The impact of frailty on clinical outcomes of older patients undergoing enhanced recovery after lumbar fusion surgery: A prospective cohort study.

BACKGROUND: Frailty is recognized as a surrogate for physiological age and has been established as a valid and independent predictor of postoperative morbidity, mortality, and complications. ERAS can enhance surgical safety by minimizing stress responses in frail patients, enabling surgeons to discharge patients earlier. However, the question of whether and to what extent the frailty impacts the post-ERAS outcomes in older patients remains. MATERIALS AND METHODS: An evidence-based ERAS program was implemented in our center from January 2019. This is a prospective cohort study of patients aged ≥75 years who underwent open transforaminal lumbar interbody fusion (TLIF) for degenerative spine disease from April 2019 to October 2021. Frailty was assessed with the Fried frailty scale (FP scale), and patients were categorized as non/prefrail (FP 0-2) or frail (FP ≥ 3). The preoperative variables, operative data, postoperative outcomes and follow-up information were compared between the two groups. Univariate and multivariate logistic regression analyses were used to identify risk factors for 90-day major complications and prolonged length of hospital stay (LOS) after surgery. RESULTS: A total of 245 patients (age of 79.8 ± 3.4 yr) who had a preoperative FP score recorded and underwent scheduled TLIF surgery were included in the final analysis. Comparisons between non-frail and prefrail/frail patients revealed no significant difference in age, sex, and surgery-related variables. Even after adjusting for multiple comparisons, the association between Fried frailty and ADL-dependency, IADL-dependency, and malnutrition remained significant. Preoperative frailty was associated with increased rates of postoperative adverse events. A higher CCI grade was an independent predictor for 90-day major complications, while Fried frailty and MNA-SF scores <12 were predictive of poor postoperative recovery. CONCLUSION: Frail older patients had more adverse post-ERAS outcomes after TLIF compared to non/prefrail older patients. Continued research and multidisciplinary collaboration will be essential to refine and optimize protocols for surgical care in frail older adults.

DEPDC5 protects CD8+ T cells from ferroptosis by limiting mTORC1-mediated purine catabolism.

Peripheral CD8+ T cell number is tightly controlled but the precise molecular mechanism regulating this process is still not fully understood. In this study, we found that epilepsy patients with loss of function mutation of DEPDC5 had reduced peripheral CD8+ T cells, and DEPDC5 expression positively correlated with tumor-infiltrating CD8+ T cells as well as overall cancer patient survival, indicating that DEPDC5 may control peripheral CD8+ T cell homeostasis. Significantly, mice with T cell-specific Depdc5 deletion also had reduced peripheral CD8+ T cells and impaired anti-tumor immunity. Mechanistically, Depdc5-deficient CD8+ T cells produced high levels of xanthine oxidase and lipid ROS due to hyper-mTORC1-induced expression of ATF4, leading to spontaneous ferroptosis. Together, our study links DEPDC5-mediated mTORC1 signaling with CD8+ T cell protection from ferroptosis, thereby revealing a novel strategy for enhancing anti-tumor immunity via suppression of ferroptosis.

Rapid detection of IDH mutations in gliomas by intraoperative mass spectrometry.

The development and performance of two mass spectrometry (MS) workflows for the intraoperative diagnosis of isocitrate dehydrogenase (IDH) mutations in glioma is implemented by independent teams at Mayo Clinic, Jacksonville, and Huashan Hospital, Shanghai. The infiltrative nature of gliomas makes rapid diagnosis necessary to guide the extent of surgical resection of central nervous system (CNS) tumors. The combination of tissue biopsy and MS analysis used here satisfies this requirement. The key feature of both described methods is the use of tandem MS to measure the oncometabolite 2-hydroxyglutarate (2HG) relative to endogenous glutamate (Glu) to characterize the presence of mutant tumor. The experiments i) provide IDH mutation status for individual patients and ii) demonstrate a strong correlation of 2HG signals with tumor infiltration. The measured ratio of 2HG to Glu correlates with IDH-mutant (IDH-mut) glioma (P < 0.0001) in the tumor core data of both teams. Despite using different ionization methods and different mass spectrometers, comparable performance in determining IDH mutations from core tumor biopsies was achieved with sensitivities, specificities, and accuracies all at 100%. None of the 31 patients at Mayo Clinic or the 74 patients at Huashan Hospital were misclassified when analyzing tumor core biopsies. Robustness of the methodology was evaluated by postoperative re-examination of samples. Both teams noted the presence of high concentrations of 2HG at surgical margins, supporting future use of intraoperative MS to monitor for clean surgical margins. The power of MS diagnostics is shown in resolving contradictory clinical features, e.g., in distinguishing gliosis from IDH-mut glioma.

Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.

Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.

A novel mitochondria-related core gene signature to predict the prognosis and evaluate tumour microenvironment in CESC single-cell validation.

Mitochondria and their related genes (MTRGs) are pivotal in the tumour microenvironment (TME) of cervical cancer, influencing prognosis and treatment response. This study developed a prognostic model using MTRGs to predict overall survival (OS) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), aiming for personalized therapy. Analysing 14 MTRGs like ISCU and NDUFA11 through techniques such as univariate Cox regression, we found that a low mitochondrial (MT) score is associated with better survival, while a high MT score predicts poorer outcomes. The TME score, particularly influenced by CD8 T cells, also correlates with prognosis, with a high score indicating favourable outcomes. The interplay between MT and TME subtypes revealed that the best prognosis is seen in patients with a low MT and high TME score. Our findings highlight the role of MTRGs as potential biomarkers and therapeutic targets in cervical cancer, offering a novel approach to improving patient outcomes through a more nuanced understanding of mitochondrial function and immune interactions within the TME. This model presents a promising avenue for enhancing the precision of prognostic assessments in CESC.

Upregulation of circRNA_0023685 promotes gastric cancer progression via a circRNA-miRNA-mRNA interaction network.

Circular RNAs (circRNAs) have been extensively studied for their critical roles as noncoding RNAs (ncRNAs) in gastric cancer (GC). In this study, we focused on the expression, function and molecular mechanism of circRNA_0023685 in gastric cancer (GC) to provide new ways for the diagnosis and treatment of GC. Firstly, a novel differentially expressed circRNA, circRNA_0023685, was identified, and its differential expression in GC plasma, tissue, and cell lines was further verified by RT-qPCR. Next, circRNA_0023685 was verified to promote the proliferation, migration and apoptosis of GC cells in vitro. CircRNA_0023685 was also proved to enhance the growth of GC tumors in xenograft models. Finally, for excavating the mechanism to promote GC, downstream microRNAs (miRNAs) and mRNAs were screened by bioinformatics analyses. After intersecting the target genes and genes enriched in GO analysis, a circRNA competing endogenous RNAs (ceRNAs) network was built. A protein-protein interaction (PPI) network was then constructed to find the candidate gene, APP. Our study confirmed that the highly expressed circRNA_0023685 could promote GC, which provided a new clinical diagnostic biomarker and therapeutic target for GC.

Prognostic value of fatty acid metabolism-related genes in colorectal cancer and their potential implications for immunotherapy.

Introduction: Colorectal cancer is one of the most common gastrointestinal cancers and the second leading cause of cancer-related death. Although colonoscopy screening has greatly improved the early diagnosis of colorectal cancer, its recurrence and metastasis are still significant problems. Tumour cells usually have the hallmark of metabolic reprogramming, while fatty acids play important roles in energy storage, cell membrane synthesis, and signal transduction. Many pathways of fatty acid metabolism (FAM) are involved in the occurrence and development of colon cancer, and the complex molecular interaction network contains a variety of genes encoding key enzymes and related products. Methods: Clinical information and RNA sequencing data were collected from TCGA and GEO databases. The prognosis model of colon cancer was constructed by LASSO-Cox regression analysis among the selected fatty acid metabolism genes with differential expression. Nomogram for the prognosis model was also constructed in order to analyze its value in evaluating the survival and clinical stage of the colon cancer patients. The differential expression of the selected genes was verified by qPCR and immunohistochemistry. GSEA and GSVA were used to analyze the enrichment pathways for high- and low-risk groups. CIBERSORT was used to analyze the immune microenvironment of colon cancer and to compare the infiltration of immune cells in the high- and low-risk groups. The "circlize" package was used to explore the correlation between the risk score signature and immunotherapy for colon cancer. Results: We analysed the differential expression of 704 FAM-related genes between colon tumour and normal tissue and screened 10 genes with prognostic value. Subsequently, we constructed a prognostic model for colon cancer based on eight optimal FAM genes through LASSO Cox regression analysis in the TCGA-COAD dataset, and its practicality was validated in the GSE39582 dataset. Moreover, the risk score calculated based on the prognostic model was validated as an independent prognostic factor for colon cancer patients. We further constructed a nomogram composed of the risk score signature, age and American Joint Committee on Cancer (AJCC) stage for clinical application. The colon cancer cohort was divided into high- and low-risk groups according to the optimal cut-off value, and different enrichment pathways and immune microenvironments were depicted in the groups. Discussion: Since the risk score signature was significantly correlated with the expression of immune checkpoint molecules, the prognostic model might be able to predict the immunotherapy response of colon cancer patients. In summary, our findings expand the prognostic value of FAM-related genes in colon cancer and provide evidence for their application in guiding immunotherapy.

