NLRP4E regulates actin cap formation through SRC and CDC42 during oocyte meiosis.

BACKGROUND: Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown. METHODS: Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E. RESULTS: NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form. CONCLUSIONS: NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.

Serum brain-derived neurotrophic factor levels in type 2 diabetes mellitus patients and its association with cognitive impairment: A meta-analysis.

OBJECTIVE: To compare the serum levels of brain-derived neurotrophic factor (BDNF) in type 2 diabetes mellitus (T2DM) patients with healthy controls (HC) and evaluate the BDNF levels in T2DM patients with/without cognitive impairment. METHODS: PubMed, EMBASE, and the Cochrane Library databases were searched for the published English literature on BDNF in T2DM patients from inception to December 2022. The BDNF data in the T2DM and HC groups were extracted, and the study quality was evaluated using the Agency for Healthcare Research and Quality. A meta-analysis of the pooled data was conducted using Review Manager 5.3 and Stata 12.0 software. RESULTS: A total of 18 English articles fulfilled with inclusion criteria. The standard mean difference of the serum BDNF level was significantly lower in T2DM than that in the HC group (SMD: -2.04, z = 11.19, P <0.001). Besides, T2DM cognitive impairment group had a slightly lower serum BDNF level compared to the non-cognitive impairment group (SMD: -2.59, z = 1.87, P = 0.06). CONCLUSION: BDNF might be involved in the neuropathophysiology of cerebral damage in T2DM, especially cognitive impairment in T2DM.

Development of a machine learning model and nomogram to predict seizures in children with COVID-19: a two-center study.

OBJECTIVE: This study aimed to use machine learning to evaluate the risk factors of seizures and develop a model and nomogram to predict seizures in children with coronavirus disease 2019 (COVID-19). MATERIAL AND METHODS: A total of 519 children with COVID-19 were assessed to develop predictive models using machine learning algorithms, including extreme gradient boosting (XGBoost), random forest (RF) and logistic regression (LR). The performance of the models was assessed using area under the receiver operating characteristic curve (AUC) values. Importance matrix plot and SHapley Additive exPlanations (SHAP) values were calculated to evaluate feature importance and to show the visualization results. The nomogram and clinical impact curve were used to validate the final model. RESULTS: Two hundred and seventeen children with COVID-19 had seizures. According to the AUC, the RF model performed the best. Based on the SHAP values, the top three most important variables in the RF model were neutrophil percentage, cough and fever duration. The nomogram and clinical impact curve also verified that the RF model possessed significant predictive value. CONCLUSIONS: Our research indicates that the RF model demonstrates excellent performance in predicting seizures, and our novel nomogram can facilitate clinical decision-making and potentially offer benefit for clinicians to prevent and treat seizures in children with COVID-19.

Two-Layer Edge Intelligence for Task Offloading and Computing Capacity Allocation with UAV Assistance in Vehicular Networks.

With the exponential growth of wireless devices and the demand for real-time processing, traditional server architectures face challenges in meeting the ever-increasing computational requirements. This paper proposes a collaborative edge computing framework to offload and process tasks efficiently in such environments. By equipping a moving unmanned aerial vehicle (UAV) as the mobile edge computing (MEC) server, the proposed architecture aims to release the burden on roadside units (RSUs) servers. Specifically, we propose a two-layer edge intelligence scheme to allocate network computing resources. The first layer intelligently offloads and allocates tasks generated by wireless devices in the vehicular system, and the second layer utilizes the partially observable stochastic game (POSG), solved by duelling deep Q-learning, to allocate the computing resources of each processing node (PN) to different tasks. Meanwhile, we propose a weighted position optimization algorithm for the UAV movement in the system to facilitate task offloading and task processing. Simulation results demonstrate the improved performance by applying the proposed scheme.

Multimodal data integration for predicting progression risk in castration-resistant prostate cancer using deep learning: a multicenter retrospective study.

