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The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown. In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC. PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells. The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.

A major component of bacterial biofilms is curli amyloid fibrils secreted by the curli biogenesis system. Understanding the curli biogenesis mechanism is critical for developing therapeutic agents for biofilm-related infections. Here we report a systematic study of the curli biogenesis system, highlighted by structural, biochemical and functional analysis of the secretion channel complexes (CsgF-CsgG) with and without the curli substrate. The dual-pore architecture of the CsgF-CsgG complex was observed and used to develop an approach to inhibit the curli secretion by physically reducing the size of the CsgF pore. We further elucidated the assembly of the CsgFG complex with curli components (CsgA and CsgB) and curli-cell association through CsgF. Importantly, the recognition of the CsgA substrate by CsgG was uncovered. Nine crevices outside of the CsgG channel provide specific and highly-conserved recognition sites for CsgA N-terminus. Together with analysis of CsgE, our study provides comprehensive insights into curli biogenesis. A major component of bacterial biofilms is curli amyloid fibrils secreted by the curli biogenesis system. Here authors use cryo-EM to visualize the secretion channel complexes (CsgF-CsgG) with and without the curli substrate and provide insights into curli biogenesis.

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of cardiopulmonary units. No cure is currently available due to an incomplete understanding of vascular remodeling. Here we identify CD146-hypoxia-inducible transcription factor 1 alpha (HIF-1α) cross-regulation as a key determinant in vascular remodeling and PAH pathogenesis. CD146 is markedly upregulated in pulmonary artery smooth muscle cells (PASMCs/SMCs) and in proportion to disease severity. CD146 expression and HIF-1α transcriptional program reinforce each other to physiologically enable PASMCs to adopt a more synthetic phenotype. Disruption of CD146-HIF-1α cross-talk by genetic ablation of Cd146 in SMCs mitigates pulmonary vascular remodeling in chronic hypoxic mice. Strikingly, targeting of this axis with anti-CD146 antibodies alleviates established pulmonary hypertension (PH) and enhances cardiac function in two rodent models. This study provides mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy for PAH through direct modulation of CD146-HIF-1α cross-regulation. Vascular remodelling contributes to the development of pulmonary hypertension (PH). Here Luo and colleagues find that increases in CD146 levels drive vascular remodelling in PH through a cross-talk with hypoxia inducible factor (HIF) signalling, and show that inhibition of CD146 can attenuate disease progression.

The blood–brain barrier (BBB) establishes a protective interface between the central neuronal system and peripheral blood circulation and is crucial for homeostasis of the CNS. BBB formation startswhen the endothelial cells (ECs) invade the CNS and pericytes are recruited to the nascent vessels during embryogenesis. Despite the essential function of pericyte–EC interaction during BBB development, the molecular mechanisms coordinating the pericyte–EC behavior and communication remain incompletely understood. Here, we report a single cell receptor, CD146, that presents dynamic expression patterns in the cerebrovasculature at the stages of BBB induction and maturation, coordinates the interplay of ECs and pericytes, and orchestrates BBB development spatiotemporally. In mouse brain, CD146 is first expressed in the cerebrovascular ECs of immature capillaries without pericyte coverage; with increased coverage of pericytes, CD146 could only be detected in pericytes, but not in cerebrovascular ECs. Specific deletion of Cd146 in mice ECs resulted in reduced brain endothelial claudin-5 expression and BBB breakdown. By analyzing mice with specific deletion of Cd146 in pericytes, which have defects in pericyte coverage and BBB integrity, we demonstrate that CD146 functions as a coreceptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular ECs. Moreover, we found that the attached pericytes in turn down-regulate endothelial CD146 by secreting TGF-β1 to promote further BBB maturation. These results reveal that the dynamic expression of CD146 controls the behavior of ECs and pericytes, thereby coordinating the formation of a mature and stable BBB.

Rescue transportation will be severely hindered under urban waterlogging disasters. To solve the problem of delayed rescue of disaster vehicles, this study is based on a hydrodynamic model and uses a 2D hydrodynamic model to numerically analyze urban waterlogging. At the same time, a 1D pipeline network is used to calculate pipeline hydrodynamics and urban hydrodynamics modeling is completed by coupling 2D hydrodynamics with a 1D pipeline network. Considering the characteristics of urban transportation, static and dynamic path planning techniques are introduced to complete vehicle rescue path planning. In the analysis of hydrodynamic models, the monitoring value of the research model at the B water accumulation location was 41.2 cm, which was closer to the actual value and had a lower relative error, outperforming similar models. In addition, in the analysis of multiple rainfall scenarios, the proportion of short-term waterlogging caused by high-intensity rainfall was relatively high. For example, in scenario 4, the proportion of waterlogging formation within half an hour was 8.8%, which was higher than that of low rainfall. In addition, in static path planning, the research technique took 821s in scenario 4 and had a shorter planning distance, which is superior to similar techniques. In dynamic programming, the research technique performed better overall with a driving time of 1,054s in scenario 5 and a shorter planning distance of 7,723m. The research technology has good application effects in urban waterlogging disaster rescue. This research will provide technical support for urban disaster analysis and rescue.