Characterization and Expression Analysis of Genes from Megalobrama amblycephala Encoding Hemoglobins with Extracellular Microbicidal Activity.

Hemoglobin (Hb) usually comprises two α and two ß subunits, forming a tetramer responsible for oxygen transportation and storage. Few studies have elucidated fish hemoglobin immune functions. Megalobrama amblycephala is a freshwater-cultured fish prevalent in China. We identified two M. amblycephala hemoglobin subunits and analyzed their expression patterns and antibacterial activities. The respective full-length cDNA sequences of the M. amblycephala Hb α (MaHbα) and ß (MaHbß) subunits were 588 and 603 bp, encoding 143 and 148 amino acids. MaHbα and MaHbß were highly homologous to hemoglobins from other fish, displaying typical globin-like domains, most heme-binding sites, and tetramer interface regions highly conserved in teleosts. In phylogenetic analyses, the hemoglobin genes from M. amblycephala and other cypriniformes clustered into one branch, and those from other fishes and mammals clustered into other branches, revealing fish hemoglobin conservation. These M. amblycephala Hb subunits exhibit different expression patterns in various tissues and during development. MaHbα is mainly expressed in the blood and brain, while MaHbß gene expression is highest in the muscle. MaHbα expression was detectable and abundant post-fertilization, with levels fluctuating during the developmental stages. MaHbß expression began at 3 dph and gradually increased. Expression of both M. amblycephala Hb subunits was down-regulated in most examined tissues and time points post-Aeromonas hydrophila infection, which might be due to red blood cell (RBC) and hematopoietic organ damage. Synthetic MaHbα and MaHbß peptides showed excellent antimicrobial activities, which could inhibit survival and growth in five aquatic pathogens. Two M. amblycephala hemoglobin subunits were identified, and their expression patterns and antibacterial activities were analyzed, thereby providing a basis for the understanding of evolution and functions of fish hemoglobins.

Neurosurgical application of pineal region tumor resection with 3D 4K exoscopy via infratentorial approach: a retrospective cohort study.

BACKGROUND: The pineal region tumors are challenging for neurosurgeons and can lead to secondary hydrocephalus. The introduction of the exoscope has provided clinical interventions with high image quality and an ergonomic system for pineal region tumor operations. In this study, the authors describe the exoscopic approach used to facilitate the surgical resection of pineal region tumors and relieve hydrocephalus. MATERIALS AND METHODS: In this retrospective cohort study, we consecutively reviewed the clinical and radiological data of 25 patients with pineal region lesions who underwent three-dimensional exoscopic tumor resection at a single center. RESULTS: The patient cohort consisted of 16 males and 9 females, with an average age of 34.6 years (range, 6-62 years; 8 cases aged ≤18). Pathological examination confirmed eight pineal gland tumors, four gliomas, nine germ cell neoplasms, two ependymomas, and two metastatic tumors. Preoperative hydrocephalus was present in 23 patients. Prior to tumor resection, external ventricular drainage (EVD) with Ommaya reservoir implantation was performed in 17 patients. Two patients received preoperative endoscopic third ventriculostomy (ETV), and five patients received a ventriculoperitoneal (VP) shunt, including one who received both procedures. Gross total resection was achieved in 19 patients (76%) in the 'head-up' park bench position using the exoscope. Eight patients (31.6%) with third ventricle invasion received subtotal resection, mainly in glioma cases, which was higher than those without invasion (0%), but not statistically significant ( P =0.278, Fisher's exact test). No new neurological dysfunction was observed after surgery. Two patients (8%) developed intracranial and pulmonary infections, and two patients (8%) suffered from pneumothorax. Hydrocephalus was significantly relieved in all patients postoperatively, and four patients with relapse hydrocephalus were cured during the long-term follow-up. Postoperative adjuvant management was recommended for indicated patients, and a mean follow-up of 24.8±14.3 months showed a satisfied outcome. CONCLUSIONS: The exoscope is a useful tool for pineal region tumor resection and hydrocephalus relief, particularly with posterior third ventricle invasion, as total resection could be achieved without obvious complication. The special superiority of the exoscope for the indicated pineal region tumors should be highlighted.