Purpose: Patients with advanced prostate cancer (PCa) often develop castration-resistant PCa (CRPC) with poor prognosis. Prognostic information obtained from multiparametric magnetic resonance imaging (mpMRI) and histopathology specimens can be effectively utilized through artificial intelligence (AI) techniques. The objective of this study is to construct an AI-based CRPC progress prediction model by integrating multimodal data. Methods and materials: Data from 399 patients diagnosed with PCa at three medical centers between January 2018 and January 2021 were collected retrospectively. We delineated regions of interest (ROIs) from 3 MRI sequences viz, T2WI, DWI, and ADC and utilized a cropping tool to extract the largest section of each ROI. We selected representative pathological hematoxylin and eosin (H&E) slides for deep-learning model training. A joint combined model nomogram was constructed. ROC curves and calibration curves were plotted to assess the predictive performance and goodness of fit of the model. We generated decision curve analysis (DCA) curves and Kaplan-Meier (KM) survival curves to evaluate the clinical net benefit of the model and its association with progression-free survival (PFS). Results: The AUC of the machine learning (ML) model was 0.755. The best deep learning (DL) model for radiomics and pathomics was the ResNet-50 model, with an AUC of 0.768 and 0.752, respectively. The nomogram graph showed that DL model contributed the most, and the AUC for the combined model was 0.86. The calibration curves and DCA indicate that the combined model had a good calibration ability and net clinical benefit. The KM curve indicated that the model integrating multimodal data can guide patient prognosis and management strategies. Conclusion: The integration of multimodal data effectively improves the prediction of risk for the progression of PCa to CRPC.

Development of a CT-based radiomics-clinical model to diagnose acute pancreatitis on nonobvious findings on CT in children with pancreaticobiliary maljunction.

OBJECTIVES: Since neither abdominal pain nor pancreatic enzyme elevation is specific for acute pancreatitis (AP), the diagnosis of AP in patients with pancreaticobiliary maljunction (PBM) may be challenging when the pancreas appears normal or nonobvious on CT. This study aimed to develop a quantitative radiomics-based nomogram of pancreatic CT for identifying AP in children with PBM who have nonobvious findings on CT. METHODS: PBM patients with a diagnosis of AP evaluated at the Children's Hospital of Soochow University from June 2015 to October 2022 were retrospectively reviewed. The radiological features and clinical factors associated with AP were evaluated. Based on the selected variables, multivariate logistic regression was used to construct clinical, radiomics, and combined models. RESULTS: Two clinical parameters and 6 radiomics characteristics were chosen based on their significant association with AP, as demonstrated in the training (area under curve [AUC]: 0.767, 0.892) and validation (AUC: 0.757, 0.836) datasets. The radiomics-clinical nomogram demonstrated superior performance in both the training (AUC, 0.938) and validation (AUC, 0.864) datasets, exhibiting satisfactory calibration (P > .05). CONCLUSIONS: Our radiomics-based nomogram is an accurate, noninvasive diagnostic technique that can identify AP in children with PBM even when CT presentation is not obvious. ADVANCES IN KNOWLEDGE: This study extracted imaging features of nonobvious pancreatitis. Then it developed and evaluated a combined model with these features.

Multi-Algorithm Analysis Reveals Pyroptosis-Linked Genes as Pancreatic Cancer Biomarkers.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at late stages, limiting treatment options and survival rates. Pyroptosis-related gene signatures hold promise as PDAC prognostic markers, but limited gene pools and small sample sizes hinder their utility. We aimed to enhance PDAC prognosis with a comprehensive multi-algorithm analysis. Using R, we employed natural language processing and latent Dirichlet allocation on PubMed publications to identify pyroptosis-related genes. We collected PDAC transcriptome data (n = 1273) from various databases, conducted a meta-analysis, and performed differential gene expression analysis on tumour and non-cancerous tissues. Cox and LASSO algorithms were used for survival modelling, resulting in a pyroptosis-related gene expression-based prognostic index. Laboratory and external validations were conducted. Bibliometric analysis revealed that pyroptosis publications focus on signalling pathways, disease correlation, and prognosis. We identified 357 pyroptosis-related genes, validating the significance of BHLHE40, IL18, BIRC3, and APOL1. Elevated expression of these genes strongly correlated with poor PDAC prognosis and guided treatment strategies. Our accessible nomogram model aids in PDAC prognosis and treatment decisions. We established an improved gene signature for pyroptosis-related genes, offering a novel model and nomogram for enhanced PDAC prognosis.

