and applied research owing to their unprecedented physical properties and a wide range of promising applications4,5. So far, such materials have mainly been produced by chemical vapour deposition, which typically requires stringent reaction conditions compared to solution-phase synthesis. Herein, we demonstrate the solution preparation of free-standing nitrogen-doped amorphous monolayer carbon with mixed five-, six- and seven-membered (5-6-7-membered) rings through the polymerization of pyrrole within the confined interlayer cavity of a removable layered-double-hydroxide template. Structural characterizations and first-principles calculations suggest that the nitrogen-doped amorphous monolayer carbon was formed by radical polymerization of pyrrole at the α, ß and N sites subjected to confinement of the reaction space, which enables bond rearrangements through the Stone-Wales transformation. The spatial confinement inhibits the C-C bond rotation and chain entanglement during polymerization, resulting in an atom-thick continuous amorphous layer with an in-plane π-conjugation electronic structure. The spatially confined radical polymerization using solid templates and ion exchange strategy demonstrates potential as a universal synthesis approach for obtaining two-dimensional covalent networks, as exemplified by the successful synthesis of monolayers of polythiophene and polycarbazole.

Negative mixing enthalpy solid solutions deliver high strength and ductility.

Body-centred cubic refractory multi-principal element alloys (MPEAs), with several refractory metal elements as constituents and featuring a yield strength greater than one gigapascal, are promising materials to meet the demands of aggressive structural applications1-6. Their low-to-no tensile ductility at room temperature, however, limits their processability and scaled-up application7-10. Here we present a HfNbTiVAl10 alloy that shows remarkable tensile ductility (roughly 20%) and ultrahigh yield strength (roughly 1,390 megapascals). Notably, these are among the best synergies compared with other related alloys. Such superb synergies derive from the addition of aluminium to the HfNbTiV alloy, resulting in a negative mixing enthalpy solid solution, which promotes strength and favours the formation of hierarchical chemical fluctuations (HCFs). The HCFs span many length scales, ranging from submicrometre to atomic scale, and create a high density of diffusive boundaries that act as effective barriers for dislocation motion. Consequently, versatile dislocation configurations are sequentially stimulated, enabling the alloy to accommodate plastic deformation while fostering substantial interactions that give rise to two unusual strain-hardening rate upturns. Thus, plastic instability is significantly delayed, which expands the plastic regime as ultralarge tensile ductility. This study provides valuable insights into achieving a synergistic combination of ultrahigh strength and large tensile ductility in MPEAs.

RNA 5-Methylcytosine Facilitates the Maternal-to-Zygotic Transition by Preventing Maternal mRNA Decay.

The maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment is converted to an environment of embryonic-driven development through dramatic reprogramming. However, how maternally supplied transcripts are dynamically regulated during MZT remains largely unknown. Herein, through genome-wide profiling of RNA 5-methylcytosine (m5C) modification in zebrafish early embryos, we found that m5C-modified maternal mRNAs display higher stability than non-m5C-modified mRNAs during MZT. We discovered that Y-box binding protein 1 (Ybx1) preferentially recognizes m5C-modified mRNAs through π-π interactions with a key residue, Trp45, in Ybx1's cold shock domain (CSD), which plays essential roles in maternal mRNA stability and early embryogenesis of zebrafish. Together with the mRNA stabilizer Pabpc1a, Ybx1 promotes the stability of its target mRNAs in an m5C-dependent manner. Our study demonstrates an unexpected mechanism of RNA m5C-regulated maternal mRNA stabilization during zebrafish MZT, highlighting the critical role of m5C mRNA modification in early development.

Binding adaptability of chemical ligands to polymorphic α-synuclein amyloid fibrils.

