Search

Cryo-electron microscopy (cryo-EM) has been widely used to reveal the structures of proteins at atomic resolution. One key challenge is that almost all proteins are predominantly adsorbed to the air-water interface during standard cryo-EM specimen preparation. The interaction of proteins with air-water interface will significantly impede the success of reconstruction and achievable resolution. Here, we highlight the critical role of impenetrable surfactant monolayers in passivating the air-water interface problems, and develop a robust effective method for high-resolution cryo-EM analysis, by using the superstructure GSAMs which comprises surfactant self-assembled monolayers (SAMs) and graphene membrane. The GSAMs works well in enriching the orientations and improving particle utilization ratio of multiple proteins, facilitating the 3.3-Å resolution reconstruction of a 100-kDa protein complex (ACE2-RBD), which shows strong preferential orientation using traditional specimen preparation protocol. Additionally, we demonstrate that GSAMs enables the successful determinations of small proteins (

Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair. Both TCR and repair-independent eviction require CSA and ubiquitination. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells, highlighting repairs prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7s deubiquitinase activity promoting TCR without abolishing repair-independent Pol II release. In summary, this study elucidates the fate of lesion-stalled Pol II, and may shed light on the molecular basis of genetic diseases caused by the defects of TCR genes.

Mapping neuronal networks is a central focus in neuroscience. While volume electron microscopy (vEM) can reveal the fine structure of neuronal networks (connectomics), it does not provide molecular information to identify cell types or functions. We developed an approach that uses fluorescent single-chain variable fragments (scFvs) to perform multiplexed detergent-free immunolabeling and volumetric-correlated-light-and-electron-microscopy on the same sample. We generated eight fluorescent scFvs targeting brain markers. Six fluorescent probes were imaged in the cerebellum of a female mouse, using confocal microscopy with spectral unmixing, followed by vEM of the same sample. The results provide excellent ultrastructure superimposed with multiple fluorescence channels. Using this approach, we documented a poorly described cell type, two types of mossy fiber terminals, and the subcellular localization of one type of ion channel. Because scFvs can be derived from existing monoclonal antibodies, hundreds of such probes can be generated to enable molecular overlays for connectomic studies.

Skillful subseasonal forecasts are crucial for various sectors of society but pose a grand scientific challenge. Recently, machine learning-based weather forecasting models outperform the most successful numerical weather predictions generated by the European Centre for Medium-Range Weather Forecasts (ECMWF), but have not yet surpassed conventional models at subseasonal timescales. This paper introduces FuXi Subseasonal-to-Seasonal (FuXi-S2S), a machine learning model that provides global daily mean forecasts up to 42 days, encompassing five upper-air atmospheric variables at 13 pressure levels and 11 surface variables. FuXi-S2S, trained on 72 years of daily statistics from ECMWF ERA5 reanalysis data, outperforms the ECMWFs state-of-the-art Subseasonal-to-Seasonal model in ensemble mean and ensemble forecasts for total precipitation and outgoing longwave radiation, notably enhancing global precipitation forecast. The improved performance of FuXi-S2S can be primarily attributed to its superior capability to capture forecast uncertainty and accurately predict the Madden-Julian Oscillation (MJO), extending the skillful MJO prediction from 30 days to 36 days. Moreover, FuXi-S2S not only captures realistic teleconnections associated with the MJO but also emerges as a valuable tool for discovering precursor signals, offering researchers insights and potentially establishing a new paradigm in Earth system science research.

Elastic stability is the basis for understanding structural responses to external stimuli in crystalline solids, including melting, incipient plasticity and fracture. In this work, elastic stability is investigated in a series of high-entropy alloys (HEAs) using in situ mechanical tests and atomic-resolution characterization in transmission electron microscopy. Under tensile loading, the HEA lattices are observed to undergo a sudden loss of ordering as the elastic strain reached ∽ 10%. Such elastic strain-induced amorphization stands in intrinsic contrast to previously reported dislocation-mediated elastic instability and defect accumulation-mediated amorphization, introducing a form of elastic instability. Together with the first principle calculations and atomic-resolution chemical mapping, we identify that the elastic strain-induced amorphization is closely related to the depressed dislocation nucleation due to the local atomic environment inhomogeneity of HEAs. Our findings provide insights for the understanding of the fundamental nature of physical mechanical phenomena like elastic instability and incipient plasticity.

