A non-canonical role of the inner kinetochore in regulating sister-chromatid cohesion at centromeres.

The 16-subunit Constitutive Centromere-associated Network (CCAN)-based inner kinetochore is well-known for connecting centromeric chromatin to the spindle-binding outer kinetochore. Here, we report a non-canonical role for the inner kinetochore in directly regulating sister-chromatid cohesion at centromeres. We provide biochemical, X-ray crystal structure, and intracellular ectopic localization evidence that the inner kinetochore directly binds cohesin, a ring-shaped multi-subunit complex that holds sister chromatids together from S-phase until anaphase onset. This interaction is mediated by binding of the 5-subunit CENP-OPQUR sub-complex of CCAN to the Scc1-SA2 sub-complex of cohesin. Mutation in the CENP-U subunit of the CENP-OPQUR complex that abolishes its binding to the composite interface between Scc1 and SA2 weakens centromeric cohesion, leading to premature separation of sister chromatids during delayed metaphase. We further show that CENP-U competes with the cohesin release factor Wapl for binding the interface of Scc1-SA2, and that the cohesion-protecting role for CENP-U can be bypassed by depleting Wapl. Taken together, this study reveals an inner kinetochore-bound pool of cohesin, which strengthens centromeric sister-chromatid cohesion to resist metaphase spindle pulling forces.

Decoding the potential role of regulatory T cells in sepsis-induced immunosuppression.

Sepsis, a multiorgan dysfunction with high incidence and mortality, is caused by an imbalanced host-to-infection immune response. Organ-support therapy improves the early survival rate of sepsis patients. In the long term, those who survive the "cytokine storm" and its secondary damage usually show higher susceptibility to secondary infections and sepsis-induced immunosuppression, in which regulatory T cells (Tregs) are evidenced to play an essential role. However, the potential role and mechanism of Tregs in sepsis-induced immunosuppression remains elusive. In this review, we elucidate the role of different functional subpopulations of Tregs during sepsis and then review the mechanism of sepsis-induced immunosuppression from the aspects of regulatory characteristics, epigenetic modification, and immunometabolism of Tregs. Thoroughly understanding how Tregs impact the immune system during sepsis may shed light on preclinical research and help improve the translational value of sepsis immunotherapy.

A prefrontal-habenular circuitry regulates social fear behaviour.

The medial prefrontal cortex (mPFC) has been implicated in the pathophysiology of social impairments including social fear. However, the precise subcortical partners that mediate mPFC dysfunction on social fear behaviour have not been identified. Employing a social fear conditioning paradigm, we induced robust social fear in mice and found that the lateral habenula (LHb) neurons and LHb-projecting mPFC neurons are synchronously activated during social fear expression. Moreover, optogenetic inhibition of the mPFC-LHb projection significantly reduced social fear responses. Importantly, consistent with animal studies, we observed an elevated prefrontal-habenular functional connectivity in subclinical individuals with higher social anxiety characterized by heightened social fear. These results unravel a crucial role of the prefrontal-habenular circuitry in social fear regulation and suggest that this pathway could serve as a potential target for the treatment of social fear symptom often observed in many psychiatric disorders.

Smurf1 polyubiquitinates on K285/K282 of the kinases Mst1/2 to attenuate their tumor-suppressor functions.

