Role of macrophages and their exosomes in orthopedic diseases.

Exosomes are vesicles with a lipid bilayer structure that carry various active substances, such as proteins, DNA, non-coding RNA, and nucleic acids; these participate in the immune response, tissue formation, and cell communication. Owing to their low immunogenicity, exosomes play a key role in regulating the skeletal immune environment. Macrophages are important immune cells that swallow various cellular and tissue fragments. M1-like and M2-like macrophages differentiate to play pro-inflammatory, anti-inflammatory, and repair roles following stimulation. In recent years, the increase in the population base and the aging of the population have led to a gradual rise in orthopedic diseases, placing a heavy burden on the social medical system and making it urgent to find effective solutions. Macrophages and their exosomes have been demonstrated to be closely associated with the pathogenesis and prognosis of orthopedic diseases. An in-depth understanding of their mechanisms of action and the interaction between them will be helpful for the future clinical treatment of orthopedic diseases. This review focuses on the mechanisms of action, diagnosis, and treatment of orthopedic diseases involving macrophages and their exosomes, including fracture healing, diabetic bone damage, osteosarcoma, and rheumatoid arthritis. In addition, we discuss the prospects and major challenges faced by macrophages and their exosomes in clinical practice.

Acute non-traffic traumatic spinal cord injury in the aging population: Analysis of the National Inpatient Sample 2005-2018.

BACKGROUND: This study aimed to determine risk factors for poor in-hospital outcomes in a large cohort of older adult patients with acute non-traffic traumatic spinal cord injury (tSCI). METHODS: This is a population-based, retrospective, observational study. Data of older adults ≥65 years with a primary discharge diagnosis of acute non-traffic tSCI were extracted from the US National Inpatient Sample (NIS) database 2005-2018. Traffic-related tSCI admissions or patients lacking complete data on age, sex and outcomes of interest were excluded. Univariate and multivariate logistic regression analysis was used to determine associations between variables and in-hospital outcomes. RESULTS: Data of 49,449 older patients (representing 246,939 persons in the US) were analyzed. The mean age was 79.9 years. Multivariable analyses revealed that severe International Classification of Disease (ICD)-based injury severity score (ICISS) (adjusted odds ratio [aOR] = 3.14, 95% confidence interval [CI]: 2.77-3.57), quadriplegia (aOR = 2.79, 95%CI: 2.34-3.32), paraplegia (aOR = 2.60, 95%CI:1.89-3.58), cervical injury with vertebral fracture (aOR = 2.19, 95%CI: 1.90-2.52), and severe liver disease (aOR = 2.33, 95%CI: 1.34-4.04) were all strong independent predictors of in-hospital mortality. In addition, malnutrition (aOR = 3.19, 95% CI: 2.93-3.48) was the strongest predictors of prolonged length of stay (LOS). CONCLUSIONS: Several critical factors for in-hospital mortality, unfavorable discharge, and prolonged LOS among US older adults with acute non-traffic tSCI were identified. In addition to the factors associated with initial severity, the presence of severe liver disease and malnutrition emerged as strong predictors of unfavorable outcomes, highlighting the need for special attention for these patient subgroups.

Inhibition of phospholipase D promotes neurological function recovery and reduces neuroinflammation after spinal cord injury in mice.

Introduction: Spinal cord injury (SCI) is a severely disabling disease. Hyperactivation of neuroinflammation is one of the main pathophysiological features of secondary SCI, with phospholipid metabolism playing an important role in regulating inflammation. Phospholipase D (PLD), a critical lipid-signaling molecule, is known to be involved in various physiological processes, including the regulation of inflammation. Despite this knowledge, the specific role of PLD in SCI remains unclear. Methods: In this study, we constructed mouse models of SCI and administered PLD inhibitor (FIPI) treatment to investigate the efficacy of PLD. Additionally, transcriptome sequencing and protein microarray analysis of spinal cord tissues were conducted to further elucidate its mechanism of action. Results: The results showed that PLD expression increased after SCI, and inhibition of PLD significantly improved the locomotor ability, reduced glial scarring, and decreased the damage of spinal cord tissues in mice with SCI. Transcriptome sequencing analysis showed that inhibition of PLD altered gene expression in inflammation regulation. Subsequently, the protein microarray analysis of spinal cord tissues revealed variations in numerous inflammatory factors. Biosignature analysis pointed to an association with immunity, thus confirming the results obtained from transcriptome sequencing. Discussion: Collectively, these observations furnish compelling evidence supporting the anti-inflammatory effect of FIPI in the context of SCI, while also offering important insights into the PLD function which may be a potential therapeutic target for SCI.

