ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus.

Autophagy-related protein 7 (ATG7) is an essential autophagy effector enzyme. Although it is well known that autophagy plays crucial roles in the infections with various viruses including influenza A virus (IAV), function and underlying mechanism of ATG7 in infection and pathogenesis of IAV remain poorly understood. Here, in vitro studies showed that ATG7 had profound effects on replication of IAV. Depletion of ATG7 markedly attenuated the replication of IAV, whereas overexpression of ATG7 facilitated the viral replication. ATG7 conditional knockout mice were further employed and exhibited significantly resistant to viral infections, as evidenced by a lower degree of tissue injury, slower body weight loss, and better survival, than the wild type animals challenged with either IAV (RNA virus) or pseudorabies virus (DNA virus). Interestingly, we found that ATG7 promoted the replication of IAV in autophagy-dependent and -independent manners, as inhibition of autophagy failed to completely block the upregulation of IAV replication by ATG7. To determine the autophagy-independent mechanism, transcriptome analysis was utilized and demonstrated that ATG7 restrained the production of interferons (IFNs). Loss of ATG7 obviously enhanced the expression of type I and III IFNs in ATG7-depleted cells and mice, whereas overexpression of ATG7 impaired the interferon response to IAV infection. Consistently, our experiments demonstrated that ATG7 significantly suppressed IRF3 activation during the IAV infection. Furthermore, we identified long noncoding RNA (lncRNA) GAPLINC as a critical regulator involved in the promotion of IAV replication by ATG7. Importantly, both inactivation of IRF3 and inhibition of IFN response caused by ATG7 were mediated through control over GAPLINC expression, suggesting that GAPLINC contributes to the suppression of antiviral immunity by ATG7. Together, these results uncover an autophagy-independent mechanism by which ATG7 suppresses host innate immunity and establish a critical role for ATG7/GAPLINC/IRF3 axis in regulating IAV infection and pathogenesis.

Engineering the interfacial orientation of MoS2/Co9S8 bidirectional catalysts with highly exposed active sites for reversible Li-CO2 batteries.

Sluggish CO2 reduction reaction (CO2RR) and evolution reaction (CO2ER) kinetics at cathodes seriously hamper the applications of Li-CO2 batteries, which have attracted vast attention as one kind of promising carbon-neutral technology. Two-dimensional transition metal dichalcogenides (TMDs) have shown great potential as the bidirectional catalysts for CO2 redox, but how to achieve a high exposure of dual active sites of TMDs with CO2RR/CO2ER activities remains a challenge. Herein, a bidirectional catalyst that vertically growing MoS2 on Co9S8 supported by carbon paper (V-MoS2/Co9S8@CP) has been designed with abundant edge as active sites for both CO2RR and CO2ER, improves the interfacial conductivity, and modulates the electron transportation pathway along the basal planes. As evidenced by the outstanding energy efficiency of 81.2% and ultra-small voltage gap of 0.68 V at 20 µA cm-2, Li-CO2 batteries with V-MoS2/Co9S8@CP show superior performance compared with horizontally growing MoS2 on Co9S8 (H-MoS2/Co9S8@CP), MoS2@CP, and Co9S8@CP. Density functional theory calculations help reveal the relationship between performance and structure and demonstrate the synergistic effect between MoS2 edge sites and Co9S8. This work provides an avenue to understand and realize rationally designed electronic contact of TMDs with specified crystal facets, but more importantly, provides a feasible guide for the design of high-performance cathodic catalyst materials in Li-CO2 batteries.

Constructing molecule-metal relay catalysis over heterophase metallene for high-performance rechargeable zinc-nitrate/ethanol batteries.