Sterile 20-like kinases Mst1 and Mst2 (Mst1/2) and large tumor suppressor 1/2 are core kinases to mediate Hippo signaling in maintaining tissue homeostasis. We have previously demonstrated that Smad ubiquitin (Ub) regulatory factor 1 (Smurf1), a HECT-type E3 ligase, ubiquitinates and in turn destabilizes large tumor suppressor 1/2 to induce the transcriptional output of Hippo signaling. Here, we unexpectedly find that Smurf1 interacts with and polyubiquitinates Mst1/2 by virtue of K27- and K29-linked Ub chains, resulting in the proteasomal degradation of Mst1/2 and attenuation of their tumor-suppressor functions. Among the potential Ub acceptor sites on Mst1/2, K285/K282 are conserved and essential for Smurf1-induced polyubiquitination and degradation of Mst1/2 as well as transcriptional output of Hippo signaling. As a result, K285R/K282R mutation of Mst1/2 not only negates the transcriptional output of Hippo signaling but enhances the tumor-suppressor functions of Mst1/2. Together, we demonstrate that Smurf1-mediated polyubiquitination on K285/K282 of Mst1/2 destabilizes Mst1/2 to attenuate their tumor-suppressor functions. Thus, the present study identifies Smurf1-mediated ubiquitination of Mst1/2 as a hitherto uncharacterized mechanism fine-tuning the Hippo signaling pathway and may provide additional targets for therapeutic intervention of diseases associated with this important pathway.

GABRP inhibits the progression of oesophageal cancer by regulating CFTR: Integrating bioinformatics analysis and experimental validation.

Oesophageal cancer (EC) is a malignancy which accounts for a substantial number of cancer-related deaths worldwide. The molecular mechanisms underlying the pathogenesis of EC have not been fully elucidated. GSE17351 and GSE20347 data sets from the Gene Expression Omnibus (GEO) database were employed to screen differentially expressed genes (DEGs). Reverse transcription quantitative PCR (RT-qPCR) was used to examine hub gene expression. ECA-109 and TE-12 cells were transfected using the pcDNA3.1 expression vector encoding GABRP. The cell counting kit-8 (CCK-8), cell scratch and Transwell assays were performed to assess the effect of GABRP on EC cell proliferation, migration and invasion. Epithelial-mesenchymal transition (EMT)-associated protein levels were measured by Western blotting. Subsequently, CFTR was knocked down to verify whether GABRP affected biological events in EC cells by targeting CFTR. Seven hub genes were identified, including GABRP, FLG, ENAH, KLF4, CD24, ABLIM3 and ABLIM1, which all could be used as diagnostic biomarkers for EC. The RT-qPCR results indicated that the expression levels of GABRP, FLG, KLF4, CD24, ABLIM3 and ABLIM1 were downregulated, whereas the expression level of ENAH was upregulated. In vitro functional assays demonstrated that GABRP overexpression suppressed the proliferation, migration, invasion and EMT of EC cells. Mechanistically, GABRP promoted the expression of CFTR, and CFTR knockdown significantly counteracted the influence of GABRP overexpression on biological events in EC cells. Overexpression of GABRP inhibited EC progression by increasing CFTR expression, which might be a new target for EC treatment.

Early left ventricular microvascular dysfunction in diabetic pigs: a longitudinal quantitative myocardial perfusion CMR study.

BACKGROUND: Microvascular pathology is one of the main characteristics of diabetic cardiomyopathy; however, the early longitudinal course of diabetic microvascular dysfunction remains uncertain. This study aimed to investigate the early dynamic changes in left ventricular (LV) microvascular function in diabetic pig model using the cardiac magnetic resonance (CMR)-derived quantitative perfusion technique. METHODS: Twelve pigs with streptozotocin-induced diabetes mellitus (DM) were included in this study, and longitudinal CMR scanning was performed before and 2, 6, 10, and 16 months after diabetic modeling. CMR-derived semiquantitative parameters (upslope, maximal signal intensity, perfusion index, and myocardial perfusion reserve index [MPRI]) and fully quantitative perfusion parameters (myocardial blood flow [MBF] and myocardial perfusion reserve [MPR]) were analyzed to evaluate longitudinal changes in LV myocardial microvascular function. Pearson correlation was used to analyze the relationship between LV structure and function and myocardial perfusion function. RESULTS: With the progression of DM duration, the upslope at rest showed a gradually increasing trend (P = 0.029); however, the upslope at stress and MBF did not change significantly (P > 0.05). Regarding perfusion reserve function, both MPRI and MPR showed a decreasing trend with the progression of disease duration (MPRI, P = 0.001; MPR, P = 0.042), with high consistency (r = 0.551, P < 0.001). Furthermore, LV MPR is moderately associated with LV longitudinal strain (r = - 0.353, P = 0.022), LV remodeling index (r = - 0.312, P = 0.033), fasting blood glucose (r = - 0.313, P = 0.043), and HbA1c (r = - 0.309, P = 0.046). Microscopically, pathological results showed that collagen volume fraction increased gradually, whereas no significant decrease in microvascular density was observed with the progression of DM duration. CONCLUSIONS: Myocardial microvascular reserve function decreased gradually in the early stage of DM, which is related to both structural (but not reduced microvascular density) and functional abnormalities of microvessels, and is associated with increased blood glucose, reduced LV deformation, and myocardial remodeling.