Long-term tadalafil once daily in Chinese men with erectile dysfunction: a 2-year final analysis of a post-marketing, multicenter, randomized, open-label trial.

The long-term safety and effectiveness of once-daily tadalafil is crucial, but limited data are available in Chinese patients with erectile dysfunction (ED). In this post-marketing, multicenter, randomized, open-label trial with 2-year follow-up, 635 ED cases were randomized to receive daily oral tadalafil 2.5 mg or 5 mg for 3 months, of whom 580 continued once-daily tadalafil 5 mg for 21 months. Treatment-emergent adverse events in the 12-month and 24-month period were similar, with the most common being viral upper respiratory tract infection, upper respiratory tract infection, and headache. Significant improvement from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) score was detected at month 12 (least squares mean [LSM] change: 7.9, 95% confidence interval [CI]: 7.5-8.4, P < 0.001) and was maintained to month 24 (LSM change: 8.6, 95% CI: 8.1-9.0, P < 0.001). The proportions of patients regaining normal erectile function (IIEF-EF score ≥26) were 43.7% and 48.0% at months 12 and 24, respectively. Global Assessment Questionnaire results showed improved erection function in 97.5% of patients and improved ability to engage in sexual activity in 95.9% of patients at month 12; these values were 96.1% and 95.0% at month 24, respectively. The quality of sexual life score based on the Sexual Life Quality Questionnaire (SLQQ) was increased by 52.2% at month 12 and by 55.3% at month 24 (both P < 0.001). The treatment satisfaction score determined by SLQQ (mean ± standard deviation) was 62.4 ± 21.0 at month 12 versus 65.9 ± 20.2 at month 24. Two-year daily application of tadalafil 5 mg in Chinese men with ED showed a favorable safety profile and durable improvement in sexual performance and satisfaction.

Sperm retrieval outcomes of contralateral testis in men with nonobstructive azoospermia and unsuccessful unilateral microdissection testicular sperm extraction.

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The Reduced Gray Matter Volume and Functional Connectivity of the Cerebellum in Type 2 Diabetes Mellitus with High Insulin Resistance.

INTRODUCTION: Insulin resistance is widely thought to be a critical feature in type 2 diabetes mellitus (T2DM), and there is significant evidence indicating a higher abundance of insulin receptors in the human cerebellum than cerebrum. However, the specific structural or functional changes in the cerebellum related to T2DM remain unclear, and the association between cerebellar alterations, insulin resistance, cognition, and emotion is yet to be determined. METHODS: We investigated neuropsychological performance, and structural and functional changes in specific cerebellar subregions in 43 T2DM patients with high insulin resistance (T2DM-highIR), 72 T2DM patients with low insulin resistance (T2DM-lowIR), and 50 controls. Furthermore, the correlation and stepwise multiple linear regression analysis were performed. RESULTS: Compared to the controls, T2DM exhibited lower cognitive scores and higher depressive/anxious scores. Furthermore, T2DM-highIR patients showed reduced gray matter volume (GMV) in the right cerebellar lobules VIIb, Crus I/II, and T2DM showed reduced GMV in left lobules I-IV compared to controls. Additionally, functional connectivity decrease was observed between the right lobules I-V and orbital part of the superior frontal gyrus in T2DM-highIR compared to both T2DM-lowIR and controls. Notably, there were negative correlations between the GMV of the lobules VIIb, Crus I/II, and updated homeostatic model assessment of insulin resistance, and positive correlation with executive/visuospatial performance in T2DM patients. CONCLUSIONS: These results suggest that the cerebellar lobules VIIb, Crus I/II, represent vulnerable brain regions in the context of insulin resistance. Overall, this study offers new insights into the neuropathophysiological mechanisms of brain impairment in patients with T2DM.