Zinc-nitrate batteries can integrate energy supply, ammonia electrosynthesis, and sewage disposal into one electrochemical device. However, current zinc-nitrate batteries still severely suffer from the limited energy density and poor rechargeability. Here, we report the synthesis of tetraphenylporphyrin (tpp)-modified heterophase (amorphous/crystalline) rhodium-copper alloy metallenes (RhCu M-tpp). Using RhCu M-tpp as a bifunctional catalyst for nitrate reduction reaction (NO3RR) and ethanol oxidation reaction in neutral solution, a highly rechargeable and low-overpotential zinc-nitrate/ethanol battery is successfully constructed, which exhibits outstanding energy density of 117364.6 Wh kg-1cat, superior rate capability, excellent cycling stability of ~400 cycles, and potential ammonium acetate production. Ex/in situ experimental studies and theoretical calculations reveal that there is a molecule-metal relay catalysis in NO3RR over RhCu M-tpp that significantly facilitates the ammonia selectivity and reaction kinetics via a low energy barrier pathway. This work provides an effective design strategy of multifunctional metal-based catalysts toward the high-performance zinc-based hybrid energy systems.

Wnt5a-Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions.

Lung branching morphogenesis requires reciprocal interactions between the epithelium and mesenchyme. How the lung branches are generated at a defined location and projected toward a specific direction remains a major unresolved issue. In this study, we investigated the function of Wnt signaling in lung branching in mice. We discovered that Wnt5a in both the epithelium and the mesenchyme plays an essential role in controlling the position and direction of lung branching. The Wnt5a signal is mediated by Vangl1/2 to trigger a cascade of noncanonical or planar cell polarity (PCP) signaling. In response to noncanonical Wnt signaling, lung cells undergo cytoskeletal reorganization and change focal adhesions. Perturbed focal adhesions in lung explants are associated with defective branching. Moreover, we observed changes in the shape and orientation of the epithelial sheet and the underlying mesenchymal layer in regions of defective branching in the mutant lungs. Thus, PCP signaling helps define the position and orientation of the lung branches. We propose that mechanical force induced by noncanonical Wnt signaling mediates a coordinated alteration in the shape and orientation of a group of epithelial and mesenchymal cells. These results provide a new framework for understanding the molecular mechanisms by which a stereotypic branching pattern is generated.

Steering the Orbital Hybridization to Boost the Redox Kinetics for Efficient Li-CO2 Batteries.

The sluggish CO2 reduction and evolution reaction kinetics are thorny problems for developing high-performance Li-CO2 batteries. For the complicated multiphase reactions and multielectron transfer processes in Li-CO2 batteries, exploring efficient cathode catalysts and understanding the interplay between structure and activity are crucial to couple with these pendent challenges. In this work, we applied the CoS as a model catalyst and adjusted its electronic structure by introducing sulfur vacancies to optimize the d-band and p-band centers, which steer the orbital hybridization and boost the redox kinetics between Li and CO2, thus improving the discharge platform of Li-CO2 batteries and altering the deposition behavior of discharge products. As a result, a highly efficient bidirectional catalyst exhibits an ultrasmall overpotential of 0.62 V and a high energy efficiency of 82.8% and circulates stably for nearly 600 h. Meanwhile, density functional theory calculations and multiphysics simulations further elucidate the mechanism of bidirectional activity. This work not only provides a proof of concept to design a remarkably efficient catalyst but also sheds light on promoting the reversible Li-CO2 reaction by tailoring the electronic structure.

Self-Assembly of Ultrathin, Ultrastrong Layered Membranes by Protic Solvent Penetration.

Flexible membranes with ultrathin thickness and excellent mechanical properties have shown great potential for broad uses in solid polymer electrolytes (SPEs), on-skin electronics, etc. However, an ultrathin membrane (<5 µm) is rarely reported in the above applications due to the inherent trade-off between thickness and antifailure ability. We discover a protic solvent penetration strategy to prepare ultrathin, ultrastrong layered films through a continuous interweaving of aramid nanofibers (ANFs) with the assistance of simultaneous protonation and penetration of a protic solvent. The thickness of a pure ANF film can be controlled below 5 µm, with a tensile strength of 556.6 MPa, allowing us to produce the thinnest SPE (3.4 µm). The resultant SPEs enable Li-S batteries to cycle over a thousand times at a high rate of 1C due to the small ionic impedance conferred by the ultrathin characteristic and regulated ionic transportation. Besides, a high loading of the sulfur cathode (4 mg cm-2) with good sulfur utilization was achieved at a mild temperature (35 °C), which is difficult to realize in previously reported solid-state Li-S batteries. Through a simple laminating process at the wet state, the thicker film (tens of micrometers) obtained exhibits mechanical properties comparable to those of thin films and possesses the capability to withstand high-velocity projectile impacts, indicating that our technique features a high degree of thickness controllability. We believe that it can serve as a valuable tool to assemble nanomaterials into ultrathin, ultrastrong membranes for various applications.