Insights into the Roles of Natural Killer Cells in Osteoarthritis.

Osteoarthritis (OA) is now widely acknowledged as a low-grade inflammatory condition, in which the intrinsic immune system plays a significant role in its pathogenesis. While the involvement of macrophages and T cells in the development of OA has been extensively reviewed, recent research has provided mounting evidence supporting the crucial contribution of NK cells in both the initiation and advancement of OA. Accumulated evidence has emerged in recent years indicating that NK cells play a critical role in OA development and progression. This review will outline the ongoing understanding of the utility of NK cells in the etiology of OA, focusing on how NK cells interact with chondrocytes, synoviocytes, osteoclasts, and other immune cells to influence the course of OA disease.

Parcellating the human brain using resting-state dynamic functional connectivity.

Brain cartography has expanded substantially over the past decade. In this regard, resting-state functional connectivity (FC) plays a key role in identifying the locations of putative functional borders. However, scant attention has been paid to the dynamic nature of functional interactions in the human brain. Indeed, FC is typically assumed to be stationary across time, which may obscure potential or subtle functional boundaries, particularly in regions with high flexibility and adaptability. In this study, we developed a dynamic FC (dFC)-based parcellation framework, established a new functional human brain atlas termed D-BFA (DFC-based Brain Functional Atlas), and verified its neurophysiological plausibility by stereo-EEG data. As the first dFC-based whole-brain atlas, the proposed D-BFA delineates finer functional boundaries that cannot be captured by static FC, and is further supported by good correspondence with cytoarchitectonic areas and task activation maps. Moreover, the D-BFA reveals the spatial distribution of dynamic variability across the brain and generates more homogenous parcels compared with most alternative parcellations. Our results demonstrate the superiority and practicability of dFC in brain parcellation, providing a new template to exploit brain topographic organization from a dynamic perspective. The D-BFA will be publicly available for download at https://github.com/sliderplm/D-BFA-618.

APP mediates tau uptake and its overexpression leads to the exacerbated tau pathology.

Alzheimer's disease (AD), as the most common type of dementia, has two pathological hallmarks, extracellular senile plaques composed of ß-amyloid peptides and intracellular neurofibrillary tangles containing phosphorylated-tau protein. Amyloid precursor protein (APP) and tau each play central roles in AD, although how APP and tau interact and synergize in the disease process is largely unknown. Here, we showed that soluble tau interacts with the N-terminal of APP in vitro in cell-free and cell culture systems, which can be further confirmed in vivo in the brain of 3XTg-AD mouse. In addition, APP is involved in the cellular uptake of tau through endocytosis. APP knockdown or N-terminal APP-specific antagonist 6KApoEp can prevent tau uptake in vitro, resulting in an extracellular tau accumulation in cultured neuronal cells. Interestingly, in APP/PS1 transgenic mouse brain, the overexpression of APP exacerbated tau propagation. Moreover, in the human tau transgenic mouse brain, overexpression of APP promotes tau phosphorylation, which is significantly remediated by 6KapoEp. All these results demonstrate the important role of APP in the tauopathy of AD. Targeting the pathological interaction of N-terminal APP with tau may provide an important therapeutic strategy for AD.

IGF-1's protective effect on OSAS rats' learning and memory.

