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Objective: This study aimed to elucidate the prognostic significance of serum soluble thrombomodulin (sTM), lung ultrasound score (LUS), and lactate levels in patients with extrapulmonary acute respiratory distress syndrome (ARDS), with the goal of refining mortality risk prediction in this cohort.Methods: In a prospective cohort of 95 patients with extrapulmonary ARDS admitted to the intensive care unit, we investigated the primary endpoint of 28-day mortality. Utilizing Lasso-Cox regression analysis, we identified independent prognostic factors for mortality. A predictive nomogram was developed incorporating these factors, and its performance was validated through several statistical measures, including the consistency index, calibration plot, internal validation curve, decision curve analysis, interventions avoided analysis, receiver operating characteristic curve analysis, and Kaplan-Meier survival analysis. We further conducted a subgroup analysis to examine the impact of prone positioning on patient outcomes.Results: The study identified baseline serum sTM, LUS, and lactate levels as independent predictors of 28-day mortality in extrapulmonary ARDS patients. The predictive nomogram demonstrated superior prognostic accuracy compared to the use of sTM, LUS, or lactate levels alone, and outperformed traditional prognostic tools such as the Acute Physiology and Chronic Health Evaluation II score and the partial pressure of arterial oxygen to fractional inspired oxygen ratio. The subgroup analysis did not show a significant impact of prone positioning on the predictive value of the identified biomarkers.Conclusion: Our study results support the development and validation of a novel prognostic nomogram that integrates key clinical biomarkers and ultrasound imaging scores to predict mortality in patients with extrapulmonary ARDS. While our research is preliminary, further studies and validation are required.

Background Lysyl oxidase enzymes (LOXs), as extracellular matrix (ECM) protein regulators, play vital roles in tumor progression by remodeling the tumor microenvironment. However, their roles in glioblastoma (GBM) have not been fully elucidated. Methods The genetic alterations and prognostic value of LOXs were investigated via cBioPortal. The correlations between LOXs and biological functions/molecular tumor subtypes were explored in The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). After Kaplan‒Meier and Cox survival analyses, a Loxl1-based nomogram and prognostic risk score model (PRSM) were constructed and evaluated by time-dependent receiver operating characteristic curves, calibration curves, and decision curve analyses. Tumor enrichment pathways and immune infiltrates were explored by single-cell RNA sequencing and TIMER. Loxl1-related changes in tumor viability/proliferation and invasion were further validated by CCK-8, western blot, wound healing, and Transwell invasion assays. Results GBM patients with altered LOXs had poor survival. Upregulated LOXs were found in IDH1-wildtype and mesenchymal (not Loxl1) GBM subtypes, promoting ECM receptor interactions in GBM. The Loxl1-based nomogram and the PRSM showed high accuracy, reliability, and net clinical benefits. Loxl1 expression was related to tumor invasion and immune infiltration (B cells, neutrophils, and dendritic cells). Loxl1 knockdown suppressed GBM cell proliferation and invasion by inhibiting the EMT pathway (through the downregulation of N-cadherin/Vimentin/Snai1 and the upregulation of E-cadherin). Conclusion The Loxl1-based nomogram and PRSM were stable and individualized for assessing GBM patient prognosis, and the invasive role of Loxl1 could provide a promising therapeutic strategy.

Hepatitis B virus (HBV) chronically infects 296 million people worldwide, posing a major global health threat. Export of HBV RNAs from the nucleus to the cytoplasm is indispensable for viral protein translation and genome replication, however the mechanisms regulating this critical process remain largely elusive. Here, we identify a key host factor embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) that binds HBV RNAs and controls their nuclear export. Using an unbiased quantitative proteomics screen, we demonstrate direct binding of ELAVL1 to the HBV pregenomic RNA (pgRNA). ELAVL1 knockdown inhibits HBV RNAs posttranscriptional regulation and suppresses viral replication. Further mechanistic studies reveal ELAVL1 recruits the nuclear export receptor CRM1 through ANP32A and ANP32B to transport HBV RNAs to the cytoplasm via specific AU-rich elements, which can be targeted by a compound CMLD-2. Moreover, ELAVL1 protects HBV RNAs from DIS3+RRP6+ RNA exosome mediated nuclear RNA degradation. Notably, we find HBV core protein is dispensable for HBV RNA-CRM1 interaction and nuclear export. Our results unveil ELAVL1 as a crucial host factor that regulates HBV RNAs stability and trafficking. By orchestrating viral RNA nuclear export, ELAVL1 is indispensable for the HBV life cycle. Our study highlights a virus-host interaction that may be exploited as a new therapeutic target against chronic hepatitis B.