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy.

BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

Unfolded Protein-Based Sandwich AIE Probe Imparts High Fluorescent Contrast for Pan-Cancer Surgical Navigation.

Fluorescence imaging-guided navigation for cancer surgery has a promising clinical application. However, pan-cancer encompasses a wide variety of cancer types with significant heterogeneity, resulting in the lack of universal and highly contrasted fluorescent probes for surgical navigation. Here, we developed an aggregation-induced emission (AIE) probe (MI-AIE-TsG, MAT) with dual activation for pan-cancer surgical navigation. MAT weakly activates fluorescence by targeting the SUR1 protein on the endoplasmic reticulum (ER) through the TsG group. Subsequently, the sulfhydryl groups on the unfolded proteins, which are highly enriched in cancer ER, react with the maleimide (MI) of MAT through the thiol-ene click reaction, further enhancing the fluorescence. The formation of a SUR1-MAT-unfolded protein sandwich complex reinforces the restriction of intramolecular motion and eliminates photoinduced electron transfer of MAT, leading to high signal-to-noise (9.2) fluorescence imaging and use for surgical navigation of pan-cancer. The generally high content of unfolded proteins in cancer cells makes MAT imaging generalizable, and it currently has proven feasibility in ovarian, cervical, and breast cancers. Meanwhile, MAT promotes cellular autophagy by hindering protein folding, thereby inhibiting cancer cell proliferation. This generalizable, high-contrast AIE fluorescent probe spans the heterogeneity of pancreatic cancer, enabling precise pancreatic cancer surgery navigation and treatment.

Cell Membrane-Anchored AND Logic Gate Aptasensor for Tumor Cell-Specific Imaging with Improved Accuracy.

Accurate and rapid imaging of tumor cells is of vital importance for early cancer diagnosis and intervention. Aptamer-based fluorescence sensors have become a potent instrument for bioimaging, while false positives and on-target off-tumors linked to single-biomarker aptasensors compromise the specificity and sensitivity of cancer imaging. In this paper, we describe a sequential response aptasensor for precise cancer cell identification that is based on a DNA "AND" logic gate. Specifically, the sensor consists of three single-stranded DNA, including the P-strand that can sensitively respond to an acid environment, the L-strand containing the ATP aptamer sequence, and the R-strand for target cell anchoring. These DNA strands hybridize with one another to create a Y-shaped structure (named Y-ALGN). The aptamer in the R-strand is utilized to anchor the sensor to the target cell membrane primarily. Responding to the extracellular acidic environment of the tumor (input 1), the I-motif sequence forms a tetramer structure so that the P-strand is released from the Y-shaped structure and exposes the ATP binding sites in the L-strand. Extracellular ATP, as input 2, continuously operates the DNA aptasensor to complete the logic computation. Upon the sequential response of both protons and ATP molecules, the aptasensor is activated with restored fluorescence on a particular cancer cell membrane. Benefiting from the precise computation capacity of the "AND" logic gate, the Y-ALGN aptasensor can distinguish between MCF-7 cells and normal cells with high accuracy. As a simple and dual-stimuli-responsive strategy, this nanodevice would offer a fresh approach for accurately diagnosing tumor cells.

Fluoride-Free Synthesis of 2D Titanium Carbide (MXenes) Assisted by scCO2 -Based Ternary Solution.