PURPOSE: Patients with obstructive sleep apnea syndrome (OSAS) frequently experience cognitive dysfunction, which may be connected to chronic intermittent hypoxia (CIH). Insulin-like growth factor-1 (IGF-1) is thought to be closely associated with cognitive function, but its role in cognitive impairment caused by OSAS is unclear. The purpose of this study was to investigate the potential protective effect of IGF-1 on cognitive impairment in OSAS rats. METHODS: Healthy male SD rats (n = 40) were randomly assigned into four groups: control group, CIH group, NS + CIH group, and IGF-1 + CIH group. All experimental rats except for those in the control group were exposed to intermittent hypoxic (IH) environments for 8 h per day over 28 days. Prior to daily exposure to IH, rats in the IGF-1 + CIH group received subcutaneous injections of IGF-1. The Morris water maze test was conducted on all experimental rats. Brain tissue testing methods included Enzyme-Linked Immunosorbent Assay, Hematoxylin and eosin staining, Immunohistochemistry, and Western blotting. RESULTS: The rat model of OSAS was successfully established following exposure to CIH and exhibited significant cognitive impairment. However, daily subcutaneous injections of IGF-1 partially restored the impaired cognitive function in OSAS rats. Compared with the control group, there was a significant decrease in the expression levels of IGF-1, p-IGF-IR, and SYP in the CIH group; however, these expression levels increased significantly in the IGF-I + CIH group. CONCLUSION: In OSAS rats, IGF-1 enhances learning memory; this effect may be linked to increased p-IGF-1R and SYP protein production in the hippocampus.

Cadmium exposure induces pyroptosis of TM4 cells through oxidative stress damage and inflammasome activation.

Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1ß (IL-1ß) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11-7082 (BAY) alleviate the release of IL-1ß and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.

Self-care behaviours of first-generation Chinese immigrants living with cardiovascular disease: A qualitative study.

AIM: To identify and describe self-care behaviours performed by Chinese immigrants living with cardiovascular disease in Australia, and factors perceived as barriers and facilitators to evidence-based cardiac self-care. DESIGN: A qualitative descriptive design. METHODS: Individual semi-structured phone interviews were conducted among participants meeting the following criteria: (1) first-generation Chinese immigrants to Australia, born in Mainland China, Hong Kong, Macao or Taiwan; (2) Australian permanent residents or citizens; (3) self-reported or medically diagnosed with coronary heart disease, stroke or heart failure; (4) able to speak English or Mandarin; (5) able to provide informed consent, excluding those with history or evidence of impaired cognition such as dementia. Participants were recruited via social media, Chinese community associations and medical centres from September 2021 to June 2022. Data were analysed using inductive and deductive thematic analysis, guided by the Middle-Range Theory of Self-Care of Chronic Illness. The study was reported in line with the COREQ checklist. RESULTS: Twenty participants were interviewed, 60% female, mean age 69.9 years. Most migrated to Australia at older age following their retirement in China; most had limited English proficiency. Many practiced adequate self-care for their CVD in self-care maintenance and monitoring. Variously, they adopted heart-healthy diets, developed exercise routines, attended medical services and closely monitored their body signs and symptoms. However, self-adjusting medications, taking Traditional Chinese Medicine and self-administering health supplements were prevalent practices and first-response management of acute cardiac symptoms was suboptimal. Linguistic and cultural barriers to obtaining mainstream heart health information meant most participants resorted to informal, anecdotal and mainland Chinese sources. CONCLUSION: Diverse factors were held responsible for sub-optimal self-care behaviours but lack of access to linguistically and culturally appropriate heart health information was widely blamed. Linguistically and culturally appropriate community-based heart health education programmes are urgently needed, targeting healthy lifestyle modification, medication literacy and cardiac symptom management. IMPACT: Study findings can be used to improve cardiac nurses' cultural sensitivity and practices targeting Chinese immigrants. Partnering with Chinese community associations offers health service providers and policymakers an innovative route to co-design and deliver targeted heart health education interventions and support for this population. PUBLIC CONTRIBUTION: Chinese community centre managers contributed to data collection by supporting participant recruitment.

