The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome.

Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.

Regulatory mucosa-associated invariant T cells controlled by ß1 adrenergic receptor signaling contribute to hepatocellular carcinoma progression.

BACKGROUND AND AIMS: The innate-like mucosa-associated invariant T (MAIT) cells are enriched in human liver and have been linked to human HCC. However, their contributions to the progression of HCC are controversial due to the heterogeneity of MAIT cells, and new MAIT cell subsets remain to be explored. APPROACH AND RESULTS: Combining single cell RNA sequencing (scRNA-seq) and flow cytometry analysis, we performed phenotypic and functional studies and found that FOXP3 + CXCR3 + MAIT cells in HCC patients were regulatory MAIT cells (MAITregs) with high immunosuppressive potential. These MAITregs were induced under Treg-inducing condition and predominantly from FOXP3 - CXCR3 + MAIT cells, which displayed mild Treg-related features and represented a pre-MAITreg reservoir. In addition, the induction and function of MAITregs were promoted by ß1 adrenergic receptor signaling in pre-MAITregs and MAITregs, respectively. In HCC patients, high proportion of the intratumoral MAITregs inhibited antitumor immune responses and was associated with poor clinical outcomes. CONCLUSIONS: Together, we reveal an immunosuppressive subset of MAIT cells in HCC patients that contributes to HCC progression, and propose a control through neuroimmune crosstalk.

IL-4-secreting CD40L+ MAIT cells support antibody production in the peripheral blood of Heonch-Schönlein purpura patients.

OBJECTIVE: Here, we explored the phenotype and function of MAIT cells in the peripheral blood of patients with HSP. METHODS: Blood samples from HSP patients and HDs were assessed by flow cytometry and single-cell RNA sequencing to analyze the proportion, phenotype, and function of MAIT cells. Th-cytokines in the serum of HSP patients were analyzed by CBA. IgA in cocultured supernatant was detected by CBA to analyze antibody production by B cells. RESULTS: The percentage of MAIT cells in HSP patients was significantly reduced compared with that in HDs. Genes related to T cell activation and effector were up-regulated in HSP MAIT cells, indicating a more activated phenotype. In addition, HSP MAIT cells displayed a Th2-like profile with the capacity to produce more IL-4 and IL-5, and IL-4 was correlated with IgA levels in the serum of HSP patients. Furthermore, CD40L was up-regulated in HSP MAIT cells, and CD40L+ MAIT cells showed an increased ability to produce IL-4 and to enhance IgA production by B cells. CONCLUSION: Our data demonstrate that MAIT cells in HSP patients exhibit an activated phenotype. The enhanced IL-4 production and CD40L expression of MAIT cells in HSP patients could take part in the pathogenesis of HSP.

Construction of Uniform LiF Coating Layers for Stable High-Voltage LiCoO2 Cathodes in Lithium-Ion Batteries.

Stabilizing LiCoO2 (LCO) at 4.5 V rather than the common 4.2 V is important for the high specific capacity. In this study, we developed a simple and efficient way to improve the stability of LiCoO2 at high voltages. After a simple sol-gel method, we introduced trifluoroacetic acid (TA) to the surface of LCO via an afterwards calcination. Meanwhile, the TA reacted with residual lithium on the surface of LCO, further leading to the formation of uniform LiF nanoshells. The LiF nanoshells could effectively restrict the interfacial side reaction, hinder the transition metal dissolution and thus achieve a stable cathode-electrolyte interface at high working-voltages. As a result, the LCO@LiF demonstrated a much superior cycling stability with a capacity retention ratio of 83.54% after 100 cycles compared with the bare ones (43.3% for capacity retention), as well as high rate performances. Notably, LiF coating layers endow LCO with excellent high-temperature performances and outstanding full-cell performances. This work provides a simple and effective way to prepare stable LCO materials working at a high voltage.

Therapeutic strategies and predictive models for Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma in adults based on data of two Chinese medical centers.