Quantum-dot optoelectronics, pivotal for lighting, lasing and photovoltaics, rely on nanocrystalline oxide electron-injection layer. Here, we discover that the prevalent surface magnesium-modified zinc oxide electron-injection layer possesses poor n-type attributes, leading to the suboptimal and encapsulation-resin-sensitive performance of quantum-dot light-emitting diodes. A heavily n-doped nanocrystalline electron-injection layer—exhibiting ohmic transport with 1000 times higher electron conductivity and improved hole blockage—is developed via a simple reductive treatment. The resulting sub-bandgap-driven quantum-dot light-emitting diodes exhibit optimal efficiency and extraordinarily-high brightness, surpassing current benchmarks by at least 2.6-fold, and reaching levels suitable for quantum-dot laser diodes with only modest bias. This breakthrough further empowers white-lighting quantum-dot light-emitting diodes to exceed the 2035 U.S. Department of Energy’s targets for general lighting, which currently accounts for ~15% of global electricity consumption. Our work opens a door for understanding and optimizing carrier transport in nanocrystalline semiconductors shared by various types of solution-processed optoelectronic devices. Zheng et al. report water vapor treatment for in-situ n-doping of ZnMgO, enabling ideal ohmic electron transport and hole blockage as the electron injection layer for quantum dot light-emitting diodes, and improving the brightness and power efficiency of R/G/B LEDs for general lighting.

Severe local acidosis causes tissue damage and pain, and is one of the hallmarks of many diseases including ischemia, cancer, and inflammation. However, the molecular mechanisms of the cellular response to acid are not fully understood. We performed an unbiased RNA interference screen and identified PAC (TMEM206) as being essential for the widely observed proton-activated Cl⁻ (PAC) currents (ICl,H ). Overexpression of human PAC in PAC knockout cells generated ICl,H with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse Pac abolished ICl,H in neurons and attenuated brain damage after ischemic stroke. The wide expression of PAC suggests a broad role for this conserved Cl⁻ channel family in physiological and pathological processes associated with acidic pH.

Over the last decade, researchers have endeavored to mimic the naturally motile microorganisms and develop artificial nano/microswimmers, which propel themselves in aqueous media. However, most of these nano/microswimmers are propelled by the self-electrophoretic mechanism, which has one critical incompetency: the inability to operate in a high concentration electrolyte solution, such as the most important body fluid, blood. This ionic quenching behavior is well backed by the classical Helmholtz–Smoluchowski theory and seems to be an insurmountable challenge which has shadowed the otherwise promising biomedical applications for artificial nano/microswimmers. Here, we propose that the active nano/microswimmer’s self-electrophoresis is fundamentally different from the passive nanoparticle electrophoresis. By significantly increasing the Dukhin number with polyelectrolyte coating and geometry optimization, a favorable deviation from the Helmholtz–Smoluchowski behavior can be realized, and ion tolerance is enhanced by over 100 times for a visible light-powered self-electrophoretic microswimmer. Electrophoretic microswimmers aren’t well suited to function in vivo because electric-field screening reduces their speed in higher ionic-strength solutions. Here the authors propose a microswimmer that exploits high surface conductance to improve this ion tolerance to enable operation in a high salt environment.

Gastric adenocarcinoma (GAC) remains a significant global public health challenge, characterized by high incidence and mortality rates. Progress in tumor immunology has introduced immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways, demonstrating substantial potential in GAC therapy. Clinical research indicates that ICIs, particularly when combined with chemotherapy or targeted therapies, significantly enhance treatment efficacy in advanced GAC and specific molecular subtypes, including microsatellite instability-high (MSI-H) and human epidermal growth factor receptor 2 (HER2)-positive patients. However, immunotherapy is also associated with a range of immune-related adverse events (irAEs), necessitating effective management strategies to ensure treatment safety and maintain patients’ quality of life. Future studies should focus on identifying new therapeutic targets, optimizing patient selection, and developing personalized treatment approaches to further improve the efficacy and safety of immunotherapy in GAC.

Angiogenesis, a process that newly-formed blood vessels sprout from pre-existing ones, is vital for vertebrate development and adult homeostasis. Previous studies have demonstrated that the neuronal guidance molecule netrin-1 participates in angiogenesis and morphogenesis of the vascular system. Netrin-1 exhibits dual activities in angiogenesis： either promoting or inhibiting angiogenesis. The anti-angiogenic activity of netrin-1 is mediated by UNC5B receptor. However, how netrin-1 promotes angiogenesis remained unclear. Here we report that CD146, an endothelial transmembrane protein of the immunoglobulin superfamily, is a receptor for netrin-1. Netrin-1 binds to CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner. Condi- tional knockout of the cd146 gene in the murine endothelium or disruption of netrin-CD146 interaction by a specific anti-CD146 antibody blocks or reduces netrin-l-induced angiogenesis. In zebrafish embryos, downregulating either netrin-la or CD146 results in vascular defects with striking similarity. Moreover, knocking down CD146 blocks ectopic vascular sprouting induced by netrin-1 overexpression. Together, our data uncover CD146 as a previously unknown receptor for netrin-1 and also reveal a functional ligand for CD146 in angiogenesis, demonstrating the involvement of netrin-CD146 signaling in angiogenesis during vertebrate development.