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Abstract Background Abducens nerve palsy is the most common isolated ocular cranial nerve palsy. In adults, nontraumatic etiologies of isolated sixth cranial nerve palsy can include vascular disease, inflammation, tumors, and a prior history of infection. Case presentation We present a case of a 52-year-old Asian male who developed acute abducens nerve palsy after vaccination with the AstraZeneca coronavirus disease 2019 vaccine. A complete workup including magnetic resonance imaging of the brain and orbits revealed no abnormalities. The patient experienced a gradual recovery over 10 weeks through alternative eye patching. The abducens nerve palsy is postulated to be correlated with the coronavirus disease 2019 vaccine. Conclusion Despite the recognized efficacy and cost benefits of coronavirus disease 2019 vaccines, clinicians should be aware of the possible association between cranial nerve palsies and coronavirus disease 2019 vaccines.

Mature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown. Here we report that accelerating the normally slow phosphorylation of the linker for activation of T cells (LAT) residue Y136 by introducing an adjacent Gly135Asp alteration (LATG135D) disrupts ligand discrimination in vivo. The enhanced self-reactivity of LATG135D T cells triggers excessive thymic negative selection and promotes T-cell anergy. During Listeria infection, LATG135D T cells expand more than wild-type counterparts in response to very weak stimuli but display an imbalance between effector and memory responses. Moreover, despite their enhanced engagement of central and peripheral tolerance mechanisms, mice bearing LATG135D show features associated with autoimmunity and immunopathology. Our data reveal the importance of kinetic proofreading in balancing tolerance and immunity.

Balancing mechanical and corrosion performance is a decisive factor in the use of high entropy and medium entropy alloys (H & MEAs) as advanced engineering structural materials. This study investigates the microstructure of Fe77.3-xMnxSi9.1Cr9.8C3.8 (x = 14, 23.2) HEAs by combining experiments and first-principles calculations to elucidate the effects of adjusting Mn content on the mechanical and corrosion properties of FCC and FCC + HCP phases. The results demonstrate that HEAs with low Mn content exhibit a single FCC phase, whereas increasing Mn content not only precipitates the HCP phase but also refines the grain size. The yield strength, compressive fracture strength, work hardening index, and plasticity of Fe77.3-xMnxSi9.1Cr9.8C3.8 (x = 14, 23.2 at.%) HEAs are 1300 and 1526 MPa, 2380 and 2332 MPa, 0.42 and 0.36, 16.7% and 16%, respectively. Both HEAs exhibit superior electrochemical and salt spray corrosion performance compared to 304 stainless steels, with the Fe63.3Mn14Si9.1Cr9.8C3.8 alloy performing the best, exhibiting a self-corrosion potential of −0.523V and a self-corrosion current density of 2.605 × 10−6 A cm−2. The excellent corrosion resistance of Fe63.3Mn14Si9.1Cr9.8C3.8 can be attributed to the moderate grain size, resulting in excellent passivation film characteristics, and the lower Mn content, leading to a higher Cr2O3 content in the passivation film. First-principles calculations reveal that Fe63.3Mn14Si9.1Cr9.8C3.8 has a lower density of states number at the Fermi level (i.e., Fe63.3Mn14Si9.1Cr9.8C3.8 is 214.145eV, Fe54.1Mn23.2Si9.1Cr9.8C3.8 is 337.077eV), a wider pseudogap width, higher work function (5.700ev, 5.189ev), and better stability. Additionally, there exists a strong trade-off between corrosion and mechanical properties due to the influence of the HCP phase and grain size.