Effect of the Dual Glucose­Dependent Insulinotropic Peptide/Gulcagon­like Peptide 1 Receptor Agonist Tirzepatide on Lipid Profile and Waist Circumference: A Systematic Review and Meta­analysis

PURPOSE: Tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide 1 receptor agonist, has been approved by the US Food and Drug Administration for the treatment of type 2 diabetes. The purpose of this meta-analysis is to evaluate the impact of tirzepatide on lipid profile and waist circumference (WC), both of which are risk factors of cardiovascular diseases. METHODS: The PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases were systematically searched for articles published from database inception to July 31, 2022. This meta-analysis included 7 randomized controlled trials with a minimum duration of 12 weeks that compared tirzepatide with placebo or other antidiabetic medications. The random-effects model was used to estimate mean differences in lipid profile and WC from baseline. The Cochrane risk-of-bias tool for randomized trials, version 2 was used to assess the outcome's risk of bias. We evaluated the evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. FINDINGS: A total of 8 articles from 7 trials with 7151 participants were included. All 3 eligible maintenance doses of tirzepatide (5, 10, and 15 mg once a week) were effective in increasing total cholesterol (TC) (P < 0.05), HDL-C (P < 0.05), VLDL-C (P < 0.01), triglyceride (TG) (P < 0.01), and WC (P < 0.01) changes from baseline compared with control agents including placebo, semaglutide, dulaglutide, and degludec. Although the evidence for VLDL-C and TGs by GRADE were high or moderate, the evidences for TC, HDL-C, and WC were low or moderate. Only 5mg once-weekly tirzepatide (P < 0.05), not 10 or 15 mg, could induce significant alteration in LDL-C before sensitivity analysis. The evidence by GRADE was moderate. IMPLICATIONS: Tirzepatide had superiority over placebo or other antidiabetic agents in controlling lipid and WC levels. However, the levels of evidence by GRADE varied greatly across different outcome indicators. Limitations of the study include evaluating secondary outcomes of original trials for the meta-analyses, not assessing the effect of baseline lipid-lowering therapy on lipid levels, and not exploring the bias induced by glycemic improvement and weight loss.

Unexpected curative effect of PD-1 inhibitor in gastric cancer with brain metastasis: A case report.

Background: Gastric cancer (GC) is the third most common cause of cancer-related death in the world. Several clinical trials have proven that the use of PD-1/PD-L1 inhibitors can improve the survival of late-stage GC patients and is suggested in NCCN and CSCO guidelines. However, the correlation between PD-L1 expression and the response to PD-1/PD-L1 inhibitors is still controversial. GC rarely develops brain metastasis (BrM) and currently there is no therapeutic protocol for GC BrMs. Case presentation: We report a case of a 46-year-old male suffering from GC with PD-L1 negative BrMs 12 years after GC resection and 5 cycles of chemotherapy. We treated the patient with the immune checkpoint inhibitor (ICI) pembrolizumab and all metastatic tumors achieved a complete response (CR). A durable remission of the tumors is confirmed after 4 years of follow-up. Conclusion: We shared a rare case with PD-L1 negative GC BrM responsive to PD-1/PD-L1 inhibitors, the mechanism of which is still unclear. The protocol of therapeutic choice for late-stage GC with BrM is urgently needed. And we are expecting biomarkers other than PD-L1 expressions to predict the efficacy of ICI treatment.