Atorvastatin causes developmental and behavioral toxicity in yellowstripe goby (Mugilogobius chulae) embryos/larvae via disrupting lipid metabolism and autophagy processes.

Atorvastatin (ATV) is one of the most commonly prescribed lipid-lowering drugs detected frequently in the environment due to its high use and low degradation rate. However, the toxic effects of residual ATV in the aquatic environment on non-target organisms and its toxic mechanisms are still largely unknown. In the present study, embryos of a native estuarine benthic fish, Mugilogobius chulae, were employed to investigate the developmental and behavioral toxic effects of ATV including environmentally relevant concentrations. The aim of this study was to provide a scientific basis for ecological risk assessment of ATV in the aquatic environment by investigating the changes of biological endpoints at multiple levels in M. chulae embryos/larvae. The results showed that ATV had significantly lethal and teratogenic effects on M. chulae embryos/larvae and caused abnormal changes in developmental parameters including hatch rate, body length, heart rate, and spontaneous movement. ATV exposure caused oxidative stress in M. chulae embryos/larvae subsequently inhibited autophagy and activated apoptosis, leading to abnormal developmental processes and behavioral changes in M. chulae embryos/larvae. The disruptions of lipid metabolism, autophagy, and apoptosis in M. chulae embryos/larvae caused by ATV exposure may pose a potential ecological risk at the population level.

Unveiling the impact of CDK8 on tumor progression: mechanisms and therapeutic strategies.

CDK8 is an important member of the cyclin-dependent kinase family associated with transcription and acts as a key "molecular switch" in the Mediator complex. CDK8 regulates gene expression by phosphorylating transcription factors and can control the transcription process through Mediator complex. Previous studies confirmed that CDK8 is an important oncogenic factor, making it a potential tumor biomarker and a promising target for tumor therapy. However, CDK8 has also been confirmed to be a tumor suppressor, indicating that it not only promotes the development of tumors but may also be involved in tumor suppression. Therefore, the dual role of CDK8 in the process of tumor development is worth further exploration and summary. This comprehensive review delves into the intricate involvement of CDK8 in transcription-related processes, as well as its role in signaling pathways related to tumorigenesis, with a focus on its critical part in driving cancer progression.

Joint Association of Lipoprotein(a) and a Family History of Coronary Artery Disease with the Cardiovascular Outcomes in Patients with Chronic Coronary Syndrome.

AIM: No data are currently available regarding the association between Lp(a) and the cardiovascular outcomes in patients with coronary artery disease (CAD) according to their family history (FHx) of CAD. This study aimed to evaluate the significance of Lp(a) in predicting major adverse cardiovascular events (MACEs) in patients with chronic coronary syndrome (CCS) with or without FHx. METHODS: A total of 6056 patients with CCS were enrolled. Information on FHx was collected, and the plasma Lp(a) levels were measured. All patients were followed up regularly. The independent and joint associations of Lp(a) and FHx with the risk of MACEs, including cardiovascular death, nonfatal myocardial infarction, and stroke, were analyzed. RESULTS: With over an average of 50.35±18.58 months follow-up, 378 MACEs were recorded. A Cox regression analysis showed an elevated Lp(a) level to be an independent predictor for MACEs in patients with [hazard ratio (HR): 2.77, 95% confidence interval (CI): 1.38-5.54] or without FHx (HR: 1.35, 95% CI: 1.02-1.77). In comparison to subjects with non-elevated Lp(a) and negative FHx, patients with elevated Lp(a) alone were at a nominally higher risk of MACEs (HR: 1.26, 95% CI: 0.96-1.67), while those with both had the highest risk (HR: 1.93, 95% CI: 1.14-3.28). Moreover, adding Lp(a) to the original model increased the C-statistic by 0.048 in subjects with FHx (p=0.004) and by 0.004 in those without FHx (p=0.391). CONCLUSIONS: The present study is the first to suggest that Lp(a) could be used to predict MACEs in CCS patients with or without FHx; however, its prognostic significance was more noteworthy in patients with FHx.

Regioselective synthesis of isoquinolinonediones through remote unactivated C(sp3)-H bonds.