α-synuclein (α-syn) assembles into structurally distinct fibril polymorphs seen in different synucleinopathies, such as Parkinson's disease and multiple system atrophy. Targeting these unique fibril structures using chemical ligands holds diagnostic significance for different disease subtypes. However, the molecular mechanisms governing small molecules interacting with different fibril polymorphs remain unclear. Here, we investigated the interactions of small molecules belonging to four distinct scaffolds, with different α-syn fibril polymorphs. Using cryo-electron microscopy, we determined the structures of these molecules when bound to the fibrils formed by E46K mutant α-syn and compared them to those bound with wild-type α-syn fibrils. Notably, we observed that these ligands exhibit remarkable binding adaptability, as they engage distinct binding sites across different fibril polymorphs. While the molecular scaffold primarily steered the binding locations and geometries on specific sites, the conjugated functional groups further refined this adaptable binding by fine-tuning the geometries and binding sites. Overall, our finding elucidates the adaptability of small molecules binding to different fibril structures, which sheds light on the diagnostic tracer and drug developments tailored to specific pathological fibril polymorphs.

mBAT-combo: A more powerful test to detect gene-trait associations from GWAS data.

Gene-based association tests aggregate multiple SNP-trait associations into sets defined by gene boundaries and are widely used in post-GWAS analysis. A common approach for gene-based tests is to combine SNPs associations by computing the sum of χ2 statistics. However, this strategy ignores the directions of SNP effects, which could result in a loss of power for SNPs with masking effects, e.g., when the product of two SNP effects and the linkage disequilibrium (LD) correlation is negative. Here, we introduce "mBAT-combo," a set-based test that is better powered than other methods to detect multi-SNP associations in the context of masking effects. We validate the method through simulations and applications to real data. We find that of 35 blood and urine biomarker traits in the UK Biobank, 34 traits show evidence for masking effects in a total of 4,273 gene-trait pairs, indicating that masking effects is common in complex traits. We further validate the improved power of our method in height, body mass index, and schizophrenia with different GWAS sample sizes and show that on average 95.7% of the genes detected only by mBAT-combo with smaller sample sizes can be identified by the single-SNP approach with a 1.7-fold increase in sample sizes. Eleven genes significant only in mBAT-combo for schizophrenia are confirmed by functionally informed fine-mapping or Mendelian randomization integrating gene expression data. The framework of mBAT-combo can be applied to any set of SNPs to refine trait-association signals hidden in genomic regions with complex LD structures.

Linking discoveries, mechanisms, and technologies to develop a clearer perspective on plant long noncoding RNAs.

Long noncoding RNAs (lncRNAs) are a large and diverse class of genes in eukaryotic genomes that contribute to a variety of regulatory processes. Functionally characterized lncRNAs play critical roles in plants, ranging from regulating flowering to controlling lateral root formation. However, findings from the past decade have revealed that thousands of lncRNAs are present in plant transcriptomes, and characterization has lagged far behind identification. In this setting, distinguishing function from noise is challenging. However, the plant community has been at the forefront of discovery in lncRNA biology, providing many functional and mechanistic insights that have increased our understanding of this gene class. In this review, we examine the key discoveries and insights made in plant lncRNA biology over the past two and a half decades. We describe how discoveries made in the pregenomics era have informed efforts to identify and functionally characterize lncRNAs in the subsequent decades. We provide an overview of the functional archetypes into which characterized plant lncRNAs fit and speculate on new avenues of research that may uncover yet more archetypes. Finally, this review discusses the challenges facing the field and some exciting new molecular and computational approaches that may help inform lncRNA comparative and functional analyses.

miR-107 reverses the multidrug resistance of gastric cancer by targeting the CGA/EGFR/GATA2 positive feedback circuit.