Synthetic Notch (synNotch) receptors are genetically encoded, modular synthetic receptors that enable mammalian cells to detect environmental signals and respond by activating user-prescribed transcriptional programs. Although some materials have been modified to present synNotch ligands with coarse spatial control, applications in tissue engineering generally require extracellular matrix (ECM)-derived scaffolds and/or finer spatial positioning of multiple ligands. Thus, we develop here a suite of materials that activate synNotch receptors for generalizable engineering of material-to-cell signaling. We genetically and chemically fuse functional synNotch ligands to ECM proteins and ECM-derived materials. We also generate tissues with microscale precision over four distinct reporter phenotypes by culturing cells with two orthogonal synNotch programs on surfaces microcontact-printed with two synNotch ligands. Finally, we showcase applications in tissue engineering by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined micropatterns. These technologies provide avenues for spatially controlling cellular phenotypes in mammalian tissues.

Vertical transistors, in which the source and drain are aligned vertically and the current flow is normal to the wafer surface, have attracted considerable attention recently. However, the realization of high-density vertical transistors is challenging, and could be largely attributed to the incompatibility between vertical structures and conventional lateral fabrication processes. Here we report a T-shape lamination approach for realizing high-density vertical sidewall transistors, where lateral transistors could be pre-fabricated on planar substrates first and then laminated onto vertical substrates using T-shape stamps, hence overcoming the incompatibility between planar processes and vertical structures. Based on this technique, we vertically stacked 60 MoS2 transistors within a small vertical footprint, corresponding to a device density over 108 cm-2. Furthermore, we demonstrate two approaches for scalable fabrication of vertical sidewall transistor arrays, including simultaneous lamination onto multiple vertical substrates, as well as on the same vertical substrate using multi-cycle layer-by-layer laminations.

For first-order phase transitions, the second derivatives of Gibbs free energy (specific heat and compressibility) diverge at the transition point, resulting in an effect known as super-elasticity along the pressure axis, or super-thermicity along the temperature axis. Here we report a chemical analogy of these singularity effects along the atomic doping axis, where the second derivative of Gibbs free energy (chemical susceptibility) diverges at the transition point, leading to an anomalously high energy barrier for dopant diffusion in co-existing phases, an effect we coin as super-susceptibility. The effect is realized in hydrogen diffusion in vanadium dioxide (VO2) with a metal-insulator transition (MIT). We show that hydrogen faces three times higher energy barrier and over one order of magnitude lower diffusivity when it diffuses across a metal-insulator domain wall in VO2. The additional energy barrier is attributed to a volumetric energy penalty that the diffusers need to pay for the reduction of latent heat. The super-susceptibility and resultant retarded atomic diffusion are expected to exist universally in all phase transformations where the transformation temperature is coupled to chemical composition, and inspires new ways to engineer dopant diffusion in phase-coexisting material systems.

Corrosion of electrocatalysts during electrochemical operations, such as low potential - high potential cyclic swapping, can cause significant performance degradation. However, the electrochemical corrosion dynamics, including structural changes, especially site and composition specific ones, and their correlation with electrochemical processes are hidden due to the insufficient spatial-temporal resolution characterization methods. Using electrochemical liquid cell transmission electron microscopy, we visualize the electrochemical corrosion of Pd@Pt core-shell octahedral nanoparticles towards a Pt nanoframe. The potential-dependent surface reconstruction during multiple continuous in-situ cyclic voltammetry with clear redox peaks is captured, revealing an etching and deposition process of Pd that results in internal Pd atoms being relocated to external surface, followed by subsequent preferential corrosion of Pt (111) terraces rather than the edges or corners, simultaneously capturing the structure evolution also allows to attribute the site-specific Pt and Pd atomic dynamics to individual oxidation and reduction events. This work provides profound insights into the surface reconstruction of nanoparticles during complex electrochemical processes.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

Non-volatile phase-change memory devices utilize local heating to toggle between crystalline and amorphous states with distinct electrical properties. Expanding on this kind of switching to two topologically distinct phases requires controlled non-volatile switching between two crystalline phases with distinct symmetries. Here, we report the observation of reversible and non-volatile switching between two stable and closely related crystal structures, with remarkably distinct electronic structures, in the near-room-temperature van der Waals ferromagnet Fe5-δGeTe2. We show that the switching is enabled by the ordering and disordering of Fe site vacancies that results in distinct crystalline symmetries of the two phases, which can be controlled by a thermal annealing and quenching method. The two phases are distinguished by the presence of topological nodal lines due to the preserved global inversion symmetry in the site-disordered phase, flat bands resulting from quantum destructive interference on a bipartite lattice, and broken inversion symmetry in the site-ordered phase.