Herein, a general strategy for the remote-site-selective cascade addition/cyclization of unactivated C(sp3)-H bonds in free alcohols and sulfonamides to build isoquinolinonedione skeletons is developed. The site selectivity occurs predominantly via a 1,5-hydrogen atom transfer (HAT) process, triggered by heteroatom-centred radicals generated directly under silver catalysis. A broad substrate scope and excellent regio-/chemo-selective control are demonstrated in this method.

Zinc finger protein 36 like 2-histone deacetylase 1 axis is involved in the bone responses to mechanical stress.

The molecular mechanism underlying the promotion of fracture healing by mechanical stimuli remains unclear. The present study aimed to investigate the role of zinc finger protein 36 like 2 (ZFP36L2)-histone deacetylase 1 (HDAC1) axis on the osteogenic responses to moderate mechanical stimulation. Appropriate stimulation of fluid shear stress (FSS) was performed on MC3T3-E1 cells transduced with ZFP36L2 and HDAC1 recombinant adenoviruses, aiming to validate the influence of mechanical stress on the expression of ZFP36L2-HDAC1 and the osteogenic differentiation and mineralization. The results showed that moderate FSS stimulation significantly upregulated the expression of ZFP36L2 in MC3T3-E1 cells (p < 0.01). The overexpression of ZFP36L1 markedly enhanced the levels of osteogenic differentiation markers, including bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), Osterix, and collagen type I alpha 1 (COL1A1) (p < 0.01). ZFP36L2 accelerated the degradation of HDAC1 by specifically binding to its 3' UTR region, thereby fulfilling its function at the post-transcriptional regulatory gene level and promoting the osteogenic differentiation and mineralization fate of cells. Mechanical unloading notably diminished/elevated the expression of ZFP36L2/HDAC1, decreased bone mineral density and bone volume fraction, hindered the release of osteogenic-related factors and vascular endothelial growth factor in callus tissue (p < 0.01), and was detrimental to fracture healing. Collectively, proper stress stimulation plays a crucial role in facilitating osteogenesis through the promotion of ZFP36L2 and subsequent degradation of HDAC1. Targeting ZFP36L2-HDAC1 axis may provide promising insights to enhance bone defect healing.

Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

Characterization and application of active human α2,6-sialyltransferases ST6GalNAc V and ST6GalNAc VI recombined in Escherichia coli.

Eukaryotic sialyltransferases play key roles in many physiological and pathological events. The expression of active human recombinant sialyltransferases in bacteria is still challenging. In the current study, the genes encoding human N-acetylgalactosaminide α2,6-sialyltransferase V (hST6GalNAc V) and N-acetylgalactosaminide α2,6-sialyltransferase VI (hST6GalNAc VI) lacking the N-terminal transmembrane domains were cloned into the expression vectors, pET-32a and pET-22b, respectively. Soluble and active forms of recombinant hST6GalNAc V and hST6GalNAc VI when coexpressed with the chaperone plasmid pGro7 were successfully achieved in Escherichia coli. Further, lactose (Lac), Lacto-N-triose II (LNT II), lacto-N-tetraose (LNT), and sialyllacto-N-tetraose a (LSTa) were used as acceptor substrates to investigate their activities and substrate specificities. Unexpectedly, both can transfer sialic acid onto all those substrates. Compared with hST6GalNAc V expressed in the mammalian cells, the recombinant two α2,6-sialyltransferases in bacteria displayed flexible substrate specificities and lower enzymatic efficiency. In addition, an important human milk oligosaccharide disialyllacto-N-tetraose (DSLNT) can be synthesized by both human α2,6-sialyltransferases expressed in E. coli using LSTa as an acceptor substrate. To the best of our knowledge, these two active human α2,6-sialyltransferases enzymes were expressed in bacteria for the first time. They showed a high potential to be applied in biotechnology and investigating the molecular mechanisms of biological and pathological interactions related to sialylated glycoconjugates.

Multi-omics pan-cancer analyses identify MCM4 as a promising prognostic and diagnostic biomarker.