Chemotherapy is still the main therapeutic strategy for gastric cancer (GC). However, most patients eventually acquire multidrug resistance (MDR). Hyperactivation of the EGFR signaling pathway contributes to MDR by promoting cancer cell proliferation and inhibiting apoptosis. We previously identified the secreted protein CGA as a novel ligand of EGFR and revealed a CGA/EGFR/GATA2 positive feedback circuit that confers MDR in GC. Herein, we outline a microRNA-based treatment approach for MDR reversal that targets both CGA and GATA2. We observed increased expression of CGA and GATA2 and increased activation of EGFR in GC samples. Bioinformatic analysis revealed that miR-107 could simultaneously target CGA and GATA2, and the low expression of miR-107 was correlated with poor prognosis in GC patients. The direct interactions between miR-107 and CGA or GATA2 were validated by luciferase reporter assays and Western blot analysis. Overexpression of miR-107 in MDR GC cells increased their susceptibility to chemotherapeutic agents, including fluorouracil, adriamycin, and vincristine, in vitro. Notably, intratumor injection of the miR-107 prodrug enhanced MDR xenograft sensitivity to chemotherapies in vivo. Molecularly, targeting CGA and GATA2 with miR-107 inhibited EGFR downstream signaling, as evidenced by the reduced phosphorylation of ERK and AKT. These results suggest that miR-107 may contribute to the development of a promising therapeutic approach for the treatment of MDR in GC.

The kiwifruit amyloplast proteome (kfALP): a resource to better understand the mechanisms underlying amyloplast biogenesis and differentiation.

The biogenesis and differentiation (B&D) of amyloplasts contributes to fruit flavor and color. Here, remodeling of starch granules, thylakoids and plastoglobules was observed during development and ripening in two kiwifruit (Actinidia spp.) cultivars - yellow-fleshed 'Hort16A' and green-fleshed 'Hayward'. A protocol was developed to purify starch-containing plastids with a high degree of intactness, and amyloplast B&D was studied using label-free-based quantitative proteomic analyses in both cultivars. Over 3000 amyloplast-localized proteins were identified, of which >98% were quantified and defined as the kfALP (kiwifruit amyloplast proteome). The kfALP data were validated by Tandem-Mass-Tag (TMT) labeled proteomics in 'Hort16A'. Analysis of the proteomic data across development and ripening revealed: 1) a conserved increase in the abundance of proteins participating in starch synthesis/degradation during both amyloplast B&D; 2) up-regulation of proteins for chlorophyll degradation and of plastoglobule-localized proteins associated with chloroplast breakdown and plastoglobule formation during amyloplast differentiation; 3) constitutive expression of proteins involved in ATP supply and protein import during amyloplast B&D. Interestingly, two different pathways of amyloplast B&D were observed in the two cultivars. In 'Hayward', significant increases in abundance of photosynthetic- and tetrapyrrole metabolism-related proteins were observed, but the opposite trend was observed in 'Hort16A'. In conclusion, analysis of the kfALP provides new insights into the potential mechanisms underlying amyloplast B&D with relevance to key fruit quality traits in contrasting kiwifruit cultivars.

Salmonella Enteritidis T1SS protein SiiD inhibits NLRP3 inflammasome activation via repressing the mtROS-ASC dependent pathway.

Inflammasome activation is an essential innate immune defense mechanism against Salmonella infections. Salmonella has developed multiple strategies to avoid or delay inflammasome activation, which may be required for long-term bacterial persistence. However, the mechanisms by which Salmonella evades host immune defenses are still not well understood. In this study, Salmonella Enteritidis (SE) random insertion transposon library was screened to identify the key factors that affect the inflammasome activation. The type I secretion system (T1SS) protein SiiD was demonstrated to repress the NLRP3 inflammasome activation during SE infection and was the first to reveal the antagonistic role of T1SS in the inflammasome pathway. SiiD was translocated into host cells and localized in the membrane fraction in a T1SS-dependent and partially T3SS-1-dependent way during SE infection. Subsequently, SiiD was demonstrated to significantly suppress the generation of mitochondrial reactive oxygen species (mtROS), thus repressing ASC oligomerization to form pyroptosomes, and impairing the NLRP3 dependent Caspase-1 activation and IL-1ß secretion. Importantly, SiiD-deficient SE induced stronger gut inflammation in mice and displayed NLRP3-dependent attenuation of the virulence. SiiD-mediated inhibition of NLRP3 inflammasome activation significantly contributed to SE colonization in the infected mice. This study links bacterial T1SS regulation of mtROS-ASC signaling to NLRP3 inflammasome activation and reveals the essential role of T1SS in evading host immune responses.

