A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.

Multiple plant developmental processes, such as lateral root development, depend on auxin distribution patterns that are in part generated by the PIN-formed family of auxin-efflux transporters. Here we propose that AUXIN RESPONSE FACTOR7 (ARF7) and the ARF7-regulated FOUR LIPS/MYB124 (FLP) transcription factors jointly form a coherent feed-forward motif that mediates the auxin-responsive PIN3 transcription in planta to steer the early steps of lateral root formation. This regulatory mechanism might endow the PIN3 circuitry with a temporal 'memory' of auxin stimuli, potentially maintaining and enhancing the robustness of the auxin flux directionality during lateral root development. The cooperative action between canonical auxin signalling and other transcription factors might constitute a general mechanism by which transcriptional auxin-sensitivity can be regulated at a tissue-specific level.

Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification involved in multiple biological processes, including DNA damage repair. This modification is catalyzed by poly(ADP-ribose) polymerase (PARP) family of enzymes. PARylation is composed of both linear and branched polymers of poly(ADP-ribose) (PAR). However, the biochemical mechanism of polymerization and biological functions of branched PAR chains are elusive. Here we show that PARP2 is preferentially activated by PAR and subsequently catalyzes branched PAR chain synthesis. Notably, the direct binding to PAR by the N-terminus of PARP2 promotes the enzymatic activity of PARP2 toward the branched PAR chain synthesis. Moreover, the PBZ domain of APLF recognizes the branched PAR chain and regulates chromatin remodeling to DNA damage response. This unique feature of PAR-dependent PARP2 activation and subsequent PARylation mediates the participation of PARP2 in DNA damage repair. Thus, our results reveal an important molecular mechanism of branched PAR synthesis and a key biological function of branched PARylation.

Self-powered implantable medical electronic devices that harvest biomechanical energy from cardiac motion, respiratory movement and blood flow are part of a paradigm shift that is on the horizon. Here, we demonstrate a fully implanted symbiotic pacemaker based on an implantable triboelectric nanogenerator, which achieves energy harvesting and storage as well as cardiac pacing on a large-animal scale. The symbiotic pacemaker successfully corrects sinus arrhythmia and prevents deterioration. The open circuit voltage of an implantable triboelectric nanogenerator reaches up to 65.2 V. The energy harvested from each cardiac motion cycle is 0.495 μJ, which is higher than the required endocardial pacing threshold energy (0.377 μJ). Implantable triboelectric nanogenerators for implantable medical devices offer advantages of excellent output performance, high power density, and good durability, and are expected to find application in fields of treatment and diagnosis as in vivo symbiotic bioelectronics.

Soft wearable electronics for underwater applications are of interest, but depend on the development of a waterproof, long-term sustainable power source. In this work, we report a bionic stretchable nanogenerator for underwater energy harvesting that mimics the structure of ion channels on the cytomembrane of electrocyte in an electric eel. Combining the effects of triboelectrification caused by flowing liquid and principles of electrostatic induction, the bionic stretchable nanogenerator can harvest mechanical energy from human motion underwater and output an open-circuit voltage over 10 V. Underwater applications of a bionic stretchable nanogenerator have also been demonstrated, such as human body multi-position motion monitoring and an undersea rescue system. The advantages of excellent flexibility, stretchability, outstanding tensile fatigue resistance (over 50,000 times) and underwater performance make the bionic stretchable nanogenerator a promising sustainable power source for the soft wearable electronics used underwater.

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

Synthesizing patchy particles with predictive control over patch size, shape, placement and number has been highly sought-after for nanoparticle assembly research, but is fraught with challenges. Here we show that polymers can be designed to selectively adsorb onto nanoparticle surfaces already partially coated by other chains to drive the formation of patchy nanoparticles with broken symmetry. In our model system of triangular gold nanoparticles and polystyrene-b-polyacrylic acid patch, single- and double-patch nanoparticles are produced at high yield. These asymmetric single-patch nanoparticles are shown to assemble into self-limited patch‒patch connected bowties exhibiting intriguing plasmonic properties. To unveil the mechanism of symmetry-breaking patch formation, we develop a theory that accurately predicts our experimental observations at all scales-from patch patterning on nanoparticles, to the size/shape of the patches, to the particle assemblies driven by patch‒patch interactions. Both the experimental strategy and theoretical prediction extend to nanoparticles of other shapes such as octahedra and bipyramids. Our work provides an approach to leverage polymer interactions with nanoscale curved surfaces for asymmetric grafting in nanomaterials engineering.