Abstract A hypothesis testing approach, based on the theorem of probability integral transformation and the Kolmogorov–Smirnov one-sample test, for performance evaluation of probabilistic seasonal rainfall forecasts is proposed in this study. By considering the probability distribution of monthly rainfalls, the approach transforms the tercile forecast probabilities into a forecast distribution and tests whether the observed data truly come from the forecast distribution. The proposed approach provides not only a quantitative measure for performance evaluation but also a cumulative probability plot for insightful interpretations of forecast characteristics such as overconfident, underconfident, mean-overestimated, and mean-underestimated. The approach has been applied for the performance evaluation of probabilistic season rainfall forecasts in northern Taiwan, and it was found that the forecast performance is seasonal dependent. Probabilistic seasonal rainfall forecasts of the Meiyu season are likely to be overconfident and mean-underestimated, while forecasts of the winter-to-spring season are overconfident. A relatively good forecast performance is observed for the summer season.

Abstract The dysregulation of pro- and anti-inflammatory processes in the brain has been linked to the pathogenesis of major depressive disorder (MDD), although the precise mechanisms remain unclear. In this study, we discovered that microglial conditional knockout of Pdcd4 conferred protection against LPS-induced hyperactivation of microglia and depressive-like behavior in mice. Mechanically, microglial Pdcd4 plays a role in promoting neuroinflammatory responses triggered by LPS by inhibiting Daxx-mediated PPARγ nucleus translocation, leading to the suppression of anti-inflammatory cytokine IL-10 expression. Finally, the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions was abolished by intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα. Our study elucidates the distinct involvement of microglial Pdcd4 in neuroinflammation, suggesting its potential as a therapeutic target for neuroinflammation-related depression.

Abstract Background Periodontitis is strongly associated with type 2 diabetes (T2D) that results in serious complications and mortality. However, the pathogenic role of periodontitis in the development of T2D and the underlain mechanism have not been fully elucidated. Methods A Mendelian randomization (MR) was performed to estimate the causality between two diseases. Bioinformatics tools, including gene ontology and pathway enrichment analyses, were employed to analyze the common differentially expressed genes (DEGs) in periodontitis and T2D. MR and colocalization analyses were then utilized to investigate the causal associations between potential pathogenic gene expression and the risk of T2D. Single cell-type expression analysis was further performed to detect the cellular localization of these genes. Results Genetically predicted periodontitis was associated with a higher risk of T2D (OR, 1.469; 95% CI, 1.117–1.930; P = 0.006) and insulin resistance (OR 1.034; 95%CI 1.001–1.068; P = 0.041). 79 common DEGs associated with periodontitis and T2D were then identified and demonstrated enrichment mainly in CXC receptor chemokine receptor binding and interleutin-17 signaling pathway. The integration of GWAS with the expression quantitative trait locis of these genes from the peripheral blood genetically prioritized 6 candidate genes, including 2 risk genes (RAP2A, MCUR1) and 4 protective genes (WNK1, NFIX, FOS, PANX1) in periodontitis-related T2D. Enriched in natural killer cells, RAP2A (OR 4.909; 95% CI 1.849–13.039; P = 0.001) demonstrated high risk influence on T2D, and exhibited strong genetic evidence of colocalization (coloc.abf-PPH4 = 0.632). Conclusions This study used a multi-omics integration method to explore causality between periodontitis and T2D, and revealed molecular mechanisms using bioinformatics tools. Periodontitis was associated with a higher risk of T2D. MCUR1, RAP2A, FOS, PANX1, NFIX and WNK1 may play important roles in the pathogenesis of periodontitis-related T2D, shedding light on the development of potential drug targets.