Doa10 (MARCHF6 in metazoans) is a large polytopic membrane-embedded E3 ubiquitin ligase in the endoplasmic reticulum (ER) that plays an important role in quality control of cytosolic and ER proteins. Although Doa10 is highly conserved across eukaryotes, it is not understood how Doa10 recognizes its substrates. Here, we define the substrate recognition mechanism of Doa10 by structural and functional analyses on Saccharomyces cerevisiae Doa10 and its model substrates. Cryo-EM analysis shows that Doa10 has unusual architecture with a large lipid-filled central cavity, and its conserved middle domain forms an additional water-filled lateral tunnel open to the cytosol. Our biochemical data and molecular dynamics simulations suggest that the entrance of the substrates degron peptide into the lateral tunnel is required for efficient polyubiquitination. The N- and C-terminal membrane domains of Doa10 seem to form fence-like features to restrict polyubiquitination to those proteins that can access the central cavity and lateral tunnel. Our study reveals how extended hydrophobic sequences at the termini of substrate proteins are recognized by Doa10 as a signal for quality control.

Traditional histochemical staining of post-mortem samples often confronts inferior staining quality due to autolysis caused by delayed fixation of cadaver tissue, and such chemical staining procedures covering large tissue areas demand substantial labor, cost and time. Here, we demonstrate virtual staining of autopsy tissue using a trained neural network to rapidly transform autofluorescence images of label-free autopsy tissue sections into brightfield equivalent images, matching hematoxylin and eosin (H&E) stained versions of the same samples. The trained model can effectively accentuate nuclear, cytoplasmic and extracellular features in new autopsy tissue samples that experienced severe autolysis, such as COVID-19 samples never seen before, where the traditional histochemical staining fails to provide consistent staining quality. This virtual autopsy staining technique provides a rapid and resource-efficient solution to generate artifact-free H&E stains despite severe autolysis and cell death, also reducing labor, cost and infrastructure requirements associated with the standard histochemical staining.

The scale at which low-carbon electricity will need to be deployed to meet economic growth, electrification, and climate goals in Africa is unprecedented, yet the potential land use and freshwater impacts from this massive build-out of energy infrastructure is poorly understood. In this study, we characterize low-impact onshore wind, solar photovoltaics, and hydropower potential in Southern Africa and identify the cost-optimal mix of electricity generation technologies under different sets of socio-environmental land use and freshwater constraints and carbon targets. We find substantial wind and solar potential after applying land use protections, but about 40% of planned or proposed hydropower projects face socio-environmental conflicts. Applying land and freshwater protections results in more wind, solar, and battery capacity and less hydropower capacity compared to scenarios without protections. While a carbon target favors hydropower, the amount of cost-competitively selected hydropower is at most 45% of planned or proposed hydropower capacity in any scenario-and is only 25% under socio-environmental protections. Achieving both carbon targets and socio-environmental protections results in system cost increases of 3-6%. In the absence of land and freshwater protections, environmental and social impacts from new hydropower development could be significant.

Abstract Ni-based catalysts are highly reactive for dry reforming of methane (DRM) but they are prone to rapid deactivation due to sintering and/or coking. In this study, we present a straightforward approach for anchoring dispersed Ni sites with strengthened metal-support interactions, which leads to Ni active sites embedded in dealuminated Beta zeolite with superior stability and rates for DRM. The process involves solid-state grinding of dealuminated Beta zeolites and nickel nitrate, followed by calcination under finely controlled gas flow conditions. By combining in situ X-ray absorption spectroscopy and ab initio simulations, it is elucidated that the efficient removal of byproducts during catalyst synthesis is conducted to strengthen Ni–Si interactions that suppress coking and sintering after 100 h of time-on-stream. Transient isotopic kinetic experiments shed light on the differences in intrinsic turnover frequency of Ni species and explain performance trends. This work constructs a fundamental understanding regarding the implication of facile synthesis protocols on metal-support interaction in zeolite-supported Ni sites, and it lays the needed foundations on how these interactions can be tuned for outstanding DRM performance.