ObjectiveTo provide both empirical support and a theoretical framework for systematically improving and optimizing the cognitive capabilities of college students through physical activity, while considering the mediating and regulating impacts of self-efficacy and negative emotion.MethodsThe study employed an overall random sampling method, examining 500 college students from five universities in Jiangsu Province using the Physical Activity Rating Scale (PARS-3), Adult Executive Function Scale (ADEXI), Positive and Negative Emotion Scale (PANAS), and General Self-Efficacy Scale (GSES).ResultsThe findings indicated that the average age of the participants was 18.41 ± 0.73 years, encompassing 215 male students (43%), and 185 female students (57%). Engagement in physical activity was significantly and positively correlated with executive function (β = 0.246, p

The Swift effect of Mg alloy is sensitive to initial texture. However, dislocation slip is the main deformation mechanism during torsion of Mg alloy. The underlying relation of Swift effect and dislocation slip is still not clarified. The effect of stress state and pre-straining on Swift effect was studied experimentally during free-end torsion for an extruded AZ31 alloy. The free-end torsion was performed with axial tension and compression stress which is lower than yield stress. It is found that the transition of axial deformation from contraction to elongation occurs when the axial stress changes from negative to positive. The pre-dislocations introduced by pre-tension promote axial shortening during torsion. While the pre-twins introduced by pre-compression are inhibition of axial shortening. The change of axial deformation is attributed to competition between twinning and prismatic slip. The axial shortening of extruded Mg alloy is generated by tensile twinning leading to c-axis strain. In contrast, the axial elongation can be generated by the activation of prismatic slip. The magnitude of axial strain generated by twinning is larger than that by prismatic slip. Moreover, the occurrence of detwinning results in axial elongation at low shear strain.

The application of Ti(C,N)-based cermets remains limited due to their low toughness. The fracture toughness of cermets can be significantly improved by using advanced sintering methods and appropriate additives. Here, cermets were prepared by spark plasma sintering (SPS) technology with graphene nanosheets (GNSs) and nano-scale tungsten carbide (WC) as additives. The effects of GNSs and sintering conditions on the microstructure, mechanical properties, and magnetic properties of Ti(C,N)-based cermets were studied. The results show that the sample with 0.6 wt% GNSs fabricated at 1450 °C, 8 min, and 35 MPa has a denser microstructure and better mechanical properties. The cermet has a Vickers hardness of HV 2415.40 and fracture toughness of 10.6 MPa·m1/2. Compared with the specimen without GNSs, the hardness and fracture toughness are significantly improved by 44.58% and 92.73%, respectively. A certain amount of GNSs can increase the movement of hard phases in the liquid phase, inhibiting their solubility and grain growth, and greatly improving the fracture toughness of cermets. The addition of nano-WC is conducive to promoting the formation of a (Ti,W) (C,N) rim phase and improving properties of cermets. SPS can activate particle surfaces and promote the densification of cermets.

The torsional deformation with shear stress is crucial for improving mechanical performance of wrought Mg alloys. Consequently, the difference of mechanical behavior between fixed-end and free-end torsion was investigated. It is found that strain hardening behavior is affected by end constraint. The decreased hardening rate is exhibited which is dominated by prismatic slip during fixed-end torsion. For free-end loading, two stages of strain hardening are presented during torsion, i.e., constant hardening rate and slowly decreased hardening rate. The basal slip dominates the onset of plastic deformation. The prismatic slip becomes dominated mechanism at large shear strain. However, the axial effect is sensitive to forward and reversal torsion. The difference of axial stress between forward and reversal torsion under fixed-end is attributed to twin growth. The difference of axial strain is small during forward and reversal torsion under free-end, which is attributed to the activation of tensile twinning.