Pazopanib Is a Potential Treatment for Coronavirus-Induced Lung Injuries.

Severe acute respiratory syndrome coronavirus 2, responsible for the severe acute respiratory syndrome known as COVID-19, has rapidly spread in almost every country and devastated the global economy and health care system. Lung injury is an early disease manifestation believed to be a major contributor to short- and long-term pathological consequences of COVID-19, and thus drug discovery aiming to ameliorate lung injury could be a potential strategy to treat COVID-19 patients. By inducing a severe acute respiratory syndrome-like pulmonary disease model through infecting A/J mice with murine hepatitis virus strain 1 (MHV-1), we show that i.v. administration of pazopanib ameliorates acute lung injuries without affecting MHV-1 replication. Pazopanib reduces cell apoptosis in MHV-1-infected lungs. Furthermore, we also identified that pazopanib has to be given no later than 48 h after the virus infection without compromising the therapeutic effect. Our study provides a potential treatment for coronavirus-induced lung injuries and support for further evaluation of pazopanib in COVID-19 patients.

Deglycosylated EpCAM regulates proliferation by enhancing autophagy of breast cancer cells via PI3K/Akt/mTOR pathway.

Autophagy is an important regulator of cellular homeostasis and its dysregulation often results in cancer. Aberrant glycosylation induced by oncogenic transformation contributes to tumor invasion and metastasis. In a previous study, we have demonstrated that EpCAM, a glycosylation protein, is associated with cell growth and metastasis in breast cancer. But the effect of EpCAM glycosylation on autophagy is not clear. the precise mechanism of regulation remains largely unknown. In this study, breast cancer cells were transfected with N-glycosylation mutation EpCAM plasmid to express deglycosylated EpCAM. The result showed that deglycosylated EpCAM promoted autophagy in breast cancer cells. We further confirmed this conclusion with the activator (Rapamycin, RAP) and inhibitor (Wortmannin) of autophagy. We also found that deglycosylated EpCAM promoted apoptosis and inhibited proliferation through activating autophagy by suppressing Akt/mTOR signaling pathway in breast cancer cells. These findings represent a novel mechanism by which deglycosylated EpCAM inhibits proliferation by enhancing autophagy of breast cancer cells via PI3K/Akt/mTOR pathway. In conclusion, the combination of autophagy modulation and EpCAM targeted therapy is a promising therapeutic strategy in the treatment of breast cancer.

Knockdown of TRIM11 suppresses cell progression and apoptosis of cervical cancer cells via PI3K/AKT pathway.

OBJECTIVE: To detect the expression pattern of TRIM11 in CC and to investigate the effect of TRIM11 knockdown on CC progression. METHODS: First, the expression pattern and function of TRIM11 in CC were inferred by GEPIA database. The expression of TRIM11 in CC tissues and cells was verified by RT-qPCR and Western blot assays. TRIM11 shRNA was transfected into CC cells. The effect of TRIM11 knockdown on CC cell proliferation and cell apoptosis was assessed by CCK-8 assay, clone formation test and flow cytometry (FCM). Furthermore, the effect of TRIM11 knockdown on cell migration and invasion was measured by Transwell assay. The apoptosis-related proteins (Bax, Bcl-2 and Cleaved caspase 3) and PI3K/AKT pathway-related proteins (PI3K, p-PI3K, AKT and p-Akt) were examined by Western blot assay. RESULTS: TRIM11 was found to be dramatically upregulated in CC tissues and cells. Besides this, TRIM11 was closely related to FIGO stage, infiltration depth and metastasis. Moreover, high expression of TRIM11 was found to be associated with poor prognosis of CC patients. Functional experiments showed that knockdown of TRIM11 obviously suppressed CC cell proliferation, migration and invasion, while accelerated cell apoptosis. In addition, the PI3K inhibitor (LY294002) was used to assess the connection between PI3K/AKT pathway and TRIM11 in CC cells. We found that TRIM11 overexpression suppressed the phosphorylation of PI3K and AKT in CC cells. CONCLUSION: Hence, TRIM11 regulates CC cell progression by modulating PI3K/AKT pathway. The results suggested that TRIM11 might be a possible target for the diagnosis and prognosis of CC patients.