Abstract Rapid glucose supply is crucial for animal survival during stress response. How the timescale of stress-induced glucose release precisely controlled by hypothalamic corticotropin-releasing hormone (CRH) neurons remains unclear. Here, we show that stress-induced hyperglycemia can be divided into at least two stages in male mice: the first fast stage is mediated by hypothalamus (paraventricular to ventromedial hypothalamus)-sympathetic (raphe pallidus nucleus to intermediolateral nucleus)-liver (HSL) axis activity; the second delayed stage is mediated by adrenal activity. Blocking the activity of HSL axis impairs predatory evoked flight responses, indicating that the HSL pathway activity is necessary for stress coping. We further reveal the intracellular signal cascade for CRH signal in the hypothalamus, which is mediated by GABAA receptor β3 subunit phosphorylation at S408/409, results in prevention of GABAA receptor membrane recruitment. Thus, we uncovered the precise timescale of glucose supply during stress which is mediated by adrenal independent HSL and adrenal dependent pathway respectively.

Abstract Seed size, a key determinant of rice yield, is regulated by brassinosteroid (BR); however, the BR pathway in rice has not been fully elucidated. Here, we report the cloning and characterization of the quantitative trait locus Rice Big Grain 1 (qRBG1) from single-segment substitution line Z499. Our data show that qRBG1 Z is an unselected rare promoter variation that reduces qRBG1 expression to increase cell number and size, resulting in larger grains, whereas qRBG1 overexpression causes smaller grains in recipient Nipponbare. We demonstrate that qRBG1 encodes a non-canonical BES1 (Bri1-EMS-Suppressor1)/BZR1(Brassinazole-Resistant1) family member, OsBZR5, that regulates grain size upon phosphorylation by OsGSK2 (GSK3-like Kinase2) and binding to D2 (DWARF2) and OFP1 (Ovate-Family-Protein1) promoters. qRBG1 interacts with OsBZR1 to synergistically repress D2, and to antagonistically mediate OFP1 for grain size. Our results reveal a regulatory network controlling grain size via OsGSK2–qRBG1–OsBZR1–D2–OFP1 module, providing a target for improving rice yield.

Abstract M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.

Abstract Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.

Abstract A deep understanding of how the host matrix influences the afterglow properties of molecule dopants is crucial for designing advanced afterglow materials. Despite its appeal, the impact of defects on the afterglow performance in molecule-doped SiO2 matrices has remained largely unexplored. Herein, we detail the synthesis of monodisperse SiO2 microparticles by hydrothermally doping molecules, such as 4-phenylpyridine, 4,4’-bipyridine, and 1,4-bis(pyrid-4-yl)benzene. Our results demonstrate that hydrothermal reactions induce not only the formation of emissive defects in the SiO2 matrix but also enable molecule doping through SiO2 pseudomorphic transformation. Optical analyses reveal a remarkable afterglow activation of doped molecules, driven by a synergistic interplay of hydrogen bonding and physical fixation. Specifically, 4-phenylpyridine doping leads to an impressive 227- and 271-fold enhancement in fluorescence and afterglow, respectively, and an extraordinary 3711-fold enhancement in the afterglow lifetime of the resulting SiO2 MPs. We also document hybrid states involving molecule dopants and SiO2 defects, explaining energy transfer from molecule dopants to defects in both singlet and triplet states. The robust achievement of molecule doping provides flexibility to tailor excitation-dependent afterglow attributes while preserving angle-dependent structural colors, facilitating the creation of diverse building blocks for multiscale optical platforms for afterglow modulation and information encoding.