The type II AAA + ATPase Drg1 is a ribosome assembly factor, functioning to release Rlp24 from the pre-60S particle just exported from nucleus, and its activity in can be inhibited by a drug molecule diazaborine. However, molecular mechanisms of Drg1-mediated Rlp24 removal and diazaborine-mediated inhibition are not fully understood. Here, we report Drg1 structures in different nucleotide-binding and benzo-diazaborine treated states. Drg1 hexamers transits between two extreme conformations (planar or helical arrangement of protomers). By forming covalent adducts with ATP molecules in both ATPase domain, benzo-diazaborine locks Drg1 hexamers in a symmetric and non-productive conformation to inhibits both inter-protomer and inter-ring communication of Drg1 hexamers. We also obtained a substrate-engaged mutant Drg1 structure, in which conserved pore-loops form a spiral staircase to interact with the polypeptide through a sequence-independent manner. Structure-based mutagenesis data highlight the functional importance of the pore-loop, the D1-D2 linker and the inter-subunit signaling motif of Drg1, which share similar regulatory mechanisms with p97. Our results suggest that Drg1 may function as an unfoldase that threads a substrate protein within the pre-60S particle.

Treatment of liver metastasis experiences slow progress owing to the severe side effects. In this study, we demonstrate a strategy capable of eliminating metastatic cancer cells in a selective manner. Nucleus-targeting W18O49 nanoparticles (WONPs) are conjugated to mitochondria-selective mesoporous silica nanoparticles (MSNs) containing photosensitizer (Ce6) through a Cathepsin B-cleavable peptide. In hepatocytes, upon the laser irradiation, the generated singlet oxygen species are consumed by WONPs, in turn leading to the loss of their photothermally heating capacity, thereby sparing hepatocyte from thermal damage induced by the laser illumination. By contrast, in cancer cells, the cleaved peptide linker allows WONPs and MSNs to respectively target nucleus and mitochondria, where the therapeutic powers could be unleashed, both photodynamically and photothermally. This ensures the energy production of cancer cells can be abolished. We further assess the underlying molecular mechanism at both gene and protein levels to better understand the therapeutic outcome.

Arthropod-borne viruses (arboviruses) can be maternally transmitted by female insects to their offspring, however, it is unknown whether male sperm can directly interact with the arbovirus and mediate its paternal transmission. Here we report that an important rice arbovirus is paternally transmitted by the male leafhoppers by hitchhiking with the sperm. The virus-sperm binding is mediated by the interaction of viral capsid protein and heparan sulfate proteoglycan on the sperm head surfaces. Mating experiments reveal that paternal virus transmission is more efficient than maternal transmission. Such paternal virus transmission scarcely affects the fitness of adult males or their offspring, and plays a pivotal role in maintenance of viral population during seasons unfavorable for rice hosts in the field. Our findings reveal that a preferred mode of vertical arbovirus transmission has been evolved by hitchhiking with insect sperm without disturbing sperm functioning, facilitating the long-term viral epidemic and persistence in nature.

The recent outbreak of Zika virus (ZIKV) was associated with birth defects and pregnancy loss when maternal infection occurs in early pregnancy, but specific mechanisms driving placental insufficiency and subsequent ZIKV-mediated pathogenesis remain unclear. Here we show, using large scale metabolomics, that ZIKV infection reprograms placental lipidome by impairing the lipogenesis pathways. ZIKV-induced metabolic alterations provide building blocks for lipid droplet biogenesis and intracellular membrane rearrangements to support viral replication. Furthermore, lipidome reprogramming by ZIKV is paralleled by the mitochondrial dysfunction and inflammatory immune imbalance, which contribute to placental damage. In addition, we demonstrate the efficacy of a commercially available inhibitor in limiting ZIKV infection, provides a proof-of-concept for blocking congenital infection by targeting metabolic pathways. Collectively, our study provides mechanistic insights on how ZIKV targets essential hubs of the lipid metabolism that may lead to placental dysfunction and loss of barrier function.

Metal hydrides have been rarely used in biomedicine. Herein, we fabricate titanium hydride (TiH1.924) nanodots from its powder form via the liquid-phase exfoliation, and apply these metal hydride nanodots for effective cancer treatment. The liquid-phase exfoliation is an effective method to synthesize these metal hydride nanomaterials, and its efficiency is determined by the matching of surface energy between the solvent and the metal hydrides. The obtained TiH1.924 nanodots can produce reactive oxygen species (ROS) under ultrasound, presenting a highly efficient sono-sensitizing effect. Meanwhile, TiH1.924 nanodots with strong near-infrared (NIR) absorbance can serve as a robust photothermal agent. By using the mild photothermal effect to enhance intra-tumoral blood flow and improve tumor oxygenation, a remarkable synergistic therapeutic effect is achieved in the combined photothermal-sonodynamic therapy. Importantly, most of these TiH1.924 nanodots can be cleared out from the body. This work presents the promises of functional metal hydride nanomaterials for biomedical applications.