Development of a mobile, high-throughput, and low-cost image-based plant growth phenotyping system.

Nondestructive plant phenotyping forms a key technique for unraveling molecular processes underlying plant development and response to the environment. While the emergence of high-throughput phenotyping facilities can further our understanding of plant development and stress responses, their high costs greatly hinder scientific progress. To democratize high-throughput plant phenotyping, we developed sets of low-cost image- and weight-based devices to monitor plant shoot growth and evapotranspiration. We paired these devices to a suite of computational pipelines for integrated and straightforward data analysis. The developed tools were validated for their suitability for large genetic screens by evaluating a cowpea (Vigna unguiculata) diversity panel for responses to drought stress. The observed natural variation was used as an input for a genome-wide association study, from which we identified nine genetic loci that might contribute to cowpea drought resilience during early vegetative development. The homologs of the candidate genes were identified in Arabidopsis (Arabidopsis thaliana) and subsequently evaluated for their involvement in drought stress by using available T-DNA insertion mutant lines. These results demonstrate the varied applicability of this low-cost phenotyping system. In the future, we foresee these setups facilitating the identification of genetic components of growth, plant architecture, and stress tolerance across a wide variety of plant species.

Identification and functional annotation of long intergenic non-coding RNAs in Brassicaceae.

Long intergenic noncoding RNAs (lincRNAs) are a large yet enigmatic class of eukaryotic transcripts that can have critical biological functions. The wealth of RNA-sequencing (RNA-seq) data available for plants provides the opportunity to implement a harmonized identification and annotation effort for lincRNAs that enables cross-species functional and genomic comparisons as well as prioritization of functional candidates. In this study, we processed >24 Tera base pairs of RNA-seq data from >16,000 experiments to identify ∼130,000 lincRNAs in four Brassicaceae: Arabidopsis thaliana, Camelina sativa, Brassica rapa, and Eutrema salsugineum. We used nanopore RNA-seq, transcriptome-wide structural information, peptide data, and epigenomic data to characterize these lincRNAs and identify conserved motifs. We then used comparative genomic and transcriptomic approaches to highlight lincRNAs in our data set with sequence or transcriptional conservation. Finally, we used guilt-by-association analyses to assign putative functions to lincRNAs within our data set. We tested this approach on a subset of lincRNAs associated with germination and seed development, observing germination defects for Arabidopsis lines harboring T-DNA insertions at these loci. LincRNAs with Brassicaceae-conserved putative miRNA binding motifs, small open reading frames, or abiotic-stress modulated expression are a few of the annotations that will guide functional analyses into this cryptic portion of the transcriptome.

Phase Change Thermal Storage Materials for Interdisciplinary Applications.

Functional phase change materials (PCMs) capable of reversibly storing and releasing tremendous thermal energy during the isothermal phase change process have recently received tremendous attention in interdisciplinary applications. The smart integration of PCMs with functional supporting materials enables multiple cutting-edge interdisciplinary applications, including optical, electrical, magnetic, acoustic, medical, mechanical, and catalytic disciplines etc. Herein, we systematically discuss thermal storage mechanism, thermal transfer mechanism, and energy conversion mechanism, and summarize the state-of-the-art advances in interdisciplinary applications of PCMs. In particular, the applications of PCMs in acoustic, mechanical, and catalytic disciplines are still in their infancy. Simultaneously, in-depth insights into the correlations between microscopic structures and thermophysical properties of composite PCMs are revealed. Finally, current challenges and future prospects are also highlighted according to the up-to-date interdisciplinary applications of PCMs. This review aims to arouse broad research interest in the interdisciplinary community and provide constructive references for exploring next generation advanced multifunctional PCMs for interdisciplinary applications, thereby facilitating their major breakthroughs in both fundamental researches and commercial applications.

Protein and lipid mass concentration measurement in tissues by stimulated Raman scattering microscopy.