The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1.

BACKGROUND: Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet. METHODS: A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide. RESULTS: This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination. CONCLUSIONS: Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.

CTGF promotes the repair and regeneration of alveoli after acute lung injury by promoting the proliferation of subpopulation of AEC2s.

BACKGROUND: Functional alveolar regeneration is essential for the restoration of normal lung homeostasis after acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Lung is a relatively quiescent organ and a variety of stem cells are recruited to participate in lung repair and regeneration after lung tissue injury. However, there is still no effective method for promoting the proliferation of endogenous lung stem cells to promote repair and regeneration. METHODS: Using protein mass spectrometry analysis, we analyzed the microenvironment after acute lung injury. RNA sequencing and image cytometry were used in the alveolar epithelial type 2 cells (AEC2s) subgroup identification. Then we used Sftpc+AEC2 lineage tracking mice and purified AEC2s to further elucidate the molecular mechanism by which CTGF regulates AEC2s proliferation both in vitro and in vivo. Bronchoalveolar lavage fluid (BALF) from thirty ARDS patients who underwent bronchoalveolar lavage was collected for the analysis of the correlation between the expressing of Krt5 in BALF and patients' prognosis. RESULTS: Here, we elucidate that AEC2s are the main facultative stem cells of the distal lung after ALI and ARDS. The increase of connective tissue growth factor (CTGF) in the microenvironment after ALI promoted the proliferation of AEC2s subpopulations. Proliferated AEC2s rapidly expanded and differentiated into alveolar epithelial type 1 cells (AEC1s) in the regeneration after ALI. CTGF initiates the phosphorylation of LRP6 by promoting the interaction between Krt5 and LRP6 of AEC2s, thus activating the Wnt signaling pathway, which is the molecular mechanism of CTGF promoting the proliferation of AEC2s subpopulation. CONCLUSIONS: Our study verifies that CTGF promotes the repair and regeneration of alveoli after acute lung injury by promoting the proliferation of AEC2s subpopulation.

OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development.

Many cancer cells maintain enhanced aerobic glycolysis due to irreversible defective mitochondrial oxidative phosphorylation (OXPHOS). This phenomenon, known as the Warburg effect, is recently challenged because most cancer cells maintain OXPHOS. However, how cancer cells coordinate glycolysis and OXPHOS remains largely unknown. Here, we demonstrate that OMA1, a stress-activated mitochondrial protease, promotes colorectal cancer development by driving metabolic reprogramming. OMA1 knockout suppresses colorectal cancer development in AOM/DSS and xenograft mice models of colorectal cancer. OMA1-OPA1 axis is activated by hypoxia, increasing mitochondrial ROS to stabilize HIF-1α, thereby promoting glycolysis in colorectal cancer cells. On the other hand, under hypoxia, OMA1 depletion promotes accumulation of NDUFB5, NDUFB6, NDUFA4, and COX4L1, supporting that OMA1 suppresses OXPHOS in colorectal cancer. Therefore, our findings support a role for OMA1 in coordination of glycolysis and OXPHOS to promote colorectal cancer development and highlight OMA1 as a potential target for colorectal cancer therapy.

Cytokine Biomarker Phenotype for Early Prediction and Triage of Sepsis in Blunt Trauma Patients.