Minichromosome Maintenance Complex Component 4 (MCM4) is a vital component of the mini-chromosome maintenance complex family, crucial for initiating the replication of eukaryotic genomes. Recently, there has been a growing interest in investigating the significance of MCM4 in different types of cancer. Despite the existing research on this topic, a comprehensive analysis of MCM4 across various cancer types has been lacking. This study aims to bridge this knowledge gap by presenting a thorough pan-cancer analysis of MCM4, shedding light on its functional implications and potential clinical applications. The study utilized multi-omics samples from various databases. Bioinformatic tools were employed to explore the expression profiles, genetic alterations, phosphorylation states, immune cell infiltration patterns, immune subtypes, functional enrichment, disease prognosis, as well as the diagnostic potential of MCM4 and its responsiveness to drugs in a range of cancers. Our research demonstrates that MCM4 is closely associated with the oncogenesis, prognosis and diagnosis of various tumors and proposes that MCM4 may function as a potential biomarker in pan-cancer, providing a deeper understanding of its potential role in cancer development and treatment.

Comparison of acidity and chemical composition of summertime cloud water and aerosol at an alpine site in Northwest China: Implications for the neutral property of clouds in the free troposphere.

Aerosol and cloud acidity are essential to human health, ecosystem health and productivity, as well as climate effects. The main chemical composition of cloud water greatly varies in different regions, resulting in substantial differences in the pH of cloud water. However, the influences of the anthropogenic emissions of acidic gases and substances, alkaline dust components, and dicarboxylic acids (diacids) on the ground concerning the acidity of cloud water in the free troposphere of the Guanzhong Plain, China, remain clear. In this study, cloud water and PM2.5 samples were simultaneously collected in the troposphere (Mt. Hua, 2060 m a.s.l). The results indicated that the cloud water was alkaline (pH = 7.6) and PM2.5 was acidic (pH = 3.2). These results showed the neutral property of clouds collected in the heavily polluted Guanzhong Plain, although most previous studies always considered acidity as a marker of pollution. The sulfate (SO42-), nitrate (NO3-), and ammonium (NH4+) (SNA) of particulate matter and cloud water in the same period were compared. SO42- was dominant in particulate matters (accounting for 63.4 % of the total SNA) but substantially decreased in cloud water (only 30.1 % of the total SNA), whereas NO3- and NH4+ increased from 28.5 % and 8.2 % to 39.8 % and 30.2 %, respectively. This could be attributed to the complex formation mechanism and sources of SO42- and NO3- in the cloud. The results of ion balance indicated that a significant deficit of inorganic anion equivalents was observed in the cloud water samples. The high concentration of diacids in the cloud phase (1237.4 µg L-1) may facilitate the formation of salt complexes with NH4+, thus influencing the acidity of the cloud water. The pH of cloud water has increased in recent decades due to the sustained reduction of sulfur dioxide, which may also affect the acidity of future precipitation.

Quantifying the Size-Dependent Shear Banding Behavior in High-Entropy Alloy-Based Nanolayered Glass.

Extensive research has shown that nanolayered structures are capable of suppressing the shear banding in metallic glass in nanoindentation experiments. However, the specific mode and mechanism of the shear banding underneath the indenter remains unknown. Also, the quantification of shear banding-induced strain localization is still a challenge. Herein, the size-dependent shear banding behavior of a CuTiZrNb high-entropy alloy-based nanolayered glass with individual layer thicknesses (h) ranging from 5 to 80 nm was systematically investigated by nanoindentation tests. It was found that the hardness of the designed structure was almost size-independent. Yet, a clear transition in the deformation modes from the cutting-like shear bands to the kinking-like ones was discovered as h decreased to 10 nm. Moreover, multiple secondary shear bands also appeared, in addition to the primary ones, in the sample with h = 10 nm. The transition leads to an obvious strain delocalization, as clearly illustrated by the proposed theoretical model, which is based on the assumption of a pure shear stress state to quantify the shear banding-induced strain localization. The strain delocalization results from the higher density of amorphous/amorphous interfaces that exhibit the change in morphology with a refined layered glass structure.

Clinical Significance of Upregulation of EZH1 Expression in Hepatocellular Carcinoma Tissues.