2D MXene-Ti3 C2 Tx holds great promise in various electronic applications, especially for electromagnetic interference (EMI) shielding devices and supercapacitors. Ti3 C2 Tx synthesis typically involves the use of hazardous fluorine-containing chemicals that can result in the formation of inert fluoride functional groups on the surface of Ti3 C2 Tx , severely degrading its properties and posing a threat to the performance of electron transfer among electrical devices. Herein, a supercritical carbon dioxide-based ternary solution (scCO2 /DMSO/HCl) to produce fluoride-free Ti3 C2 Tx in mild conditions (via 0.5 m HCl, 20 MPa, 32 °C) is reported. The fluorine-free Ti3 C2 Tx films electrode presents an excellent gravimetric capacitance of 320 F g-1 at 2 mV s-1 in 1 m H2 SO4 . Besides, it is demonstrated that fluorine-free Ti3 C2 Tx films exhibit outstanding EMI shielding efficiency of 53.12 dB at 2.5 µm thickness. The findings offer a mild and practical approach to producing fluoride-free Ti3 C2 Tx and open opportunities for exploring MXenes' potential applications in various fields.

Achieving Uniform Li Deposition and Suppressed Electrolyte Flammability in Li-Metal Batteries via Designing Localized High-Concentration Electrolytes.

The increasing need for energy storage devices with high energy density has led to significant interest in Li-metal batteries (LMBs). However, the use of commercial electrolytes in LMBs is problematic due to their flammability, inadequate performance at low temperatures, and tendency to promote the growth of lithium dendrites and other flaws. This study introduces a localized high-concentration electrolyte (LHCE) that addresses these issues by employing non-flammable electrolyte components and incorporating carefully designed additives to enhance flame retardancy and low-temperature performance. By incorporating additives to optimize the electrolyte, it is possible to attain inorganic-dominated solid electrolyte interphases on both the cathode and anode. This achievement results in a uniform deposition of lithium, as well as the suppression of electrolyte decomposition and cathode deterioration. Consequently, this LHCE achieve over 300 stable cycles for both LiNi0.9Mn0.05Co0.05O2||Li cells and LiCoO2||Li cells, as well as 50 cycles for LiNi0.8Mn0.1Co0.1O2 (NCM811||Li) pouch cells. Furthermore, NCM811||Li cells maintain 84% discharge capacity at -20 °C, in comparison to the capacity at room temperature. The utilization of this electrolyte presents novel perspectives for the safe implementation of LMBs.

The microbiome dynamics and interaction of endosymbiotic Symbiodiniaceae and fungi are associated with thermal bleaching susceptibility of coral holobionts.

The thermal bleaching percentage of coral holobionts shows interspecific differences under heat-stress conditions, which are closely related to the coral-associated microbiome. However, the ecological effects of community dynamics and interactions between Symbiodiniaceae and fungi on coral thermal bleaching susceptibility remain unclear. In this study, we analyzed the diversity, community structure, functions, and potential interaction of Symbiodiniaceae and fungi among 18 coral species from a high thermal bleaching risk atoll using next-generation sequencing. The results showed that heat-tolerant C3u sub-clade and Durusdinium dominated the Symbiodiniaceae community of corals and that there were no core amplicon sequence variants in the coral-associated fungal community. Fungal richness and the abundance of confirmed functional animal-plant pathogens were significantly positively correlated with the coral thermal bleaching percentage. Fungal indicators, including Didymellaceae, Chaetomiaceae, Schizophyllum, and Colletotrichum, were identified in corals. Each coral species had a complex Symbiodiniaceae-fungi interaction network (SFIN), which was driven by the dominant Symbiodiniaceae sub-clades. The SFINs of coral holobionts with low thermal bleaching susceptibility exhibited low complexity and high betweenness centrality. These results indicate that the extra heat tolerance of coral in Huangyan Island may be linked to the high abundance of heat-tolerant Symbiodiniaceae. Fungal communities have high interspecific flexibility, and the increase of fungal diversity and pathogen abundance was correlated with higher thermal bleaching susceptibility of corals. Moreover, fungal indicators were associated with the degrees of coral thermal bleaching susceptibility, including both high and intermediate levels. The topological properties of SFINs suggest that heat-tolerant coral have limited fungal parasitism and strong microbial network resilience.IMPORTANCEGlobal warming and enhanced marine heatwaves have led to a rapid decline in coral reef ecosystems worldwide. Several studies have focused on the impact of coral-associated microbiomes on thermal bleaching susceptibility in corals; however, the ecological functions and interactions between Symbiodiniaceae and fungi remain unclear. We investigated the microbiome dynamics and potential interactions of Symbiodiniaceae and fungi among 18 coral species in Huangyan Island. Our study found that the Symbiodiniaceae community of corals was mainly composed of heat-tolerant C3u sub-clade and Durusdinium. The increase in fungal diversity and pathogen abundance has close associations with higher coral thermal bleaching susceptibility. We first constructed an interaction network between Symbiodiniaceae and fungi in corals, which indicated that restricting fungal parasitism and strong interaction network resilience would promote heat acclimatization of corals. Accordingly, this study provides insights into the role of microorganisms and their interaction as drivers of interspecific differences in coral thermal bleaching.