BACKGROUND: Altered levels of inflammatory markers secondary to severe trauma present a major problem to physicians and are prone to interfering with the clinical identification of sepsis events. This study aimed to establish the profiles of cytokines in trauma patients to characterize the nature of immune responses to sepsis, which might enable early prediction and individualized treatments to be developed for targeted intervention. METHODS: A 15-plex human cytokine magnetic bead assay system was used to measure analytes in citrated plasma samples. Analysis of the kinetics of these cytokines was performed in 40 patients with severe blunt trauma admitted to our trauma center between March 2016 and February 2017, with an Injury Severity Score (ISS) greater than 20 with regard to sepsis (Sepsis-3) over a 14-d time course. RESULTS: In total, the levels of six cytokines were altered in trauma patients across the 1-, 3-, 5-, 7-, and 14-d time points. Additionally, IL-6, IL-10, IL-15, macrophage derived chemokine (MDC), GRO, sCD40 L, granulocyte colony-stimulating factor (G-CSF), and fibroblast growth factor (FGF)-2 levels could be used to provide a significant discrimination between sepsis and nonsepsis patients at day 3 and afterward, with an area under the curve (AUC) of up to 0.90 through a combined analysis of the eight biomarkers (P < 0.001). Event-related analysis demonstrated 1.5- to 4-fold serum level changes for these cytokines within 72 h before clinically apparent sepsis. CONCLUSIONS: Cytokine profiles demonstrate a high discriminatory ability enabling the timely identification of evolving sepsis in trauma patients. These abrupt changes enable sepsis to be detected up to 72 h before clinically overt deterioration. Defining cytokine release patterns that distinguish sepsis risk from trauma patients might enable physicians to initiate timely treatment and reduce mortality. Large prospective studies are needed to validate and operationalize the findings. TRIAL REGISTRATION: Clinicaltrials, NCT01713205. Registered October 22, 2012, https://register. CLINICALTRIALS: gov/NCT01713205.

Deep Transfer Learning for Cerebral Cortex Using Area-Preserving Geometry Mapping.

Limited sample size hinders the application of deep learning in brain image analysis, and transfer learning is a possible solution. However, most pretrained models are 2D based and cannot be applied directly to 3D brain images. In this study, we propose a novel framework to apply 2D pretrained models to 3D brain images by projecting surface-based cortical morphometry into planar images using computational geometry mapping. Firstly, 3D cortical meshes are reconstructed from magnetic resonance imaging (MRI) using FreeSurfer and projected into 2D planar meshes with topological preservation based on area-preserving geometry mapping. Then, 2D deep models pretrained on ImageNet are adopted and fine-tuned for cortical image classification on morphometric shape metrics. We apply the framework to sex classification on the Human Connectome Project dataset and autism spectrum disorder (ASD) classification on the Autism Brain Imaging Data Exchange dataset. Moreover, a 2-stage transfer learning strategy is suggested to boost the ASD classification performance by using the sex classification as an intermediate task. Our framework brings significant improvement in sex classification and ASD classification with transfer learning. In summary, the proposed framework builds a bridge between 3D cortical data and 2D models, making 2D pretrained models available for brain image analysis in cognitive and psychiatric neuroscience.

Tim-3 regulates sepsis-induced immunosuppression by inhibiting the NF-κB signaling pathway in CD4 T cells.

Immunosuppression in response to severe sepsis remains a serious human health concern. Evidence of sepsis-induced immunosuppression includes impaired T lymphocyte function, T lymphocyte depletion or exhaustion, increased susceptibility to opportunistic nosocomial infection, and imbalanced cytokine secretion. CD4 T cells play a critical role in cellular and humoral immune responses during sepsis. Here, using an RNA sequencing assay, we found that the expression of T cell-containing immunoglobulin and mucin domain-3 (Tim-3) on CD4 T cells in sepsis-induced immunosuppression patients was significantly elevated. Furthermore, the percentage of Tim-3+ CD4 T cells from sepsis patients was correlated with the mortality of sepsis-induced immunosuppression. Conditional deletion of Tim-3 in CD4 T cells and systemic Tim-3 deletion both reduced mortality in response to sepsis in mice by preserving organ function. Tim-3+ CD4 T cells exhibited reduced proliferative ability and elevated expression of inhibitory markers compared with Tim-3-CD4 T cells. Colocalization analyses indicated that HMGB1 was a ligand that binds to Tim-3 on CD4 T cells and that its binding inhibited the NF-κB signaling pathway in Tim-3+ CD4 T cells during sepsis-induced immunosuppression. Together, our findings reveal the mechanism of Tim-3 in regulating sepsis-induced immunosuppression and provide a novel therapeutic target for this condition.