Cell mass and chemical composition are important aggregate cellular properties that are especially relevant to physiological processes, such as growth control and tissue homeostasis. Despite their importance, it has been difficult to measure these features quantitatively at the individual cell level in intact tissue. Here, we introduce normalized Raman imaging (NoRI), a stimulated Raman scattering (SRS) microscopy method that provides the local concentrations of protein, lipid, and water from live or fixed tissue samples with high spatial resolution. Using NoRI, we demonstrate that protein, lipid, and water concentrations at the single cell are maintained in a tight range in cells under the same physiological conditions and are altered in different physiological states, such as cell cycle stages, attachment to substrates of different stiffness, or by entering senescence. In animal tissues, protein and lipid concentration varies with cell types, yet an unexpected cell-to-cell heterogeneity was found in cerebellar Purkinje cells. The protein and lipid concentration profile provides means to quantitatively compare disease-related pathology, as demonstrated using models of Alzheimer's disease. This demonstration shows that NoRI is a broadly applicable technique for probing the biological regulation of protein mass, lipid mass, and water mass for studies of cellular and tissue growth, homeostasis, and disease.

Realization of Honeycomb Tellurene with Topological Edge States.

The two-dimensional (2D) honeycomb lattice has attracted intensive research interest due to the appearance of Dirac-type band structures as the consequence of two sublattices in the honeycomb structure. Introducing strong spin-orbit coupling (SOC) leads to a gap opening at the Dirac point, transforming the honeycomb lattice into a 2D topological insulator as a platform for the quantum spin Hall effect (QSHE). In this work, we realize a 2D honeycomb-structured film with tellurium, the heaviest nonradioactive element in Group VI, namely, tellurene, via molecular beam epitaxy. We revealed the gap opening of 160 meV at the Dirac point due to the strong SOC in the honeycomb-structured tellurene by angle-resolved photoemission spectroscopy. The topological edge states of tellurene are detected via scanning tunneling microscopy/spectroscopy. These results demonstrate that tellurene is a novel 2D honeycomb lattice with strong SOC, and they unambiguously prove that tellurene is a promising candidate for a room-temperature QSHE system.

Coherent Control of a Few-Channel Hole Type Gatemon Qubit.

Gatemon qubits are the electrically tunable cousins of superconducting transmon qubits. In this work, we demonstrate the full coherent control of a gatemon qubit based on hole carriers in a Ge/Si core/shell nanowire, with the longest coherence times in group IV material gatemons to date. The key to these results is a high-quality Josephson junction obtained using a straightforward and reproducible annealing technique. We demonstrate that the transport through the narrow junction is dominated by only two quantum channels, with transparencies up to unity. This novel qubit platform holds great promise for quantum information applications, not only because it incorporates technologically relevant materials, but also because it provides new opportunities, like an ultrastrong spin-orbit coupling in the few-channel regime of Josephson junctions.

Gate-tunable Intrinsic Anomalous Hall Effect in Epitaxial MnBi2Te4 Films.

The anomalous Hall effect (AHE) is an important transport signature revealing topological properties of magnetic materials and their spin textures. Recently, MnBi2Te4 has been demonstrated to be an intrinsic magnetic topological insulator. However, the origin of its intriguing AHE behaviors remains elusive. Here, we demonstrate the Berry curvature-dominated intrinsic AHE in wafer-scale MnBi2Te4 films. By applying back-gate voltages, we observe an ambipolar conduction and n-p transition in ∼7-layer MnBi2Te4, where a quadratic relation between the AHE resistance and longitudinal resistance suggests its intrinsic AHE nature. In particular, for ∼3-layer MnBi2Te4, the AHE sign can be tuned from pristine negative to positive. First-principles calculations unveil that such an AHE reversal originated from the competing Berry curvature between oppositely polarized spin-minority-dominated surface states and spin-majority-dominated inner bands. Our results shed light on the underlying physical mechanism of the intrinsic AHE and provide new perspectives for the unconventional sign-tunable AHE.