Chinese Medicine Leptochloa chinensis Inhibits the Malignant Behaviors of Renal Cell Carcinoma 786-O Cells by Regulating the mTOR Pathway.

BACKGROUND: Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system that seriously threatens human life and health. This study aims to explore the role of the traditional Chinese medicine Leptochloa chinensis in the pathogenesis of RCC. Meanwhile, this study also revealed the molecular biological mechanism of its antitumor activity. METHODS: Human RCC 786-O cells were cultured in the RPMI-1640 medium, which contains different concentrations of Leptochloa chinensis (1,000, 3,000, and 9,000 µg/ml). MTT and flow cytometry assays were used to detect the viability of 786-O cells. Transwell and wound healing assays were used to detect cell metastasis. The protein expression was observed by western blot analysis. RESULTS: Leptochloa can inhibit cell proliferation and induce apoptosis in RCC 786-O cells. In addition, Leptochloa can weaken the migration and invasion of 786-O cells. More importantly, Leptochloa can block the mTOR pathway by inhibiting the protein expression of p-mTOR. Moreover, the high concentration of Leptochloa chinensis has a better inhibitory effect on 786-O cells. CONCLUSION: The traditional Chinese medicine Leptochloa chinensis inhibits the viability and metastasis of 786-O cells by blocking the mTOR pathway.

Hierarchical Core-Shell Structure of 2D VS2@VC@N-Doped Carbon Sheets Decorated by Ultrafine Pd Nanoparticles: Assembled in a 3D Rosette-like Array on Carbon Fiber Microelectrode for Electrochemical Sensing.

The development of two-dimensional (2D) nanohybrid materials with heterogeneous components in nanoscale and three-dimensional (3D) well-ordered assembly in microscale has been regarded as an effective way to improve their overall performances by the synergistic coupling of the optimized structure and composition. In this work, we reported the design and synthesis of a new type of hierarchically core-shell structure of 2D VS2@VC@N-doped carbon (NC) sheets decorated by ultrafine Pd nanoparticles (PdNPs), which were vertically grown on carbon fiber (CF) and assembled into a unique 3D rosette-like array. The resultant VS2@VC@NC-PdNPs modified CF microelectrode integrated the structural and electrochemical properties of the heterogeneous hybridization of core-shell VS2@VC@NC-PdNPs sheets with a unique rosette-like array structure, and gave rise to a significant improvement in terms of electron transfer ability, electrocatalytic activity, stability, and biocompatibility. Under the optimized conditions, the VS2@VC@NC-PdNPs modified CF microelectrode demonstrated excellent electrochemical sensing performance towards biomarker hydrogen peroxide (H2O2) including a high sensitivity of 152.7 µA cm-2 mM-1, a low detection limit of 50 nM (a signal-to-noise ratio of 3:1), as well as good reproducibility and anti-interference ability, which could be used for the real-time in situ electrochemical detection of H2O2 in live cancer cells and cancer tissue. The remarkable performances of the proposed nanohybrid microelectrode will have a profound impact on the design of diverse 2D layered materials as a promising candidate for electrochemical biosensing applications.

PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome.

The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase-1 and drive the maturation of proinflammatory cytokines IL-1ß and IL-18. NLRP3 inflammasome activity must be tightly controlled, as its over-activation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo-like kinase 4 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA-mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3-associated inflammatory diseases.

In situ growth of Fe(ii)-MOF-74 nanoarrays on nickel foam as an efficient electrocatalytic electrode for water oxidation: a mechanistic study on valence engineering.

In this work, our theoretical results first demonstrate that varying the metal valence in MOFs plays a significant role in tuning their stable intrinsic electronic structure. Different valence Fe(ii) and Fe(iii) based pristine MOF-74 nanoarrays on nickel foam are further synthesized as electrodes for highly efficient electrocatalytic water oxidation.

Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc.

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity, but the underlying molecular mechanisms remain incompletely understood. In this study, Sin1, a key component of mTOR complex 2 (mTORC2), specifically regulates B cell growth and metabolism. Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism. Sin1 deficiency also severely impairs B-cell proliferation, antibody responses, and anti-viral immunity. At the molecular level, Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2, respectively. Therefore, our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.