Abstract Spermiogenesis, the complex transformation of haploid spermatids into mature spermatozoa, relies on precise spatiotemporal regulation of gene expression at the post-transcriptional level. The mechanisms underlying this critical process remain incompletely understood. Here, we identify centrosomal protein 112 (CEP112) as an essential regulator of mRNA translation during this critical developmental process. Mutations in CEP112 are discovered in oligoasthenoteratospermic patients, and Cep112-deficient male mice recapitulate key phenotypes of human asthenoteratozoospermia. CEP112 localizes to the neck and atypical centrioles of mature sperm and forms RNA granules during spermiogenesis, enriching target mRNAs such as Fsip2, Cfap61, and Cfap74. Through multi-omics analyses and the TRICK reporter assay, we demonstrate that CEP112 orchestrates the translation of target mRNAs. Co-immunoprecipitation and mass spectrometry identify CEP112’s interactions with translation-related proteins, including hnRNPA2B1, EEF1A1, and EIF4A1. In vitro, CEP112 undergoes liquid-liquid phase separation, forming condensates that recruit essential proteins and mRNAs. Moreover, variants in patient-derived CEP112 disrupt phase separation and impair translation efficiency. Our results suggest that CEP112 mediates the assembly of RNA granules through liquid-liquid phase separation to control the post-transcriptional expression of fertility-related genes. This study not only clarifies CEP112’s role in spermatogenesis but also highlights the role of phase separation in translational regulation, providing insights into male infertility and suggesting potential therapeutic targets.

Abstract β-Branched aromatic α-amino acids are valuable building blocks in natural products and pharmaceutically active compounds. However, their chemical or enzymatic synthesis is challenging due to the presence of two stereocenters. We design phenylalanine ammonia lyases (PAL) variants for the direct asymmetric synthesis of β-branched aromatic α-amino acids. Based on extensive computational analyses, we unravel the enigma behind PAL’s inability to accept β-methyl cinnamic acid (β-MeCA) as substrate and achieve the synthesis of the corresponding amino acids of β-MeCA and analogs using a double (PcPAL-L256V-I460V) and a triple mutant (PcPAL-F137V-L256V-I460V). The reactions are scaled-up using an optimized E. coli based whole-cell biotransformation system to produce ten β-branched phenylalanine analogs with high diastereoselectivity (dr > 20:1) and enantioselectivity (ee > 99.5%) in yields ranging from 41-71%. Moreover, we decipher the mechanism of PcPAL-L256V-I460V for the acceptance of β-MeCA and converting it with excellent stereoselectivity by computational simulations. Thus, this study offers an efficient method for synthesizing β-branched aromatic α-amino acids.

Abstract The redox state of a planetary mantle affects its thermal evolution. The redox evolution of lunar mantle, however, remains unclear due to limited oxygen fugacity (fO2) constraints from young lunar samples. Here, we report vanadium (V) oxybarometers on olivine and spinel conducted on 27 Chang’e-5 basalt fragments from 2.0 billion years ago. These fragments yield an average fO2 of ΔIW -0.84 ± 0.65 (2σ), which closely aligns with the Apollo samples from 3.6–3.0 billion years ago. This temporal uniformity indicates the lunar mantle remained reduced. This observation reveals that the processes responsible for oxidizing mantles of Earth and Mars either did not occur or had negligible oxidizing effects on the Moon. The long-term reduced mantle may lead to a distinctive volatile degassing pathway for the Moon. It could also make the lunar mantle more difficult to melt, preventing internal heat dissipation and consequently resulting in a slow cooling rate.

Abstract Enhancing drought tolerance in crops and understanding the underlying mechanisms have been subject of intense research. The precise function and molecular mechanisms of B-box zinc finger proteins (BBX) remain elusive. Here, we report a natural allele of BBX18 (BBX18 TT ) that encodes a C-terminal truncated protein. While most wild tomato germplasms contain the BBX18 CC allele and show more drought tolerant, modern cultivated tomatoes mostly carry BBX18 TT allele and are more drought sensitive. Knockout of BBX18 leads to improved drought tolerance in transgenic plants of cultivated tomato. Ascorbate peroxidase 1 (APX1) is identified as a BBX18-interacting protein that acts as a positive regulator of drought resistance in tomato. Chromatin immunoprecipitation sequencing analyses reveal that BBX18 binds to a unique cis-acting element of the APX1 promoter and represses its gene expression. This study provides insights into the molecular mechanism underlying drought resistance mediated by the BBX18-APX1 module in plants.

Abstract The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.

Abstract The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution.