OBJECTIVE: This study aims to establish an effective predictive model for predicting Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma (TFE3-RCC) and develop optimal therapeutic strategies. METHODS: Data from 4961 patients diagnosed with renal cell carcinoma at two medical centers in China were retrospectively analyzed. A cohort of 1571 patients from Zhejiang Provincial People's Hospital (Ra cohort) was selected to construct the model. Another cohort of 1124 patients from the Second Affiliated Hospital of Zhejiang Chinese Medical University was used for external validation (the Ha cohort). All patients with TFE3-RCC in both cohorts were included in the Ta cohort for the prognostic analysis. Univariate and multivariate binary logistic regression analyses were performed to identify independent predictors of the predictive nomogram. The apparent performance of the model was validated. Decision curve analysis was also performed to assess the clinical utility of the developed model. Factors associated with progression and prognosis in the Ta cohort were analyzed using the log-rank method, and Cox regression analysis and Kaplan-Meier survival curves were used to describe the effects of factors on prognosis and progression. RESULTS: Univariate and multivariate logistic regression analyses demonstrated that age, sex, BMI, smoking, eosinophils, and LDL were independent predictors of TFE3-RCC. Therefore, a predictive nomogram for TFE3-RCC, which had good discriminatory power (AUC = 0.796), was constructed. External validation (AUC = 0.806) also revealed good predictive ability. The calibration curves displayed good consistency between the predicted and observed incidences of TFE3-RCC. Invasion of regional lymph nodes, tyrosine kinase inhibitors, and surgical methods were independent factors associated with progression. Tyrosine kinase inhibitors are independent prognostic factors. CONCLUSION: This study not only proposed a high-precision clinical prediction model composed of various variables for the early diagnosis of Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma but also optimized therapeutic strategies through prognostic analysis.

HERD-1 mediates multiphase condensate immiscibility to regulate small RNA-driven transgenerational epigenetic inheritance.

Biomolecular condensates, such as the nucleolus, stress granules/processing bodies and germ granules, are multiphase assemblages whose formation mechanisms and significance remain poorly understood. Here we identify protein constituents of the spatiotemporally ordered P, Z and M multiphase condensates in Caenorhabditis elegans germ granules using optimized TurboID-mediated proximity biotin labelling. These include 462, 41 and 86 proteins localizing to P, Z and M condensates, respectively, of which 522 were previously unknown protein constituents. Each condensate's proteins are enriched for distinct classes of structured and intrinsically disordered domains, suggesting divergent functions and assembly mechanisms. Through a functional screen, we identify a germ granule protein, HERD-1, which prevents the mixing of P, Z and M condensates. Mixing in herd-1 mutants correlates with disorganization of germline small RNA pathways and prolonged epigenetic inheritance of RNA interference-induced gene silencing. Forced mixing of these condensate components using a nanobody with specific binding activity against green fluorescent protein also extends epigenetic inheritance. We propose that active maintenance of germ granule immiscibility helps to organize and regulate small RNA-driven transgenerational epigenetic inheritance in C. elegans.

Motility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function.

Dysfunction of invariant natural killer T (iNKT) cells contributes to immune resistance of tumors. Most mechanistic studies focus on their static functional status before or after activation, not considering motility as an important characteristic for antigen scanning and thus anti-tumor capability. Here we show via intravital imaging, that impaired motility of iNKT cells and their exclusion from tumors both contribute to the diminished anti-tumor iNKT cell response. Mechanistically, CD1d, expressed on macrophages, interferes with tumor infiltration of iNKT cells and iNKT-DC interactions but does not influence their intratumoral motility. VCAM1, expressed by cancer cells, restricts iNKT cell motility and inhibits their antigen scanning and activation by DCs via reducing CDC42 expression. Blocking VCAM1-CD49d signaling improves motility and activation of intratumoral iNKT cells, and consequently augments their anti-tumor function. Interference with macrophage-iNKT cell interactions further enhances the anti-tumor capability of iNKT cells. Thus, our findings provide a direction to enhance the efficacy of iNKT cell-based immunotherapy via motility regulation.

Retrospective analysis of robot-assisted laparoscopic transabdominal anterior approach for the treatment of lumbar paravertebral schwannoma.