Hepatitis B virus (HBV) chronically infects 296 million individuals and there is no cure. As an important step of viral life cycle, the mechanisms of HBV egress remain poorly elucidated. With proteomic approach to identify capsid protein (HBc) associated host factors and siRNA screen, we uncovered tumor susceptibility gene 101 (TSG101). Knockdown of TSG101 in HBV-producing cells, HBV-infected cells and HBV transgenic mice suppressed HBV release. Co-immunoprecipitation and site mutagenesis revealed that VFND motif in TSG101 and Lys-96 ubiquitination in HBc were essential for TSG101-HBc interaction. In vitro ubiquitination experiment demonstrated that UbcH6 and NEDD4 were potential E2 ubiquitin-conjugating enzyme and E3 ligase that catalyzed HBc ubiquitination, respectively. PPAY motif in HBc and Cys-867 in NEDD4 were required for HBc ubiquitination, TSG101-HBc interaction and HBV egress. Transmission electron microscopy confirmed that TSG101 or NEDD4 knockdown reduces HBV particles count in multivesicular bodies (MVBs). Our work indicates that TSG101 recognition for NEDD4 ubiquitylated HBc is critical for MVBs mediated HBV egress.

Background: With the gradual increase in prevalence in recent years, non-alcoholic steatohepatitis (NASH) has become one of the significant health problems that urgently needs to be addressed worldwide. GanShuang Granules (GSG) is derived from the classical Chinese formula Xiaoyao San and mainly used in the clinical treatment of chronic liver diseases.Objective: In this study, we aim to gain a deeper insight into the inhibiting effects of GSG on non-alcoholic fatty liver disease (NAFLD) rats and preliminarily elucidate the underlying intervention mechanisms.Methods: First, High performance liquid chromatography (UHPLC-Q/Orbitrap-MS/MS) was used for the active compounds prediction in GSG. Then the data was mapped to mzCloud database. The targets corresponding to GSG compounds were collected from public databases, along with disease genes for NAFLD. The core targets and molecular mechanisms of GSG for NAFLD treatment were predicted by protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Molecular docking of the core target-component interactions was simulated using AutoDock Vina software. The effect of GSG on NASH rats was evaluated by pathological staining and analysis of various index results. Finally, the candidate targets were further validated by ELISA and western blot (WB) analyses.Results: Combining UHPLC-Q/Orbitrap-MS/MS data analysis and public database data, a total of 346 cross-targets were obtained, corresponding to 81 compounds. The subnetwork with an MCODE score of 53.623 is a potential core target group for this study. GO and KEGG enrichment analyses showed that the targets of GSG in NAFLD were mostly related to oxidative stress, the NF-κB signaling pathway, and the apoptosis signaling pathway. By integrating the results of network pharmacology analysis, the core objectives of this study mainly include AKT1, CASP9, TNF, and CASP8. The core ingredients are related to resveratrol and fisetin. The molecular docking results indicated key binding activity between AKT1-fisetin, AKT1-Resveratrol, and CASP8-fisetin. Moreover, GSG could improve the inflammatory status and restore the abnormal lipid accumulation of NAFLD/NASH liver, and these levels are further verified by pathological staining and detection of related indicators. Mechanistically, GSG could regulate protein expression levels in the liver for P65, p-P65, IKB, p-IKB, IKK, caspase-3, -8, -9, and cytochrome C, etc. It reflects the inhibitory effect of GSG on the NF-κB/IκB signaling pathway.Conclusion: Our results suggested that GSG demonstrated therapeutic effects on NAFLD/NASH rats, and these may be mainly reflected in the inhibitory effects on the NF-κB/IκB signaling pathway and its downstream inflammation and apoptosis signals.

RNA-binding proteins (RBPs), being pivotal elements in both physiological and pathological processes, possess the ability to directly impact RNA, thereby exerting a profound influence on cellular life. Furthermore, the dysregulation of RBPs not only induces alterations in the expression levels of genes associated with cancer but also impairs the occurrence of post-transcriptional regulatory mechanisms. Consequently, these circumstances can give rise to aberrations in cellular processes, ultimately resulting in alterations within the proteome. An aberrant proteome can disrupt the equilibrium between oncogenes and tumor suppressor genes, promoting cancer progression. Given their significant role in modulating gene expression and post-transcriptional regulation, directing therapeutic interventions towards RBPs represents a viable strategy for combating drug resistance in cancer treatment. RBPs possess significant potential as diagnostic and prognostic markers for diverse cancer types. Gaining comprehensive insights into the structure and functionality of RBPs, along with delving deeper into the molecular mechanisms underlying RBPs in tumor drug resistance, can enhance cancer treatment strategies and augment the prognostic outcomes for individuals afflicted with cancer.