Abstract Despite the pivotal role of stannum doping in achieving ultrahigh piezoelectric performance in barium titanate-based ceramics, the fundamental mechanisms underlying this enhancement remain elusive. Here, we introduce a single variable nonstoichiometric stannum strategy in lead-free barium titanate-based ceramics with giant piezoelectricity, revealing that stannum doping contributes intrinsically and extrinsically to enhance piezoelectricity. Density functional theory calculations elucidate the intrinsic enhancement of polarization arising from lattice distortion and increased space for titanium-oxygen bonds induced by optimal stannum doping, which is corroborated by Rayleigh analysis. A phase transition from ferroelectric multiphase coexistence to paraelectric phase is observed, alongside a rapid miniaturized and eventually disappeared domains with increasing stannum doping. This evolution in phase structure and domain configuration induces a nearly vanishing polarization anisotropy and low domain wall energy, facilitating easy polarization rotation and domain wall motion, thereby significantly contributing to the extrinsic piezoelectric response. Consequently, the origins of ultrahigh performance can be attributed to the synergistic effect of stannum-induced intrinsic and extrinsic contributions in barium titanate-based ceramics. This study provides fundamental insights into the role of doping elements and offers guidance for the design of high-performance piezoelectrics.

Abstract Ferroelectrics are essential in memory devices for multi-bit storage and high-density integration. Ferroelectricity mainly exists in compounds but rare in single-element materials due to their lack of spontaneous polarization in the latter. However, we report a room-temperature ferroelectricity in quasi-one-dimensional Te nanowires. Piezoelectric characteristics, ferroelectric loops and domain reversals are clearly observed. We attribute the ferroelectricity to the ion displacement created by the interlayer interaction between lone-pair electrons. Ferroelectric polarization can induce a strong field effect on the transport along the Te chain, giving rise to a self-gated ferroelectric field-effect transistor. By utilizing ferroelectric Te nanowire as channel, the device exhibits high mobility (~220 cm2·V−1·s−1), continuous-variable resistive states can be observed with long-term retention (>105 s), fast speed (1.92 TB/cm2). Our work provides opportunities for single-element ferroelectrics and advances practical applications such as ultrahigh-density data storage and computing-in-memory devices.

Abstract The family of coinage-metal-based cyclic trinuclear complexes exhibits abundant photophysical properties, promising for diverse applications. However, their utility in biochemistry is often hindered by large particle size and strong hydrophobicity. Meanwhile, the investigation into multi-photon excited luminescence within this family remained undocumented, limiting their potential in bio-imaging. Herein, we unveil the multi-photon excited luminescent properties of pyrazolate-based trinuclear gold(I) clusters, facilitated by excimeric gold(I)···gold(I) interactions, revealing a nonlinear optical phenomenon within this family. Furthermore, to address issues of poor biocompatibility, we employ electrospinning coupled with hydroxypropyl-beta-cyclodextrin as the matrix to fabricate a flexible, durable, transparent, and red emissive film with a photoluminescence quantum yield as high as 88.3%. This strategy not only produces the film with sufficient hydrophilicity and stability, but also achieves the downsizing of trinuclear gold(I) clusters from microscale to nanoscale. Following the instantaneous dissolution of the film in the media, the released trinuclear gold(I) nanoparticles have illuminated cells and bacteria through a real-time, non-toxic, multi-photon bio-imaging approach. This achievement offers a fresh approach for utilizing coinage-metal-based cyclic trinuclear complexes in biochemical fields.

Abstract Salivary proteins of insect herbivores can suppress plant defenses, but the roles of many remain elusive. One such protein is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the saliva of the Recilia dorsalis (RdGAPDH) leafhopper, which is known to transmit rice gall dwarf virus (RGDV). Here we show that RdGAPDH was loaded into exosomes and released from salivary glands into the rice phloem through an exosomal pathway as R. dorsalis fed. In infected salivary glands of R. dorsalis, the virus upregulated the accumulation and subsequent release of exosomal RdGAPDH into the phloem. Once released, RdGAPDH consumed H2O2 in rice plants owing to its –SH groups reacting with H2O2. This reduction in H2O2 of rice plant facilitated R. dorsalis feeding and consequently promoted RGDV transmission. However, overoxidation of RdGAPDH could cause potential irreversible cytotoxicity to rice plants. In response, rice launched emergency defense by utilizing glutathione to S-glutathionylate the oxidization products of RdGAPDH. This process counteracts the potential cellular damage from RdGAPDH overoxidation, helping plant to maintain a normal phenotype. Additionally, salivary GAPDHs from other hemipterans vectors similarly suppressed H2O2 burst in plants. We propose a strategy by which plant viruses exploit insect salivary proteins to modulate plant defenses, thus enabling sustainable insect feeding and facilitating viral transmission.