Genetic insights into the association between serum cytokines and frozen shoulder risk: A bidirectional mendelian randomization study.

BACKGROUND: Although existing studies have indicated a connection between chronic low-grade inflammation and the onset of frozen shoulder (FS), the precise causal relationship between distinct circulating inflammatory factors and FS has yet to be thoroughly evaluated. In this study, we employed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between systemic cytokines and FS. METHODS: A genome-wide association dataset comprising 41 serum cytokines from 8,293 individuals of Finnish descent was utilized, along with FS data from the UK Biobank included 10,104 FS cases and 451,099 controls. The primary MR method was the inverse variance weighted approach, and four additional MR techniques (MR-Egger, weighted median, simple mode, and weighted mode) were also employed to support and validate the findings. Heterogeneity and horizontal pleiotropy assessments were assessed using Cochrane's Q and MR-Egger intercept tests. Moreover, a series of sensitivity analyses were conducted to strengthen the accuracy and credibility of these findings. RESULTS: Based on the IVW method, genetically predicted increasing levels of growth regulated oncogene alpha (GROa) (OR=1.08, 95 % CI 1.02-1.13, P=0.005), interferon gamma-induced protein 10 (IP-10) (OR=1.09, 95 % CI 1.02-1.17, P=0.010), regulated on activation, C-C Motif Chemokine Ligand 5 (CCL5) (OR=1.11, 95 % CI 1.03-1.20, P=0.007) were suggestively associated with an increased risk of FS. Reverse MR analysis revealed no significant causal effect of FS on the 41 systemic inflammatory factors. No heterogeneity or horizontal pleiotropy was observed in our analysis. CONCLUSION: This study established a causal association between 41 systemic inflammatory factors and FS, indicating that elevated levels of GROa, IP-10 and CCL5 were associated with a higher risk of FS. Further research is warranted to explore the potential of these biomarkers as early predictors and therapeutic targets for FS.

Surface-engineered erythrocyte membrane-camouflage fluorescent bioprobe for precision ovarian cancer surgery.