Abstract A series of hyperbranched polymer surfactants (HBP-C8, HBP-C12 and HBP-C16) were synthesized by the reaction between hydroxyl-terminated hyperbranched polymers (HBP) and fatty acyl chloride. The structure of obtained hyperbranched polymer surfactant was characterized by FTIR, NMR and GPC. The results showed that the products have amphiphilic structure. The thermal property of the hyperbranched polymer surfactant investigated by DSC and TGA was strongly influenced by the length of end alkyl chain. Surface activity of hyperbranched polymer surfactant was analyzed by surface tension method and UV spectrophotometry, respectively. The results showed that hyperbranched polymer surfactant took on better surface activity, which can effectively reduce the surface tension of the water. The hyperbranched polymer surfactant has a lower critical micelle concentration (CMC) and displays single molecular micellar properties, which can package small hydrophilic molecules in relatively low concentration. Graphical abstract

Previous studies have shown that males with substance use disorder (SUD) in their first mandatory detoxification experience high rates of depression. It is unknown whether this high depression incidence contributes to impaired inhibition. In this work, two studies were undertaken to examine the role of depression in cognitive inhibition in heroin and methamphetamine withdrawal. We used the Beck Depression Inventory (BDI) and the self-control scale (SCS) to explore the relationship between depression and impulse inhibition in patients participating in mandatory drug treatment for the first time (Study 1). The results showed that depression negatively predicted impulse inhibition. The Stroop color–word interference task was used to explore the role of patients’ depression in their inhibitory abilities (Study 2). The results showed that the high-depression group had weaker inhibition performances in the Stroop color–word interference task compared to the low-depression group. This study shows that cognitive inhibition is weaker in people with high-depression addiction than in those with low depression. This result suggests that attention should be paid to the role of depressive comorbidity when conducting working memory training treatment for substance addiction.

Coronavirus disease 2019 (COVID-19) tremendously impacts the physical and mental health of humans worldwide. Consequently, studies on COVID-19 remain extensive. However, most of them were mainly focused on the pathological mechanisms and treatment methods from medical perspectives. Various reports have indicated that COVID-19 is closely related to stigma and discrimination, but little statistical information has been integrated quantitatively to describe the situation in China. Thus, this study investigated the COVID-19-related stigma of individuals. We collected the online survey data from 1,920 Chinese participants from October to December 2020. Findings showed that 306 (15.94%), 285 (14.84%), 265 (13.80%), and 100 (5.21%) participants endorsed stigma toward individuals in high-risk areas, recovered patients with COVID-19, families of recovered patients with COVID-19, and frontline healthcare providers, respectively. To understand the possible factors that could impact the COVID-19-related stigma, knowledge about COVID-19 was investigated. Generally, knowledge about COVID-19 was negatively associated with COVID-19-related stigma in general, while no significant relationship existed between the knowledge about COVID-19 and the COVID-19-related stigma in the groups who had held COVID-19-related stigma. Ultimately, individuals showed COVID-19-related stigma toward recovered patients and their families, individuals in high-risk areas, and frontline healthcare providers to some extent. The results of this study can provide reference to nations, governments, and organizations in addressing the stigma issues raised by the COVID-19 pandemic.