BACKGROUND AND AIMS: The incidence and mortality of hepatocellular carcinoma (HCC) are increasing. It is urgent to develop more effective HCC biomarkers for diagnosis and treatment. This project intends to verify the expression of enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1) and its mechanism in HCC. METHODS: This study integrates global microarray and high-throughput sequencing datasets, combined with internal immunohistochemistry, to analyze the expression and prognostic value of EZH1 in HCC. Functional enrichment analysis was conducted to investigate transcriptional targets, which were achieved by intersecting HCC over-expressed genes, EZH1 co-expressed genes and putative transcriptional targets. The relationship between EZH1 and anticancer drugs was detected by drug sensitivity analysis. RESULTS: In this study, 84 datasets from 40 platforms (3,926 HCC samples and 3,428 non-cancerous liver tissues) were included to show the high expression of EZH1 in HCC. Immunohistochemistry with 159 HCC samples and 62 non-HCC samples confirmed the high expression level. HCC patients with high EZH1 expression had worse survival prognoses. Gene ontology and Reactome analysis revealed that metabolism-related pathways, including autophagy, are critical for HCC. Interestingly, as one of the EZH1 potential transcriptional targets, autophagy-related 7 (ATG7) appeared in the above pathways. ATG7 was positively correlated with EZH1, upregulated in HCC, and mediated poor prognosis. Upregulation of EZH1 was found to be in contact with HCC anti-tumor drug resistance. CONCLUSIONS: The upregulation of EZH1 expression can promote the occurrence of HCC and lead to poor clinical progression and drug resistance; these effects may be mediated by regulating ATG7.

Chinese Expert Consensus on the Clinical Diagnosis and Management of Statin Intolerance.

The clinical benefits of statins have well-established and recognized worldwide. Although statins are well-tolerated generally, however, the report of statin-related adverse event and statin intolerance are common in China, which results in insufficient use of statins and poor adherence. The main reason may be attributed to confusions or misconceptions in the clinical diagnosis and management in China, including the lack of unified definitions and diagnostic standards, broad grasp of diagnosis, and unscientific management strategies. Based on that, this consensus carefully summarized the statin-related gene polymorphism and statin usage issue among Chinese population, and comprehensively reviewed global research data on statin intolerance, referenced guidelines, and consensus literature on statin intolerance in foreign and different regions, proposes an appropriate and easy to implement statin intolerance definition as well as corresponding diagnostic criteria and management strategies for Chinese clinicians, in order to improve the clinical application of statin drugs and enhance the prevention and treatment level of atherosclerotic cardiovascular disease in China.

The role of foam cells in spinal cord injury: challenges and opportunities for intervention.

Spinal cord injury (SCI) results in a large amount of tissue cell debris in the lesion site, which interacts with various cytokines, including inflammatory factors, and the intrinsic glial environment of the central nervous system (CNS) to form an inhibitory microenvironment that impedes nerve regeneration. The efficient clearance of tissue debris is crucial for the resolution of the inhibitory microenvironment after SCI. Macrophages are the main cells responsible for tissue debris removal after SCI. However, the high lipid content in tissue debris and the dysregulation of lipid metabolism within macrophages lead to their transformation into foamy macrophages during the phagocytic process. This phenotypic shift is associated with a further pro-inflammatory polarization that may aggravate neurological deterioration and hamper nerve repair. In this review, we summarize the phenotype and metabolism of macrophages under inflammatory conditions, as well as the mechanisms and consequences of foam cell formation after SCI. Moreover, we discuss two strategies for foam cell modulation and several potential therapeutic targets that may enhance the treatment of SCI.

Risk factors analyses associated with postoperative infection in choledochoscopy for intrahepatic bile duct stones (IHDs): a single-center retrospective study in real-world setting.

BACKGROUND: Choledochoscopy is a highly effective approach for managing intrahepatic bile duct stones (IHDs). However, postoperative infection is a common complication that significantly impacts treatment outcomes. Despite its clinical relevance, the risk factors associated with this procedure remain largely unexplored. METHODS: This study focused on a consecutive cohort of patients who underwent choledochoscopy for IHDs at our institution between January 2016 and December 2022. The primary objective was to analyze the relationship between various clinical factors and postoperative infection, and to compare the postoperative infection of different choledochoscopic procedures. RESULTS: The study cohort consisted of 126 patients, with 60 individuals (47.6%) experiencing postoperative infection. Notably, preoperative biliary obstruction (odds ratio [OR] 1.861; 95% confidence interval [CI] 1.314-8.699; p = 0.010) and operation time (OR 4.414; 95% CI 1.635-12.376; p = 0.004) were identified as risk factors for postoperative infection. Additionally, biliary tract infections (60.00%) were primarily responsible for postoperative infection, with Escherichia coli (47.22%) being the predominant bacterial strain identified in bile cultures. Furthermore, biliary tract obstruction (OR 4.563; 95% CI 1.554-13.401; p = 0.006) and body mass index (BMI) (OR 1.186; 95% CI 1.015-1.386; p = 0.031) were determined to be independent risk factors for postoperative biliary tract infection. CONCLUSIONS: The occurrence of postoperative infection in patients undergoing choledochoscopy was primarily associated with the duration of the operation and the presence of preoperative biliary obstruction.