Abstract Introduction To determine risk factors associated with postoperative cerebrospinal fluid leaks (CSFLs) after intrathecal drug delivery system (IDDS) and external pump implantation. Methods The clinical data of 248 patients with advanced cancer who underwent IDDS implantation from January 2021 to December 2022 at the Department of Pain Medicine at the Hunan Cancer Hospital were retrospectively reviewed. Information regarding age, gender, height, weight, body mass index (BMI), tumour type, albumin levels, haemoglobin levels, history of diabetes and pre- and postoperative anti-tumour therapy was collected and analysed. Results Postoperative CSFLs occurred in 7 of 231 patients (3.30%). Statistical analysis indicated that gender, age, height, weight, BMI, tumour type, albumin levels, haemoglobin levels, history of diabetes, pre- and postoperative chemotherapy, pre- and postoperative radiotherapy, preoperative immunotherapy and postoperative targeted therapy were not independent factors for CSFLs. Preoperative targeted therapy [odds ratio (OR): 16.64; 95% confidence interval (CI): 1.42, 195.56; P = 0.01] and postoperative immunotherapy (OR: 13.38; 95% CI: 1.60, 111.65; P = 0.017) were factors associated with an increased postoperative CSFL rate. Of the two locations where CSFLs can occur, the back (puncture site of catheter, n = 4) and the hypochondriac region (location of infusion port implanted, n = 3), back CSFLs occurred earlier than in the hypochondriac region (18.25 ± 6.45 vs 115 ± 62.02 days, P = 0.032). Conclusion Based on the data from our study, the timing of preoperative targeted therapy and postoperative immunotherapy should be considered to prevent the occurrence of CSFLs in cancer pain patients who have an IDDS and external pump.

Abstract A knowledge graph can effectively showcase the essential characteristics of data and is increasingly emerging as a significant means of integrating information in the field of artificial intelligence. Coronary artery plaque represents a significant etiology of cardiovascular events, posing a diagnostic challenge for clinicians who are confronted with a multitude of nonspecific symptoms. To visualize the hierarchical relationship network graph of the molecular mechanisms underlying plaque properties and symptom phenotypes, patient symptomatology was extracted from electronic health record data from real-world clinical settings. Phenotypic networks were constructed utilizing clinical data and protein‒protein interaction networks. Machine learning techniques, including convolutional neural networks, Dijkstra's algorithm, and gene ontology semantic similarity, were employed to quantify clinical and biological features within the network. The resulting features were then utilized to train a K-nearest neighbor model, yielding 23 symptoms, 41 association rules, and 61 hub genes across the three types of plaques studied, achieving an area under the curve of 92.5%. Weighted correlation network analysis and pathway enrichment were subsequently utilized to identify lipid status-related genes and inflammation-associated pathways that could help explain the differences in plaque properties. To confirm the validity of the network graph model, we conducted coexpression analysis of the hub genes to evaluate their potential diagnostic value. Additionally, we investigated immune cell infiltration, examined the correlations between hub genes and immune cells, and validated the reliability of the identified biological pathways. By integrating clinical data and molecular network information, this biomedical knowledge graph model effectively elucidated the potential molecular mechanisms that collude symptoms, diseases, and molecules.

Abstract Colorectal cancer (CRC) arises via the progressive accumulation of dysregulation in key genes including oncogenes and tumor-suppressor genes. Prostaglandin-endoperoxide synthase 2 (PTGS2, also called COX2) acts as an oncogenic driver in CRC. Here, we explored the upstream transcription factors (TFs) responsible for elevating PTGS2 expression in CRC cells. The results showed that PTGS2 silencing repressed cell growth, migration and invasion in HCT116 and SW480 CRC cells. The two fragments (499–981 bp) and (1053–1434 bp) were confirmed as the core TF binding profiles of the PTGS2 promoter. PTGS2 expression positively correlated with RUNX1 level in colon adenocarcinoma (COAD) samples using the TCGA-COAD dataset. Furthermore, RUNX1 acted as a positive regulator of PTGS2 expression by promoting transcriptional activation of the PTGS2 promoter via the 1086–1096 bp binding motif. In conclusion, our study demonstrates that PTGS2 upregulation induced by the TF RUNX1 promotes CRC cell growth, migration and invasion, providing an increased rationale for the use of PTGS2 inhibitors in CRC prevention and treatment.