Autophagic cargoes ensure selective autophagy for the recognition and removal of various cytosolic aggregated proteins, damaged organelles, or pathogens. Stress granules (SGs), as antiviral immune complexes, serve a positive role in the type I interferon (IFN) response and can be targeted by autophagy (termed granulophagy). However, the cargo of granulophagy remains elusive, and it is still unknown whether granulophagy plays a role in viral infection. Here, we found that histone deacetylase 6 (HDAC6), a component of viral RNA-induced SGs, is a novel granulophagic cargo that is recognized by p62/Sequestosome 1 (SQSTM1) and mediates the degradation of SGs in coxsackievirus A16 (CA16)-infected cells. CA16 viral RNA activated the protein kinase RNA-activated (PKR)/eukaryotic translation initiation factor 2-alpha (eIF2α) pathway to promote SG assembly. The SGs were degraded by CA16-triggered autophagy via the interaction between the ubiquitin-associated (UBA) domain of p62 and the ubiquitin-binding domain (UBD) of HDAC6, which was bridged by a poly-ubiquitin chain. We also found that granulophagy repressed the type I interferon response and facilitated viral replication. These results suggest that HDAC6 might be the first identified granulophagic cargo and granulophagy could be a strategy that viruses apply to repress the antiviral immune response.

The variation of strain paths induces anisotropy during practical sheet forming processes, which is very important for the subsequent processing technology of anisotropic Mg alloys. In this study, two-step loading tests (tension-tension) were performed to clarify the effect of strain path changes on the evolution of anisotropy on rolled AZ31 sheet. Specimens were preloaded with tension along the rolling direction (RD) with 9% of prestrain. Then, second tension was conducted along 0°, 30°, 45°, 60° and 90° from the RD. It was found that yield strength during the second loading increased along the same direction compared to uniaxial tension without prestraining. For the second loading, the yield strength and flow stress decreased with the increase of the angle from the RD. It was found that the strain path change resulted in stronger anisotropy than that induced by texture. Moreover, it was found that the main deformation modes were basal and prismatic slips during the second loading based on visco-plastic self-consistent (VPSC) modeling. The relative activities of basal and prismatic slips were affected by the second loading direction due to texture evolution. The mechanical anisotropy induced by strain path changes was ascribed to the coupling of the heterogeneous distribution of dislocations and texture evolution induced by prestraining.

Autophagy is an important homeostatic process for the degradation of cytosolic proteins and organelles and has been reported to play an important role in cellular responses to pathogens and virus replication. However, the role of autophagy in Coxsackievirus A16 (CA16) infection and pathogenesis remains unknown. Here, we demonstrated that CA16 infection enhanced autophagosome formation, resulting in increased extracellular virus production. Moreover, expression of CA16 nonstructural proteins 2C and 3C was sufficient to trigger autophagosome accumulation by blocking the fusion of autophagosomes with lysosomes. Interestingly, we found that Immunity-related GTPase family M (IRGM) was crucial for the activation of CA16 infection-induced autophagy; in turn, reducing IRGM expression suppressed autophagy. Expression of viral protein 2C enhanced IRGM promoter activation, thereby increasing IRGM expression and inducing autophagy. CA16 infection inhibited Akt/mTOR signaling and activated extracellular signal-regulated kinase (ERK) signaling, both of which are necessary for autophagy induction. In summary, CA16 can use autophagy to enhance its own replication. These results raise the possibility of targeting the autophagic pathway for the treatment of hand, foot, and mouth disease (HFMD).

Objective: To investigate the potential pharmacological mechanisms of Ganshuang granules (, GSG) in treating non-alcoholic fatty liver (NAFLD)., Methods: All the active components and targets of GSG were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Protein-Protein interaction network, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology function annotation of common targets were analyzed to predict the mechanisms of action of GSG in the treatment of NAFLD. Then, the mouse models of NAFLD were constructed in a diet-induced manner and treated with GSG. The levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway-related proteins in the liver of mice in each group were measured by enzyme linked immunosorbent assay and Western blot, respectively., Results: Network pharmacology revealed a total of 159 potential targets of GSG for the treatment of NAFLD. Functional enrichment analysis indicated that the PI3K/AKT signaling pathway may be involved during GSG treatment of NAFLD. Further experiments showed that the significantly decreased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total cholesterol, triglyceride and low-density lipoprotein cholesterol levels in NAFLD model mice serum after GSG treatment, as well as the expression levels of IL-6 and TNF-α in the liver. Furthermore, drug intervention increased the protein expression levels of phosphorylated-PI3K (P-PI3K) and P-AKT in the liver of the model group mice, and decreased the protein expression level of sterol regulatory element-binding protein 1., Conclusion: We found that GSG is effective in treating NAFLD and the potential therapeutic targets may be involved in PI3K/AKT signaling pathway.