PURPOSE: Fluorescence imaging-guided surgery has been used in oncology. However, for tiny tumors, the current imaging probes are still difficult to achieve high-contrast imaging, leading to incomplete resection. In this study, we achieved precise surgical resection of tiny metastatic cancers by constructing an engineering erythrocyte membrane-camouflaged bioprobe (AR-M@HMSN@P). METHODS: AR-M@HMSN@P combined the properties of aggregation-induced emission luminogens (AIEgens) named PF3-PPh3 (P), with functional erythrocyte membrane modified by a modular peptide (AR). Interestingly, AR was composed of an asymmetric tripodal pentapeptide scaffold (GGKGG) with three appended modulars: KPSSPPEE (A6) peptide, RRRR (R4) peptide and cholesterol. To verify the specificity of the probe in vitro, SKOV3 cells with overexpression of CD44 were used as the positive group, and HLF cells with low expression of CD44 were devoted as the control group. The AR-M@HMSN@P fluorescence imaging was utilized to provide surgical guidance for the removal of micro-metastatic lesions. RESULTS: In vivo, the clearance of AR-M@HMSN@P by the immune system was reduced due to the natural properties inherited from erythrocytes. Meanwhile, the A6 peptide on AR-M@HMSN@P was able to specifically target CD44 on ovarian cancer cells, and the electrostatic attraction between the R4 peptide and the cell membrane enhanced the firmness of this targeting. Benefiting from these multiple effects, AR-M@HMSN@P achieved ultra-precise tumor imaging with a signal-to-noise ratio (SNR) of 15.2, making it possible to surgical resection of tumors < 1 mm by imaging guidance. CONCLUSION: We have successfully designed an engineered fluorescent imaging bioprobe (AR-M@HMSN@P), which can target CD44-overexpressing ovarian cancers for precise imaging and guide the resection of minor tumors. Notably, this work holds significant promise for developing biomimetic probes for clinical imaging-guided precision cancer surgery by exploiting their externally specified functional modifications.

Xiashengella succiniciproducens gen. nov., sp. nov., a succinate-producing bacterium isolated from an anaerobic digestion tank in the family Marinilabiliaceae of the order Bacteroidales.

A strictly anaerobic, motile bacterium, designated as strain Ai-910T, was isolated from the sludge of an anaerobic digestion tank in China. Cells were Gram-stain-negative rods. Optimal growth was observed at 38 °C (growth range 25-42 °C), pH 8.5 (growth range 5.5-10.5), and under a NaCl concentration of 0.06% (w/v) (range 0-2.0%). Major cellular fatty acids were iso-C15 : 0 and anteiso-C15 : 0. The respiratory quinone was MK-7. Using xylose as the growth substrate, succinate was produced as the fermentation product. Phylogenetic analysis based on the 16 S rRNA gene sequences indicated that strain Ai-910T formed a distinct phylogenetic lineage that reflects a new genus in the family Marinilabiliaceae, sharing high similarities to Alkaliflexus imshenetskii Z-7010T (92.78%), Alkalitalea saponilacus SC/BZ-SP2T (92.51%), and Geofilum rubicundum JAM-BA0501T (92.36%). Genomic similarity (average nucleotide identity and digital DNA-DNA hybridization) values between strain Ai-910T and its phylogenetic neighbors were below 65.27 and 16.90%, respectively, indicating that strain Ai-910T represented a novel species. The average amino acid identity between strain Ai-910T and other related members of the family Marinilabiliaceae were below 69.41%, supporting that strain Ai-910T was a member of a new genus within the family Marinilabiliaceae. Phylogenetic, genomic, and phenotypic analysis revealed that strain Ai-910T was distinguished from other phylogenetic relatives within the family Marinilabiliaceae. The genome size was 3.10 Mbp, and the DNA G + C content of the isolate was 42.8 mol%. Collectively, differences of the phenotypic and phylogenetic features of strain Ai-910T from its close relatives suggest that strain Ai-910T represented a novel species in a new genus of the family Marinilabiliaceae, for which the name Xiashengella succiniciproducens gen. nov., sp. nov. was proposed. The type strain of Xiashengella succiniciproducens is Ai-910T (= CGMCC 1.17893T = KCTC 25,304T).

Molecular mechanism of bovine Gasdermin D-mediated pyroptosis.