Differential effects of sleep deprivation on behavior and microglia in a brain-region-specific manner in young and aged male mice.

Microglia, resident immune cells in the central nervous system, constantly monitor the state of the surrounding brain activity. The animal model induced by sleep deprivation (SD) is widely used to study the pathophysiological mechanisms of insomnia and bipolar disorder. However, it remains unclear whether SD affects behaviors in young and aged male mice and microglia in various brain regions. In this study, we confirmed brain region-specific changes in microglial density and morphology in the accumbens nucleus (Acb), amygdala (AMY), cerebellum (Cb), corpus callosum (cc), caudate putamen, hippocampus (HIP), hypothalamus (HYP), medial prefrontal cortex (mPFC), and thalamus (TH) of young mice. In addition, the density of microglia in old mice was higher than that in young mice. Compared with young mice, old mice showed a markedly increased microglial size, decreased total length of microglial processes, and decreased maximum length. Importantly, we found that 48-h SD decreased microglial density and morphology in old mice, whereas SD increased microglial density and morphology in most observed brain regions in young mice. SD-induced hyperactivity was observed only in young mice but not in old mice. Moreover, microglial density (HIP, AMY, mPFC, CPu) was significantly positively correlated with behaviors in SD- and vehicle-treated young mice. Contrarily, negative correlations were shown between the microglial density (cc, Cb, TH, HYP, Acb, AMY) and behaviors in vehicle-treated young and old mice. These results suggest that SD dysregulates the homeostatic state of microglia in a region- and age-dependent manner. Microglia may be involved in regulating age-related behavioral responses to SD.

Serum tRNA-derived fragments as potential biomarkers in children with acute intussusception.

Introduction: Pediatric intussusception is one of the most common causes of bowel obstruction in the pediatric population. Affected children have one section of the intestine sliding into the adjacent section. Intestinal ischemia-reperfusion injury (I/R) can occur during pediatric intussusception, and any delay in diagnosis or treatment can lead to loss of intestinal viability that requires bowel resection. The aim of the present study was to investigate whether transfer ribonucleic acid (tRNA)-derived fragments (tRFs) can serve as candidate biomarkers for pediatric intussusception. Material and methods: Using high-throughput sequencing technology, we identified differentially expressed tRFs, and ultimately selected three tRFs to establish a signature as a predictive biomarker of pediatric intussusception. Selection of these three upregulated genes was verified using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We conducted receiver operator characteristic (ROC) curve analysis to evaluate the predictive accuracy of the selected genes for pediatric intussusception. Results: We detected 732 tRFs and tRNA-derived stress-induced RNA (tiRNAs), 1705 microRNAs (miRNAs), 52 differentially expressed miRNAs, and 34 differentially expressed tRFs and tiRNAs between patients and controls. Compared with controls, we found 33 upregulated miRNAs, 24 upregulated tRFs and tiRNAs, 19 downregulated miRNAs, and 10 downregulated tRFs and tiRNAs in children with intussusception. Using qPCR, the expression trends of tRF-Leu-TAA-006, tRF-Gln-TTG-033 and tRF-Lys-TTT-028 were consistent with the sequencing results. AUCs of tRF-Leu-TAA-006, tRF-Gln-TTG-033 and tRF-Lys-TTT-028 were 0.984, 0.970 and 0.837, respectively. Conclusions: Circulating tRF-Leu-TAA-006, tRF-Gln-TTG-033 and tRF-Lys-TTT-028 expression might be a novel potential biomarker for diagnosis of pediatric intussusception.

Lifestyle improvement and the reduced risk of cardiovascular disease: the China-PAR project.

BACKGROUND: The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China). METHODS: A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated. RESULTS: A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98). CONCLUSIONS: Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.