Abstract Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4’s potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab’s efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.

Abstract Nipah virus infection, one of the top priority diseases recognized by the World Health Organization, underscores the urgent need to develop effective countermeasures against potential epidemics and pandemics. Here, we identify a fully human single-domain antibody that targets a highly conserved cryptic epitope situated at the dimeric interface of the Nipah virus G protein (receptor binding protein, RBP), as elucidated through structures by high-resolution cryo-electron microscopy (cryo-EM). This unique binding mode disrupts the tetramerization of the G protein, consequently obstructing the activation of the F protein and inhibiting viral membrane fusion. Furthermore, our investigations reveal that this compact antibody displays enhanced permeability across the blood-brain barrier (BBB) and demonstrates superior efficacy in eliminating pseudovirus within the brain in a murine model of Nipah virus infection, particularly compared to the well-characterized antibody m102.4 in an IgG1 format. Consequently, this single-domain antibody holds promise as a therapeutic candidate to prevent Nipah virus infections and has potential implications for vaccine development.

Abstract Chloroplasts are key players in photosynthesis and immunity against microbial pathogens. However, the precise and timely regulatory mechanisms governing the control of photosynthesis-associated nuclear genes (PhANGs) expression in plant immunity remain largely unknown. Here we report that TaPIR1, a Pst-induced RING-finger E3 ubiquitin ligase, negatively regulates Pst resistance by specifically interacting with TaHRP1, an atypical transcription factor histidine-rich protein. TaPIR1 ubiquitinates the lysine residues K131 and K136 in TaHRP1 to regulate its stability. TaHRP1 directly binds to the TaHRP1-binding site elements within the PhANGs promoter to activate their transcription via the histidine-rich domain of TaHRP1. PhANGs expression induces the production of chloroplast-derived ROS. Although knocking out TaHRP1 reduces Pst resistance, TaHRP1 overexpression contributes to photosynthesis, and chloroplast-derived ROS production, and improves disease resistance. TaPIR1 expression inhibits the downstream activation of TaHRP1 and TaHRP1-induced ROS accumulation in chloroplasts. Overall, we show that the TaPIR1-mediated ubiquitination and degradation of TaHRP1 alters PhANGs expression to disrupt chloroplast function, thereby increasing plant susceptibility to Pst.

Abstract Cations such as K+ play a key part in the CO2 electroreduction reaction, but their role in the reaction mechanism is still in debate. Here, we use a highly symmetric Ni-N4 structure to selectively probe the mechanistic influence of K+ and identify its interaction with chemisorbed CO2 −. Our electrochemical kinetics study finds a shift in the rate-determining step in the presence of K+. Spectral evidence of chemisorbed CO2 − from in-situ X-ray absorption spectroscopy and in-situ Raman spectroscopy pinpoints the origin of this rate-determining step shift. Grand canonical potential kinetics simulations - consistent with experimental results - further complement these findings. We thereby identify a long proposed non-covalent interaction between K+ and chemisorbed CO2 −. This interaction stabilizes chemisorbed CO2 − and thus switches the rate-determining step from concerted proton electron transfer to independent proton transfer. Consequently, this rate-determining step shift lowers the reaction barrier by eliminating the contribution of the electron transfer step. This K+-determined reaction pathway enables a lower energy barrier for CO2 electroreduction reaction than the competing hydrogen evolution reaction, leading to an exclusive selectivity for CO2 electroreduction reaction.