Abstract Background The gut microbiota and their hosts profoundly affect each other’s physiology and evolution. Identifying host-selected traits is crucial to understanding the processes that govern the evolving interactions between animals and symbiotic microbes. Current experimental approaches mainly focus on the model bacteria, like hypermutating Escherichia coli or the evolutionary changes of wild stains by host transmissions. A method called atmospheric and room temperature plasma (ARTP) may overcome the bottleneck of low spontaneous mutation rates while maintaining mild conditions for the gut bacteria. Results We established an experimental symbiotic system with gnotobiotic bee models to unravel the molecular mechanisms promoting host colonization. By in vivo serial passage, we tracked the genetic changes of ARTP-treated Snodgrassella strains from Bombus terrestris in the non-native honeybee host. We observed that passaged isolates showing genetic changes in the mutual gliding locus have a competitive advantage in the non-native host. Specifically, alleles in the orphan mglB, the GTPase activating protein, promoted colonization potentially by altering the type IV pili-dependent motility of the cells. Finally, competition assays confirmed that the mutations out-competed the ancestral strain in the non-native honeybee gut but not in the native host. Conclusions Using the ARTP mutagenesis to generate a mutation library of gut symbionts, we explored the potential genetic mechanisms for improved gut colonization in non-native hosts. Our findings demonstrate the implication of the cell mutual-gliding motility in host association and provide an experimental system for future study on host-microbe interactions. Video Abstract

Abstract Backgrounds Intraplacental choriocarcinoma (IC) is an extremely rare subtype of gestational choriocarcinoma. The long-term follow-up and reproductive outcomes of IC patients remain unclear. Here, we report a series of 14 cases and conduct a literature review to assess the fertility and recurrence results of this rare disease. Results Fourteen patients with pathologically confirmed IC treated in Peking Union Medical College Hospital between January 2002 and July 2022 were included in this study. Half of them had metastatic IC and were treated by chemotherapy with or without surgery. Only 1 patient had chemoresistant disease, but she achieved complete remission after immunotherapy. The median follow-up time was 45.5 months (range 4-192), and no recurrence occurred. One metastatic IC patient who achieved remission after chemotherapy had a full-term delivery. Among the 5 patients with fertility demands, 3 abandoned their pursuit of pregnancy because of “fear and worry about choriocarcinoma recurrence”. We reviewed a total of 89 cases of IC in English and Chinese literature from 1963 to 2022, and only 5 cases with subsequent pregnancy were reported, all of them were nonmetastatic IC cases. Conclusions IC is sensitive to chemotherapy and has good long-term remission and a low recurrence rate. Patients with metastatic or nonmetastatic IC can have good pregnancy results after treatment. Doctors should pay more attention to the psychology of these patients. Clinical trial registration N/A.

Abstract Sodium (Na) metal is a competitive anode for next‐generation energy storage applications in view of its low cost and high‐energy density. However, the uncontrolled side reactions, unstable solid electrolyte interphase (SEI) and dendrite growth at the electrode/electrolyte interfaces impede the practical application of Na metal as anode. Herein, a heterogeneous Na‐based alloys interfacial protective layer is constructed in situ on the surface of Na foil by self‐diffusion of liquid metal at room temperature, named “HAIP Na.” The interfacial Na‐based alloys layer with good electrolyte wettability and strong sodiophilicity, and assisted in the construction of NaF‐rich SEI. By means of direct visualization and theoretical simulation, we verify that the interfacial Na‐based alloys layer enabling uniform Na+ flux deposition and suppressing the dendrite growth. As a result, in the carbonate‐based electrolyte, the HAIP Na||HAIP Na symmetric cells exhibit a remarkably enhanced cycling life for more than 650 h with a capacity of 1 mAh cm−2 at a current density of 1 mA cm−2. When the HAIP Na anode is paired with sulfurized polyacrylonitrile (SPAN) cathode, the SPAN||HAIP Na full cells demonstrate excellent rate performance and cycling stability.