Clinical Effect of Rehabilitation New Fluid Combined with Sanjie Analgesic Capsules in the Treatment of Granulomatous Mastitis and Thyroiditis and Impact on Immune Indexes of Patients.

Objective: To analyze the clinical effect of rehabilitation new fluid combined with Sanjie analgesic capsules in the treatment of granulomatous lobular mastitis (GLM) and thyroiditis and the impact on immune indexes of patients. Methods: For a retrospective study, we selected 150 patients with GLM and 150 patients with thyroiditis admitted to The Fourth Hospital of Shijiazhuang from January 2021 to January 2022. We divided them into three groups based on the treatment methods. Control group 1 (CG1) included patients treated with rehabilitation new fluid alone, while control group 2 (CG2) included patients treated with the Sanjie analgesic capsules alone. The third group, the observation group (OG), included patients treated with rehabilitation new fluid (extract of drying body from Periplaneta americana) at an oral dose of 10 ml combined with Sanjie analgesic capsules. There were 50 patients in each group. The clinical efficacy, symptom improvement, the level changes of free triiodothyronine (FT3), free tetraiodothyronine (FT4), and thyroid stimulating hormone (TSH), and the changes of immune indexes such as CD4+ (cluster of differentiation 4+), CD25+ (cluster of differentiation 25+), CD68+ (cluster of differentiation 68+) and CD138+ (cluster of differentiation 138+) were analyzed. Results: After treatment, the total treatment effectiveness of GLM in the OG was 94%, which was significantly higher than 80% in the CG1 and 78% in the CG2 (P = .037, .021), while the total treatment effectiveness of thyroiditis in the OG was 92%, which was significantly higher than 76% in the CG1 and 74% in the CG2 (P = .029, 0.017). The scores of breast pain, breast overflow, tumor size, local skin changes, and axillary fossa lymphadenectasis of the affected side in the OG of GLM were better than those in CG1 (Pbreast pain < .001, 95%CI: 0.573-1.747; Pbreast overflow = .022, 95%CI: 0.074-0.905; Ptumor size = .008, 95%CI: 0.231-1.489; Plocal skin changes = .001, 95%CI: 0.382-1.498; Paxillary fossa lymphadenectasis of the affected side = .011, 95%CI: 0.096-0.704) and CG2 (Pbreast pain = .001, 95%CI: 0.449-1.711; Pbreast overflow = .049, 95%CI: 0.002-0.798; Ptumor size =0.019, 95%CI: 0.132-1.428; Plocal skin changes < .001, 95%CI: 0.563-1.517; Paxillary fossa lymphadenectasis of the affected side = .001, 95%CI: 0.202-0.678). The levels of FT3 and FT4 in the OG of thyroiditis were higher than CG1 (PFT3 < .001, 95%CI: 0.951-1.590; PFT4 < .001, 95%CI: 1.421-2.618) and CG2 (PFT3 < .001, 95%CI: 0.943-1.643; PFT4 < .001, 95%CI: 1.521-2.758), and the TSH level was lower compared with CG1 (PTSH < .001, 95%CI: 2.409-3.070) and CG2 (PTSH < .001, 95%CI: 2.540-3.230). The immune indexes of GLM were improved, and the levels of CD4+, CD25+, CD68+, and CD138+ in the OG were better than those in the CG1 (PCD4+ < .001, 95%CI: 2.967-4.912; PCD25+ < .001, 95%CI: 3.707-5.212; PCD68+ < .001, 95%CI: 1.445-2.200; PCD138+ < .001, 95%CI: 3.922-5.510) and CG2 (PCD4+ < .001, 95%CI: 3.093-4.995; PCD25+ < .001, 95%CI: 3.527-4.904; PCD68+ < .001, 95%CI: 1.334-2.216; PCD138+ < .001, 95%CI: 3.878-5.352). The immune indexes of thyroiditis were improved, and the levels of CD4+, CD25+, CD68+, and CD138+ in the OG were better than those in the CG1 (PCD4+ < .001, 95%CI: 4.235-6.117; PCD25+ < .001, 95%CI: 3.300-4.810; PCD68+ < .001, 95%CI: 1.173-1.939; PCD138+ < .001, 95%CI: 3.704-4.881) and CG2 (PCD4+ < .001, 95%CI: 3.136-5.422; PCD25+ < .001, 95%CI: 3.182-4.615; PCD68+ < .001, 95%CI: 1.216-2.113; PCD138+ < .001, 95%CI: 4.145-5.527). Conclusion: The clinical effect of rehabilitation new fluid combined with Sanjie analgesic capsule in the treatment of GLM and thyroiditis is remarkable, which enables enhancement of the treatment efficiency, and improves patients' clinical symptoms, functional indexes, and the levels of immune indexes, as a direction for the follow-up treatment in the clinic.