Pyroptosis is a form of programmed cell death characterized by cell swelling, pore formation in the plasma membrane, lysis, and releases of cytoplasmic contents. To date, the molecular mechanism of human and murine Gasdermin D-mediated pyroptosis have been fully investigated. However, studies focusing on molecular mechanism of bovine Gasdermin D (bGSDMD)-mediated pyroptosis and its function against pathogenic infection were unclear. In the present study, we demonstrate that bovine caspase-1 (bCaspase-1) cleaves bGSDMD at amino acid residue D277 to produce an N-terminal fragment (bGSDMD-p30) which leads to pyroptosis. The amino acid residues T238 and F239 are critical for bGSDMD-p30-mediated pyroptosis. The loop aa 278-299, L293 and A380 are the key sites for autoinhibitory structure of the full length of bGSDMD. In addition, bCaspase-3 also cleaves bGSDMD at residue Asp86 without inducing cell death. Therefore, our study provides the first detailed elucidation of the mechanism of bovine GSDMD-mediated pyroptosis. The results will establish a significant foundation for future research on the role of pyroptosis in bovine infectious diseases.

Palliative procedures for advanced obstructive colorectal cancer: a systematic review and meta-analysis.

PURPOSE: Advanced obstructive colorectal cancer (AOCC) presents surgical challenges. Consideration must be given to alleviating symptoms and also quality of life and survival time. This study compared prognostic efficacies of palliative self-expanding metal stents (SEMSs) and surgery to provide insights into AOCC treatment. METHODS: PubMed, Web of Science, MEDLINE, and Cochrane Library were searched for studies that met inclusion criteria. Using a meta-analysis approach, postoperative complications, survival rates, and other prognostic indicators were compared between patients treated with SEMSs and those treated surgically. Network meta-analysis was performed to compare prognoses between SEMS, primary tumor resection (PTR), and stoma/bypass (S/B). RESULTS: Twenty-one studies were selected (1754 patients). The odds ratio (OR) of SEMS for clinical success compared with surgery was 0.32 (95% confidence interval [CI] 0.15, 0.65). The ORs for early and late complications were 0.34 (95% CI 0.19, 0.59) and 2.30 (95% CI 1.22, 4.36), respectively. The ORs for 30-day mortality and stoma formation were 0.65 (95% CI 0.42, 1.01) and 0.11 (95% CI 0.05, 0.22), respectively. Standardized mean difference in hospital stay was - 2.08 (95% CI - 3.56, 0.59). The hazard ratio for overall survival was 1.24 (95% CI 1.08, 1.42). Network meta-analysis revealed that SEMS had the lowest incidence of early complications and rate of stoma formation and the shortest hospital stay. PTR ranked first in clinical success rate and had the lowest late-complication rate. The S/B group exhibited the lowest 30-day mortality rate. CONCLUSION: Among palliative treatments for AOCC, SEMSs had lower early complication, stoma formation, and 30-day mortality rates and shorter hospital stays. Surgery had higher clinical success and overall survival rates and lower incidence of late complications. Patient condition/preferences should be considered when selecting AOCC treatment.

Potential adaptation of scleractinian coral Pocillopora damicornis during hypo-salinity stress caused by extreme pre-flood rainfall over south China.

Global warming intensifies the water cycle, resulting in significant increases in precipitation and river runoff, which brings severe hypo-salinity stress to nearshore coral reefs. Ecological investigations have found that some corals exhibit remarkable adaptability to hypo-salinity stress during mass-bleaching events. However, the exact cause of this phenomenon remains unclear. To elucidate the potential molecular mechanism leading to high tolerance to hypo-salinity stress, Pocillopora damicornis was used as a research object in this study. We compared the differences in transcriptional responses and symbiotic microbiomes between bleaching and unbleaching P. damicornis during hypo-salinity stress caused by extreme pre-flood rainfall over South China in 2022. The results showed that: (1) Under hypo-salinity stress, the coral genes related to immune defense and cellular stress were significantly upregulated in bleaching corals, indicating more severe immune damage and stress, and the Symbiodiniaceae had no significant gene enrichment. Conversely, metabolic genes related to glycolysis/gluconeogenesis were significantly downregulated in unbleaching corals, whereas Symbiodiniaceae genes related to oxidative phosphorylation were significantly upregulated to meet the energy requirements of coral holobiont; (2) C1d was the dominant Symbiodiniaceae subclade in all samples, with no significant difference between the two groups; (3) The symbiotic bacterial community structure was reorganized under hypo-salinity stress. The abundance of opportunistic bacteria increased significantly in bleaching coral, whereas the relative abundance of probiotics was higher in unbleaching coral. This may be due to severe immune damage, making the coral more susceptible to opportunistic infection and bleaching. These results suggest that long-term hypo-salinity acclimation in the Pearl River Estuary enhances the tolerance of some corals to hypo-salinity stress. Corals with higher tolerance may reduce energy consumption by slowing down their metabolism, improve the energy metabolism of Symbiodiniaceae to meet the energy requirements of the coral holobiont, and alter the structure of symbiotic bacterial communities to avoid bleaching.