Abstract To achieve high power conversion efficiency in perovskite/silicon tandem solar cells, it is necessary to develop a promising wide-bandgap perovskite absorber and processing techniques in relevance. To date, the performance of devices based on wide-bandgap perovskite is still limited mainly by carrier recombination at their electron extraction interface. Here, we demonstrate assembling a binary two-dimensional perovskite by both alternating-cation-interlayer phase and Ruddlesden−Popper phase to passivate perovskite/C60 interface. The binary two-dimensional strategy takes effects not only at the interface but also in the bulk, which enables efficient charge transport in a wide-bandgap perovskite solar cell with a stabilized efficiency of 20.79% (1 cm2). Based on this absorber, a monolithic perovskite/silicon tandem solar cell is fabricated with a steady-state efficiency of 30.65% assessed by a third party. Moreover, the tandem devices retain 96% of their initial efficiency after 527 h of operation under full spectral continuous illumination, and 98% after 1000 h of damp-heat testing (85 °C with 85% relative humidity).

Abstract Influenza virus infection remains a major global health problem and requires a universal vaccine with broad protection against different subtypes as well as a rapid-response vaccine to provide immediate protection in the event of an epidemic outbreak. Here, we show that intranasal administration of probiotic Escherichia coli Nissle 1917 activates innate immunity in the respiratory tract and provides immediate protection against influenza virus infection within 1 day. Based on this vehicle, a recombinant strain is engineered to express and secret five tandem repeats of the extracellular domain of matrix protein 2 from different influenza virus subtypes. Intranasal vaccination with this strain induces durable humoral and mucosal responses in the respiratory tract, and provides broad protection against the lethal challenge of divergent influenza viruses in female BALB/c mice. Our findings highlight a promising delivery platform for developing mucosal vaccines that provide immediate and sustained protection against respiratory pathogens.

Abstract Renewable-driven electrocatalytic nitrate conversion offers a promising alternative to alleviate nitrate pollution and simultaneously harvest green ammonia. However, due to the complex proton-electron transfer processes, the reaction mechanism remains elusive, thereby limiting energy efficiency. Here, we adopt Ni(OH)₂ as a model catalyst to investigate the dynamic evolution of the reaction interface. A proposed OH cycle mechanism involves the formation of a locally OH-enriched microenvironment to promote the hydrogenation process, which is identified through in-situ spectroscopy and isotopic labelling. By further activating the dynamic state through the implementation of surface vacancies via plasma, we achieve a high Faradaic efficiency of almost 100%. The activated interface accelerates the OH cycle by enhancing dehydroxylation, water dissociation, and OH adsorption, thereby promoting nitrate electroreduction and inhibiting hydrogen evolution. We anticipate that rational activation of the dynamic interfacial state can facilitate electrocatalytic interface activity and improve reaction efficiency.

Abstract Palladium catalyzed tandem reaction represents a one-pot synthetic approach to efficiently synthesize complex functionalized molecules while reducing synthetic steps, aligning with the principles of green chemistry. However, achieving a direct cascade of the aza-Wacker and Povarov reactions in one-pot synthesis presents a challenge due to substrate compatibility issues between the two reactions. In this work, we describe an aza-Wacker/Povarov reaction employing a highly electrophilic palladium catalyst, which effectively converts anilines and 1,6-dienes into hexahydro-cyclopenta[b]quinolines. The optimized conditions yield up to 79%, with a diastereoselectivity > 20:1. Substrate range testing reveals compatibility with various sensitive functional groups, and successful late-stage modifications are performed on several natural products and drug molecules, demonstrating the versatility and practicality of the method. Additionally, a preliminary investigation into the reaction mechanism suggests an aza-Wacker process followed by a Povarov process.

Abstract Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.

Abstract Three-dimensional (3D) imaging of individual atoms is a critical tool for discovering new physical phenomena and developing new technologies in microscopic systems. However, the current single-atom-resolved 3D imaging methods are limited to static circumstances or a shallow detection range. Here, we demonstrate a generic dynamic 3D imaging method to track the extensive motion of single ions by exploiting the engineered point-spread function (PSF). We show that the image of a single ion can be engineered into a helical PSF, thus enabling single-snapshot acquisition of the position information of the ion in the trap. A preliminary application of this technique is demonstrated by recording the 3D motion trajectory of a single trapped ion and reconstructing the 3D dynamical configuration transition between the zig and zag structures of a 5-ion crystal. This work opens the path for studies on single-atom-resolved dynamics in both trapped-ion and neutral-atom systems.