Effect of roxadustat on red blood cell lifespan in patients with long-term haemodialysis: a single-centre, prospective, single-arm study.

Background: Reduced survival of red blood cells (RBCs) in patients with chronic kidney disease (CKD) is thought to contribute to renal anaemia. Although renal anaemia improved greatly because of the wide use of erythropoiesis-stimulating agents (ESAs) and the advancement of dialysis techniques, RBC longevity seems not to be obviously ameliorated. Methods: In this single-centre, single-arm trial, patients who had been undergoing haemodialysis and ESA therapy with epoetin alfa for at least 12 weeks changed their anti-anaemia drugs from epoetin alfa to oral roxadustat three times per week for 24 weeks. The primary endpoint was the change in RBC lifespan from baseline at week 24. The change in the circulating percentage of eryptotic RBCs, RBC deformability and RBC oxygen transport ability were also assessed. Results: A total of 27 patients were enrolled, with 26 completing the full course of intervention. At baseline, the average RBC lifespan was 60.1 days [standard deviation (SD) 14.4; n = 27]. At the end of the study period, 26 patients had an RBC lifespan measurement (83.9 days on average; SD 21.9). The RBC lifespan increased by 22.8 days on average [95% confidence interval (CI) 15.5-30.0, P < .001]. This equated to an average RBC lifespan increase of 39.2% (95% CI 27.8-50.6). The percentage of circulating eryptotic RBCs, erythrocyte filtration index and the pressure at which haemoglobin is 50% saturated decreased significantly from baseline to week 24 (1.39 ± 0.44% versus 0.89 ± 0.25%, P < .0001; 0.29 ± 0.12 versus 0.16 ± 0.08, P < .0001 and 32.54 ± 4.83 versus 28.40 ± 2.29, P < .001, respectively). Conclusion: Roxadustat prolonged RBC lifespan in patients with long-term haemodialysis.

Multivariate classification based on large-scale brain networks during early abstinence predicted lapse among male detoxified alcohol-dependent patients.

Identifying biomarkers to predict lapse of alcohol-dependence (AD) is essential for treatment and prevention strategies, but remains remarkably challenging. With an aim to identify neuroimaging features for predicting AD lapse, 66 male AD patients during early-abstinence (baseline) after hospitalized detoxification underwent resting-state functional magnetic resonance imaging and were then followed-up for 6 months. The relevance-vector-machine (RVM) analysis on baseline large-scale brain networks yielded an elegant model for differentiating relapsing patients (n = 38) from abstainers, with the area under the curve of 0.912 and the accuracy by leave-one-out cross-validation of 0.833. This model captured key information about neuro-connectome biomarkers for predicting AD lapse.

Cefmetazole sodium as an allosteric effector that regulates the oxygen supply efficiency of adult hemoglobin.