Prevalence, outcomes and associated factors of SARS-CoV-2 infection in psoriasis patients of Southwest China: a cross-sectional survey.

In this study we aimed to investigate the prevalence of SARS-CoV-2 infection in psoriasis patients, and outcomes of SARS-CoV-2 infection and associated risk factors. A cross-sectional survey was conducted from February 2023 to March 2023. Information was obtained with online questionnaire about psoriasis patients on demographic characteristics, clinical characteristics, SARS-CoV-2 infection and outcomes, vaccination, and routine protection against COVID-19. Logistic regression analysis was used to explore risk factors with SARS-CoV-2 infection and exacerbation of psoriasis. A total of 613 participants were recruited. 516 (84.2%) were infected, and associated factors were sex, working status, routine protection against COVID-19, COVID-19 vaccination, impaired nail, infection exacerbate psoriasis, and severity of psoriasis. Among the patients infected with SARS-CoV-2, 30 (5.8%) required hospitalization, 122 (23.6%) had psoriasis exacerbation due to SARS-CoV-2 infection, and associated factors were subtype of psoriasis, discontinuation of psoriasis treatment during SARS-CoV-2 infection, response following COVID-19 vaccination, and severity of psoriasis. Booster dose vaccination contributed a low probability of COVID-19 sequelae. COVID-19 vaccine's effectiveness was unsatisfactory, while booster dose vaccination reduced the occurrence of COVID-19 sequelae in psoriasis patients of Southwest China. Patients treated with psoriasis shown to be safe, without a higher incidence of SARS-CoV-2 infection or COVID-19hospitalization compared to untreated patients. Stopping treatment during SARS-CoV-2 infection led to psoriasis exacerbation, so psoriasis treatment could be continued except severe adverse reaction.

Excavation method optimization and mechanical responses investigating of a shallow buried super large section tunnels: a case study in Zhejiang.

The construction of super large section (SLS) shallow buried tunnels involves challenges related to their large span, high flat rate, and complex construction process. Selecting an appropriate excavation method is crucial for ensuring stability, controlling costs, and managing the construction timeline. This study focuses on the selection of excavation methods and the mechanical responses of SLS tunnels in different types of surrounding rock. The research is based on the Yangjiashan tunnel project in Zhejiang Province, China, which is a four-line highway tunnel with a span of 21.3 m. Three sequential excavation methods were proposed and simulated using the three-dimensional finite difference method: the "upper first and lower later" side drift (SD) method, the central diaphragm method, and the top heading and bench (HB) method. The mechanical response characteristics of tunnel construction under these methods were investigated, including rock deformation, rock pressure, and the internal forces acting on the primary support. By comparing the performance of the three construction methods in rock masses of Grades III to V, the study aimed to determine the optimal construction method for SLS tunnels considering factors such as safety, cost, and schedule. Field tests were conducted to evaluate the effectiveness of the optimized construction scheme. The results of the field monitoring indicated that the "upper first and lower later" SD method in Grade V rock mass and the HB method in Grade III to IV rock mass are feasible and cost-effective under certain conditions. The research findings provide valuable insights for the design and construction of SLS tunnels in complex conditions, serving as a reference for engineers and project managers.

Targeting TYK2 alleviates Rab27A-induced malignant progression of non-small cell lung cancer via disrupting IFNα-TYK2-STAT-HSPA5 axis.

Rab27A is a small GTPase-mediating exosome secretion, which participates in tumorigenesis of multiple cancer types. Understanding the biological role of Rab27A in non-small cell lung cancer (NSCLC) is of great importance for oncological research and clinical treatment. In this study, we investigate the function and internal mechanism of Rab27A in NSCLC. Results show that Rab27A is overexpressed in NSCLC, and regulates the tumor proliferation, migration, invasion, and cell motility in vitro and in vivo, and is negatively regulated by miR-124. Further research reveals that upregulated Rab27A can induce the production of IFNα in the medium by mediating exosome secretion. Then IFNα activates TYK2/STAT/HSPA5 signaling to promote NSCLC cell proliferation and metastasis. This process can be suppressed by TYK2 inhibitor Cerdulatinib. These results suggest that Rab27A is involved in the pathogenesis of NSCLC by regulating exosome secretion and downstream signaling, and inhibitors targeting this axis may become a promising strategy in future clinical practice.