Reactive oxygen species (ROS) play vital roles in intestinal inflammation. Therefore, eliminating ROS in the inflammatory site by antioxidant enzymes such as catalase and superoxide dismutase may effectively curb inflammatory bowel disease (IBD). Here, Escherichia coli Nissle 1917 (ECN), a kind of oral probiotic, was genetically engineered to overexpress catalase and superoxide dismutase (ECN-pE) for the treatment of intestinal inflammation. To improve the bioavailability of ECN-pE in the gastrointestinal tract, chitosan and sodium alginate, effective biofilms, were used to coat ECN-pE via a layer-by-layer electrostatic self-assembly strategy. In a mouse IBD model induced by different chemical drugs, chitosan/sodium alginate coating ECN-pE (ECN-pE(C/A)2) effectively relieved inflammation and repaired epithelial barriers in the colon. Unexpectedly, such engineered EcN-pE(C/A)2 could also regulate the intestinal microbial communities and improve the abundance of Lachnospiraceae_NK4A136 and Odoribacter in the intestinal flora, which are important microbes to maintain intestinal homeostasis. Thus, this study lays a foundation for the development of living therapeutic proteins using probiotics to treat intestinal-related diseases.

Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

PTEN is a multifaceted tumor suppressor that is highly sensitive to alterations in expression or function. The PTEN C-tail domain, which is rich in phosphorylation sites, has been implicated in PTEN stability, localization, catalytic activity, and protein interactions, but its role in tumorigenesis remains unclear. To address this, we utilized several mouse strains with nonlethal C-tail mutations. Mice homozygous for a deletion that includes S370, S380, T382 and T383 contain low PTEN levels and hyperactive AKT but are not tumor prone. Analysis of mice containing nonphosphorylatable or phosphomimetic versions of S380, a residue hyperphosphorylated in human gastric cancers, reveal that PTEN stability and ability to inhibit PI3K-AKT depends on dynamic phosphorylation-dephosphorylation of this residue. While phosphomimetic S380 drives neoplastic growth in prostate by promoting nuclear accumulation of β-catenin, nonphosphorylatable S380 is not tumorigenic. These data suggest that C-tail hyperphosphorylation creates oncogenic PTEN and is a potential target for anti-cancer therapy.

The rapid diagnosis of respiratory virus infection through breath and blow remains challenging. Here we develop a wireless, battery-free, multifunctional pathogenic infection diagnosis system (PIDS) for diagnosing SARS-CoV-2 infection and symptom severity by blow and breath within 110 s and 350 s, respectively. The accuracies reach to 100% and 92% for evaluating the infection and symptom severity of 42 participants, respectively. PIDS realizes simultaneous gaseous sample collection, biomarker identification, abnormal physical signs recording and machine learning analysis. We transform PIDS into other miniaturized wearable or portable electronic platforms that may widen the diagnostic modes at home, outdoors and public places. Collectively, we demonstrate a general-purpose technology for rapidly diagnosing respiratory pathogenic infection by breath and blow, alleviating the technical bottleneck of saliva and nasopharyngeal secretions. PIDS may serve as a complementary diagnostic tool for other point-of-care techniques and guide the symptomatic treatment of viral infections.

MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration. However, whether myofibers-expressed MyoD exerts its metabolic function in regulating whole body energy homeostasis in vivo remains largely unknown. Here, we report that genetic deletion of Myod in male mice enhances the oxidative metabolism of muscle and, intriguingly, renders the male mice resistant to high fat diet-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identify 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in male Myod KO mice. Functionally, the administration of DLPC significantly ameliorates HFD-induced obesity in male mice. Mechanistically, DLPC is found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in male mice. Collectively, our findings not only uncover a novel function of MyoD in controlling systemic energy homeostasis through the muscle-derived lipokine DLPC but also suggest that the DLPC might have clinical potential for treating obesity in humans.

Transdermal drug delivery has been regarded as an alternative to oral delivery and subcutaneous injection. However, needleless transdermal delivery of biomacromolecules remains a challenge. Herein, a transdermal delivery platform based on biocompatible fluorocarbon modified chitosan (FCS) is developed to achieve highly efficient non-invasive delivery of biomacromolecules including antibodies and antigens. The formed nanocomplexes exhibits effective transdermal penetration ability via both intercellular and transappendageal routes. Non-invasive transdermal delivery of immune checkpoint blockade antibodies induces stronger immune responses for melanoma in female mice and reduces systemic toxicity compared to intravenous injection. Moreover, transdermal delivery of a SARS-CoV-2 vaccine in female mice results in comparable humoral immunity as well as improved cellular immunity and immune memory compared to that achieved with subcutaneous vaccine injection. Additionally, FCS-based protein delivery systems demonstrate transdermal ability for rabbit and porcine skins. Thus, FCS-based transdermal delivery systems may provide a compelling opportunity to overcome the skin barrier for efficient transdermal delivery of bio-therapeutics.