Prognosis of LSPD versus TIPS for the treatment of esophagogastric variceal bleeding in cirrhosis.

BACKGROUND: This study aimed to compare postoperative complications in patients with esophagogastric variceal bleeding (EVB) who underwent laparoscopic splenectomy combined with pericardial devascularization (LSPD) versus transjugular intrahepatic portosystemic shunt (TIPS) procedures. METHODS: A retrospective collection of medical records was conducted from January 2014 to May 2020 at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The study included patients from the departments of trauma surgery, interventional radiology, and general surgery who were diagnosed with EVB caused by portal hypertension and treated with LSPD or TIPS. Follow-up data were obtained to assess the occurrence of postoperative complications in both groups. RESULTS: A total of 201 patients were included in the study, with 104 cases in the LSPD group and 97 cases in the TIPS group. There was no significant difference in the 1-year and 3-year post-surgery survival rates between the TIPS and LSPD groups (P = 0.669, 0.066). The 3-year survival rate of Child-Pugh B patients in the LSPD group was higher than TIPS group (P = 0.041). The LSPD group also had a significantly higher rate of freedom from rebleeding at 3-year post-surgery compared to the TIPS group (P = 0.038). Stratified analysis showed no statistically significant difference in the rebleeding rate between the two groups. Furthermore, the LSPD group had a higher rate of freedom from overt hepatic encephalopathy at 1-year and 3-year post-surgery compared to the TIPS group (P = 0.007, < 0.001). The LSPD group also had a lower rate of severe complications at 3-year post-surgery compared to the TIPS group (P = 0.020). CONCLUSION: Compared to TIPS, LSPD does not increase the risk of mortality and rebleeding, while demonstrating fewer complications. In patients classified as Child-Pugh A and B, the use of LSPD for treating EVB is both safe and effective.

Development and validation of a liquid chromatography-tandem mass spectrometry method for simultaneous quantification of eight Xiakucao Oral liquid-related compounds in rat plasma and its application in pharmacokinetic study.

Xiakucao Oral Liquid (XKCOL) has been widely used for treating mammary gland hyperplasia and goiter in China. However, its pharmacokinetic data have been missing to date. To conduct its pharmacokinetic study, we established an LC-tandem mass spectrometry method for the simultaneous determination of eight XKCOL-related compounds in rat plasma. Liquid-liquid extraction was used for the sampling process. Chromatographic separation was performed on a Phenomenon Luna C18 column with a mobile phase of methanol and 2 mM ammonium acetate, using gradient elution at a flow rate of 0.8 mL/min. Detection was performed in the multiple reaction monitoring mode using negative electrospray ionization (ESI-) with optimized MS parameters. Endogenous substances and carryover did not interfere in the detection of analytes. The calibration curves showed a good linear relationship within the linear ranges. The intra- and inter-batch accuracy and precision were 94.8%-110.0% and ≤11.2%, respectively. There was no significant matrix effect and the recovery was reproducible. The dilution of samples did not affect the accuracy and precision. The solution and plasma samples were stable under the various test conditions. The major components of XKCOL absorbed into the blood were salvianic acid A and rosmarinic acid. They demonstrated linear kinetics over the dose range used in this study.