BACKGROUND: The main objective of this study was to investigate the impact of robot-assisted laparoscopic resection on paravertebral tumours using the anterior peritoneal approach. METHODS: A retrospective analysis to identify patients with paravertebral tumours. A total of 21 patients, who underwent robot-assisted laparoscopic transabdominal anterior approach surgery from March 2012 to August 2020. RESULTS: The median operation time was 66.2 ± 14.5 min, with a range of 0-100 min. Intraoperative blood loss was minimal, with a median of 11.4 ± 7.9 mL and a range of 5-30 mL. The median tumour length was 4.8 ± 2.3 cm, ranging from 2.1 to 11.3 cm. Postoperative hospitalisation lasted for a median of 3.2 ± 0.9 days. During the 48-month follow-up period, no tumour recurrence or residual was observed in any patient. CONCLUSIONS: Robot-assisted laparoscopic resection of lumbar paravertebral schwannoma proved to be a safe and viable surgical approach. It offers a relatively new treatment option for paraspinal schwannoma.

Petal-like Mn-doped α-Ni(OH)2 nanosheets for high-performance Li-S cathode material.

Lithium-sulphur (Li-S) batteries are high-energy-density and cost-effective batteries. Herein, petal-like Ni1-x Mn x (OH)2 (x ≈ 0.04) nanosheets were synthesised using a hydrothermal method and the electrical conductivity of Ni(OH)2 was improved by applying the cathode functional materials in Li-S batteries. With up to 5 mg cm-2 of S content in the cathode, the fabricated Ni1-x Mn x (OH)2 electrode exhibited specific discharge capacities up to 1375 and 1150 mA h g-1 at 0.2 and 0.5C, and retained this capacity at 813 and 714 mA h g-1 after 200 cycles, respectively. Electrochemical measurement results show that Ni1-x Mn x (OH)2 plays a critical role in Li-S batteries as it has a larger specific surface area than Ni(OH)2, which has superior adsorption performance toward lithium polysulphides. Moreover, the conductivity performance of Ni1-x Mn x (OH)2 is significantly better than that of Ni(OH)2, which improves the electrochemical reaction kinetics of the Li-S batteries.

Clinicopathological and prognostic significance of Ephrin A3 in bladder urothelial carcinoma.

Ephrin A3 (EFNA3) is a member of the Eph/ephrin tyrosine kinase family, which is associated with multiple signaling pathways involved in cell growth and tumor cell metastasis. Aberrant regulation of EFNA3 is associated with the occurrence and development of various types of cancer. However, despite the high incidence of EFNA3 upregulation in cancer, studies concerning EFNA3 in urothelial carcinoma have not, to the best of our knowledge, been conducted. In the present study, bioinformatics analyses using data from multiple online databases were performed to confirm the upregulation of EFNA3 in bladder cancer. The co-expression gene set of EFNA3 and enriched signaling pathways were also analyzed. In addition, immunohistochemistry was conducted to detect EFNA3 expression in 491 clinically confirmed bladder urothelial carcinoma samples and 80 non-cancerous bladder tissues. Kaplan-Meier survival analysis, binary logistic regression analysis, and Cox regression analysis were conducted to confirm the validity of EFNA3 in predicting patient prognosis and its significance in clinical pathology. Statistical analysis demonstrated a significant association between EFNA3 expression levels with tumor size, lymph node metastasis, distant metastasis, and pathological grade. In conclusion, high EFNA3 expression may be a potential biomarker that indicates bladder tumor occurrence and patient prognosis.

[Influence of short-term weight intervention on glycolipid metabolism of patients with type II diabetes].

OBJECTIVE: To explore how health management of short-term weight intervention affects glycolipid metabolism of patients with type II diabetes. METHODS: Overweight or obese type II diabetes mellitus patients were under weight intervention for 45 days with health management model and the epidemiologic method of self control. RESULTS: Compared with before intervention, the levels of both fasting blood-glucose (FBG) and blood-glucose 2 hours after meal, weight, BMI, waistline, hip circumference and upper arm circumference of the patients after intervention lowered significantly (P < 0.05), levels of serum TC, HDL-C, LDL-C increased obviously (P < 0.05), and TG levels did not change significantly. CONCLUSIONS: Due to the particularity of their blood lipid metabolism mentioned above, when carrying out health management of short-term weight intervention on patients with type II diabetes.

A multi-magneto-inductive sensor array system for real-time magnetic field imaging of ferromagnetic targets.