Allosteric effectors play an important role in regulating the oxygen supply efficiency of hemoglobin for blood storage and disease treatment. However, allosteric effectors that are approved by the US FDA are limited. In this study, cefmetazole sodium (CS) was found to bind adult hemoglobin (HbA) from FDA library (1338 compounds) using surface plasmon resonance imaging high-throughput screening. Using surface plasmon resonance (SPR), the interaction between CS and HbA was verified. The oxygen dissociation curve of HbA after CS interaction showed a significant increase in P50 and theoretical oxygen-release capacity. Acid-base sensitivity (SI) exhibited a decreasing trend, although not significantly different. An oxygen dissociation assay indicated that CS accelerated HbA deoxygenation. Microfluidic modulated spectroscopy showed that CS changed the ratio of the alpha-helix to the beta-sheet of HbA. Molecular docking suggested CS bound to HbA's ß-chains via hydrogen bonds, with key amino acids being N282, K225, H545, K625, K675, and V544.The results of molecular dynamics simulations (MD) revealed a stable orientation of the HbA-CS complex. CS did not significantly affect the P50 of bovine hemoglobin, possibly due to the lack of Valß1 and Hisß2, indicating that these were the crucial amino acids involved in HbA's oxygen affinity. Competition between the 2,3-Diphosphoglycerate (2,3-DPG) and CS in the HbA interaction was also determined by SPR, molecular docking and MD. In summary, CS could interact with HbA and regulate the oxygen supply efficiency via forming stable hydrogen bonds with the ß-chains of HbA, and showed competition with 2,3-DPG.Communicated by Ramaswamy H. Sarma.

Evolving Trends and Burden of Inflammatory Bowel Disease in Asia, 1990-2019: A Comprehensive Analysis Based on the Global Burden of Disease Study.

BACKGROUND: Asia's inflammatory bowel disease (IBD) burden has rapidly increased recently, but the epidemiological trends in Asia remain unclear. We report IBD's incidence, prevalence, mortality, and Disability-Adjusted Life Years (DALY) in 52 Asian countries from 1990 to 2019. METHODS: Data from the Global Burden of Disease 2019 were analyzed for IBD burden across 52 countries, using metrics like incidence, prevalence, mortality rates, and DALY. The epidemiological trend of IBD from 1990 to 2019 was assessed with the Joinpoint and APC methods. Decomposition and frontier analyses examined factors behind IBD case and death changes. The NORPRED forecasted Asia's morbidity and mortality trends from 2019 to 2044. RESULTS: From 1990 to 2019, The incidence and prevalence of IBD increased in Asia, while mortality and DALY decreased. East Asia had the highest increase in disease burden. IBD incidence was highest among the 30-34 age group, with prevalence peaking in the 45-49 age group. In high-income regions, IBD peak age shifted to younger groups. Decompose analysis showed population growth as the primary factor for the increasing IBD cases in Asia. NORDPRED model predicted a continued IBD burden increase in Asia over the next 25 years. CONCLUSIONS: Between 1990 and 2019, ASIR and ASPR of IBD in Asia increased, while ASMR and ASDR decreased. Due to population growth and aging, the IBD burden is expected to rise over the next 25 years, particularly in East Asia.

Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain.

Acute administration of MK-801 (dizocilpine), an N-methyl-D-aspartate receptor (NMDAR) antagonist, can establish animal models of psychiatric disorders. However, the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown. Here, we found rapid elimination of microglia in the prefrontal cortex (PFC) and hippocampus (HPC) of mice following administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 (pexidartinib) in drinking water. Single administration of MK-801 induced hyperactivity in the open-field test (OFT). Importantly, PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801. However, neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity. Importantly, microglial density in the PFC and HPC was significantly correlated with behavioral changes. In addition, common and distinct glutamate-, GABA-, and inflammation-related gene (116 genes) expression patterns were observed in the brains of PLX3397- and/or MK-801-treated mice. Moreover, 10 common inflammation-related genes ( CD68, CD163, CD206, TMEM119, CSF3R, CX3CR1, TREM2, CD11b, CSF1R, and F4/80) with very strong correlations were identified in the brain using hierarchical clustering analysis. Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes ( NLRP3, CD163, CD206, F4/80, TMEM119, and TMEM176a), but not glutamate- or GABA-related genes in PLX3397- and MK-801-treated mice. Thus, our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist, which is associated with modulation of immune-related genes in the brain.