Analysis of Pediatric Surgical Disease Spectrum in a Tertiary Hospital.

Objective: To analyze the main disease composition of children hospitalized in pediatric surgery, explore the correlation between disease types and gender, and provide a reference for hospital management and pediatric disease prevention. Methods: Using ICD-10 codes as the classification standard for disease diagnosis, a statistical analysis was conducted on the disease composition of children hospitalized in the Pediatric Surgery Department of the Second Affiliated Hospital of Xi'an Jiaotong University from January 1, 2015, to December 31, 2015, followed by the establishment of a clinical database. A total of 1647 male patients and 817 female patients were enrolled in the study, resulting in a male-to-female ratio of 2:1. The age range of the patients spanned from 0 to 18 years, with a marked imbalance in patient distribution among the various age groups. Statistical analysis was conducted using SPSS version 18.0 software. A chi-square test was performed to analyze the differences in the composition of disease systems and the composition of major diseases in terms of sex and age. Results: Pediatric patients were admitted with complex and diverse diseases in 2015, involving 15 systems of the human body and 400 diseases. Digestive system diseases, tumors, congenital malformations, and genitourinary system diseases were the top four diseases accounting for 83.5% of all pediatric cases. 561 patients were aged 0 years, accounting for 22.3% of all cases, while 1,801 patients fell within the 0-5 years age group, constituting 73.1% of the total. The differences in disease system composition among different sex and age groups of pediatric surgical inpatients were statistically significant (P = .001). There are statistically significant differences in the length of hospital stay and hospitalization costs among pediatric surgical inpatients in different age groups (P = .001). Conclusion: To strengthen the diagnosis and treatment of pediatric surgical diseases, we should strengthen the construction of key departments, optimize the consultation process according to the characteristics of children's disease spectrum, and improve the level of diagnosis and treatment of pediatric surgical diseases.

Risk factors for postoperative surgical site infections after anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

OBJECTIVES: The primary aim was to evaluate risk factors for surgical site infections after anterior cruciate ligament reconstruction (ACLR). The secondary aim was to investigate the surgical site infection incidence rate and the mean time to postoperative surgical site infection symptoms. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase and Web of Science were searched from database inception to September 2021 and updated in April 2022. ELIGIBILITY CRITERIA: Quantitative, original studies reporting potential risk factors for surgical site infections after ACLR were included. RESULTS: Twenty-three studies with 3871 infection events from 469 441 ACLRs met the inclusion criteria. Male sex (OR 1.78, p< 0.00001), obesity (OR 1.82, p=0.0005), tobacco use (OR 1.37, p=0.01), diabetes mellitus (OR 3.40, p=0.002), steroid use history (OR 4.80, p<0.00001), previous knee surgery history (OR 3.63, p=0.02), professional athlete (OR 4.56, p=0.02), revision surgery (OR 2.05, p=0.04), hamstring autografts (OR 2.83, p<0.00001), concomitant lateral extra-articular tenodesis (OR 3.92, p=0.0001) and a long operating time (weighted mean difference 8.12, p=0.005) were identified as factors that increased the risk of surgical site infections (superficial and deep) after ACLR. Age, outpatient or inpatient surgery, bone-patellar tendon-bone autografts or allografts and a concomitant meniscus suture did not increase the risk of surgical site infections. The incidence of surgical site infections after ACLR was approximately 1% (95% CI 0.7% to 1.2%). The mean time from surgery to the onset of surgical site infection symptoms was approximately 17.1 days (95% CI 13.2 to 21.0 days). CONCLUSION: Male sex, obesity, tobacco use, diabetes mellitus, steroid use history, previous knee surgery history, professional athletes, revision surgery, hamstring autografts, concomitant lateral extra-articular tenodesis and a long operation time may increase the risk of surgical site infections after ACLR. Although the risk of surgical site infections after ACLR is low, raising awareness and implementing effective preventions for risk factors are priorities for clinicians to reduce the incidence of surgical site infections due to its seriousness.