In this Note, we develop a real-time magnetic field imaging system by employing a multi-magneto-inductive (MI) sensor array. The sensor array consists of 3 × 3 tri-axial MI sensors, which we constructed by using three sensor coils. Outputs from several rows of sensors are routed to a master-controller responsible for data pre-processing and data reconstruction. The data are streamed to a host computer via a universal serial bus interface, and the image can be generated and displayed at a rate of several frames per second. The magnetic field imaging is implemented on a knowledge of the MI sensors' response, magnetic field perturbations, and the nature of the ferromagnetic object respecting permeability and conductivity. The performance of the system has been further evaluated by extensive numerical modeling of magnetic field distribution patterns with partial differential equation solution. The proposed magnetic field imaging system can be employed in many potential applications, for instance, medicine, security screening, quality assurance, and other areas of nondestructive evaluation, designs associated with magnetic fields, teaching, and research.

A modular magneto-inductive sensor for low vector magnetic field measurements.

The low magnetic field measurement has been utilized since ancient times in order to find economic resources, to detect magnetic anomalies, etc. In this case, the vector magnetic survey can simultaneously obtain the modulus and direction information of the magnetic field, which can contribute to obtaining more precise information and characteristics of magnetic field resources. This paper is concerned with the potential to exploit the signals of vector magnetic field measurement with a magneto-inductive (MI) sensor. To evaluate the capability of the MI sensor, a test platform is set up and its performance, including the noise floor, the resolution, and the sensitivity, is comprehensively characterized. Furthermore, a comparative geomagnetic observation and magnetic anomaly detection among the proposed MI sensor, a high-precision Overhauser sensor, and a commonly used and accepted commercial MI sensor are conducted. The experimental results identify the capability of the proposed MI sensor in weak magnetic detection.

Promoted Deposition of Three-Dimensional Li2S on Catalytic Co Phthalocyanine Nanorods for Stable High-Loading Lithium-Sulfur Batteries.

The sulfur redox in Li-S batteries involves a complex sequence of solid-liquid-solid conversions, and reaction catalysis has recently become a focused area for further advancement. The deposition of solid Li2S from liquid Li2S4 contributes to three-quarters of the total theoretical capacity and is therefore of great significance over the entire cathode reaction. This study demonstrates a cathode material composed of carbon nanofibers decorated with catalytic Co phthalocyanine nanorods (CoPc@CNF), which are highly effective in promoting the deposition of Li2S in three-dimensional (3D) fine particles rather than 2D thin films. This significantly alleviates cathode passivation during cell charge and discharge, leading to obviously improved sulfur utilization and cycling stability for high loading cathodes. DFT calculations indicate that the promoted 3D deposition of Li2S is related to the facilitated migration of deposition precursors (Li2S4 and Li-ions) to migrate on the CoPc nanorods. Lithium-sulfur (Li-S) pouch cells were prepared with high specific (954 mAh g-1), areal (4.8 mAh cm-2), and total (235 mAh) capacities achieved at 0.5 C under high sulfur content. As metal phthalocyanines possess a high structural variability, this study provides opportunities to the design of a new class of Li-S cathode materials.

[Correlations of trace elements, glucose and body compositions in type 2 diabetics].

OBJECTIVE: To evaluate the difference in trace elements between diabetic and control groups, and to explore the correlations between trace elements and serum glucose, body compositions in patients with type 2 diabetes mellitus. METHODS: 72 diabetics and 64 controls are selected randomly. The level of serum trace elements, the ratio of copper, zinc were measured and compared between the two groups. A correlation was conducted for the serum trace elements, serum glucose and body compositions and 64 controls are selected randomly. RESULTS: There was a very significant difference in some serum trace elements level between diabetic and control groups (P < 0.01). Serum zinc, selenium,chromium were significantly lower in diabetic group compared with the control group (P < 0.01), copper was significantly higher (P < 0.01). Negative correlations were showed between zinc and serum glucose, manganese and the content of protein, the content of trace elements, hip circumference. And positive correlations were showed between copper and serum glucose, copper and waist circumference. CONCLUSION: It is concluded that there is trace elements metabolism disorder in patients with type 2 diabetes mellitus. The correction for this disorder might have significant value for the treatment of diabetics and prevention of complications.

Prior administration of vitamin K2 improves the therapeutic effects of zoledronic acid in ovariectomized rats by antagonizing zoledronic acid-induced inhibition of osteoblasts proliferation and mineralization.

Zoledronic acid (ZA) exerts complex influence on bone by suppressing bone resorption, mostly due to the direct osteoclasts inhibition and uncertain influence on osteoblasts. Vitamin K2 (VK2, Menaquinone-4) as an anabolic agent stimulates bone formation via anti-apoptosis in osteoblasts and mild osteoclasts inhibition. Based on these knowledge, the therapeutic effect of the combined or sequential therapy of VK2 and ZA depends on the influence on the osteoblasts, since both cases exert similar inhibitory effect on osteoclasts. In a series of in vitro studies, we confirmed the protective effect of VK2 in osteoblasts culture, especially when followed by exposure to ZA, and the proliferation and mineralization inhibition induced by ZA towards osteoblasts. For mechanism study, expression of bcl-2/bax, Runx2 and Sost in cells were examined. For in vivo studies, an osteoporosis animal model was established in rats via ovariectomy (OVX) and subjected to sequential treatment, namely VK2 followed by ZA. Bone mineral density (BMD) was measured by Dual energy X-ray absorptionmetry (DEXA), morphology and mechanical parameters by micro-computed tomography (micro-CT), mechanical strength by an electro-hydraulic fatigue-testing machine. The bone calcium, hydroxyproline content, blood lipids were evaluated using microplate technique, and the bone surface turnover was evaluated using the fluorescence in corporation method. It was found that VK2 pretreatment partially prevented the inhibition of bone formation caused by ZA, which was reflected by indices like BMD, bone calcium content and bone strength. The underling mechanisms for protection of VK2 pretreatment, mainly demonstrated via in vitro studies, included inhibiting apoptosis and depressing Sost expression in osteoblasts, which in turn improved the osteoporosis therapeutic effects of ZA. These findings suggested that pretreatment with VK2 before ZA therapy might serve a new long-term therapy protocol for osteoporosis.

Dietary cholesterol interacts with SREBF1 to modulate obesity in Chinese children.

SCOPE: Sterol regulatory element binding protein 1 gene (SREBF1) is an important candidate gene for obesity that could be affected by cholesterol. Different SREBF1 gene variants may have distinct responses to cholesterol, leading to different risks for obesity and obesity-related metabolic traits. Thus, we performed a gene-by-diet correlation analysis to test whether SREBF1 gene variation modulate the relationship between cholesterol and obesity. METHODS AND RESULTS: A total of 642 school-aged children in Jinan, China, were selected by stratified cluster nested sampling. Anthropometric and biochemical measurements, as well as genotyping of tag single nucleotide polymorphisms (SNPs) of SREBF1, were performed in this sample. Nutritional intake assessments were completed using a 24-h dietary recall for three consecutive days. Multilevel mixed-effects linear regression was used to test interactions between SREBF1 SNPs and cholesterol intakes for obesity. Results showed that SREBF1 rs2236513/rs2297508/rs4925119 strongly modulated the relationship between cholesterol intake and serum LDL-cholesterol/total cholesterol levels (p < 0.001). While SREBF1 rs4925118 modulated the relationship between cholesterol intake and homeostasis model assessment of insulin resistance related characteristics (p < 0.05). CONCLUSION: These results suggest that cholesterol intake recommendation may need to account for SREBF1 variation.

[Study of anti-atherosclerosic effect of grape seed extract and its mechanism].

In order to observe the anti-atherosclerosic effect of the grape seed extract and its mechanism, the 50C57/6J mice are divided randomly into 5 group (normal control group, hyperlipidemia model group, low and high grape seed extract groups(0.2 mg/gBW, 0.6 mg/gBW), and drug control group(0.2 mg/gBW). After twenty-one weeks, plasma oxidized low density lipoprotein (OX-LDL), serum nitric oxide (NO) and intercellular adhesion molecule-1 (ICAM-1) are measured and the form of aortic valves are observed pathologically. The results show that the levels of plasma OX-LDL, and ICAM-1 are significantly lower in grape seed extract group than those in model group while the levels of NO are higher in grape seed extract group than that in model group (P < 0.01). The thickness of aortic valves consisting of foam cell and endothelium hyperplasia in grape seed extract group is lighter than that of model group. The results indicate that the grape seed extract has inhibitary effect on atherosclerosis in C57BL/6J mice, and the possible mechanism may be related to inhibition of the increase of OX-LDL, and ICAM-1, reduction of the damage of vascular endothelium and protection of the function of vascular endothelium.