Genetic evidence for causal association between migraine and dementia: a mendelian randomization study.

BACKGROUND: There is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: Summary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran's Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis. RESULTS: Migraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02-0.14; P = 0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02-0.06; P = 7.760E-5). Sensitivity analyses demonstrated the robustness of our findings. CONCLUSION: Our study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.

Hepatic GDP-fucose transporter SLC35C1 attenuates cholestatic liver injury and inflammation by inducing CEACAM1 N153 fucosylation.

BACKGROUND AND AIMS: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport GDP-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases. APPROACH AND RESULTS: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis (OC) and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 (Slc35c1 cKO) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T-cell, neutrophil and F4/80 macrophage infiltration, but did not affect the levels of serum and liver BA in mouse models of cholestasis. LC-MS/MS analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and PLC/PRF/5-ASBT cells. CONCLUSIONS: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation.

Enhancing monolignol ferulate conjugate levels in poplar lignin via OsFMT1.

BACKGROUND: The phenolic polymer lignin is one of the primary chemical constituents of the plant secondary cell wall. Due to the inherent plasticity of lignin biosynthesis, several phenolic monomers have been shown to be incorporated into the polymer, as long as the monomer can undergo radicalization so it can participate in coupling reactions. In this study, we significantly enhance the level of incorporation of monolignol ferulate conjugates into the lignin polymer to improve the digestibility of lignocellulosic biomass. RESULTS: Overexpression of a rice Feruloyl-CoA Monolignol Transferase (FMT), OsFMT1, in hybrid poplar (Populus alba x grandidentata) produced transgenic trees clearly displaying increased cell wall-bound ester-linked ferulate, p-hydroxybenzoate, and p-coumarate, all of which are in the lignin cell wall fraction, as shown by NMR and DFRC. We also demonstrate the use of a novel UV-Vis spectroscopic technique to rapidly screen plants for the presence of both ferulate and p-hydroxybenzoate esters. Lastly we show, via saccharification assays, that the OsFMT1 transgenic p oplars have significantly improved processing efficiency compared to wild-type and Angelica sinensis-FMT-expressing poplars. CONCLUSIONS: The findings demonstrate that OsFMT1 has a broad substrate specificity and a higher catalytic efficiency compared to the previously published FMT from Angelica sinensis (AsFMT). Importantly, enhanced wood processability makes OsFMT1 a promising gene to optimize the composition of lignocellulosic biomass.

Association between Pre-operative Body Mass Index and Surgical Infection in Perihilar Cholangiocarcinoma Patients Treated with Curative Resection: A Multi-center Study.

Background: The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA) patients treated with curative resection. Methods: Consecutive pCCA patients were enrolled from four tertiary hospitals between 2008 and 2022. According to pre-operative BMI, the patients were divided into three groups: low BMI (≤18.4 kg/m2), normal BMI (18.5-24.9 kg/m2), and high BMI (≥25.0 kg/m2). The incidence of surgical infection among the three groups was compared. Multivariable logistic regression models were used to determine the independent risk factors associated with surgical infection. Results: A total of 371 patients were enrolled, including 283 patients (76.3%) in the normal BMI group, 30 patients (8.1%) in the low BMI group, and 58 patients (15.6%) in the high BMI group. The incidence of surgical infection was significantly higher in the patients in the low BMI and high BMI groups than in the normal BMI group. The multivariable logistic regression model showed that low BMI and high BMI were independently associated with the occurrence of surgical infection. Conclusions: The pCCA patients with a normal BMI treated with curative resection could have a lower risk of surgical infection than pCCA patients with an abnormal BMI.

Identifying therapeutic target genes for migraine by systematic druggable genome-wide Mendelian randomization.

BACKGROUND: Currently, the treatment and prevention of migraine remain highly challenging. Mendelian randomization (MR) has been widely used to explore novel therapeutic targets. Therefore, we performed a systematic druggable genome-wide MR to explore the potential therapeutic targets for migraine. METHODS: We obtained data on druggable genes and screened for genes within brain expression quantitative trait locis (eQTLs) and blood eQTLs, which were then subjected to two-sample MR analysis and colocalization analysis with migraine genome-wide association studies data to identify genes highly associated with migraine. In addition, phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic drugs. RESULTS: We identified 21 druggable genes significantly associated with migraine (BRPF3, CBFB, CDK4, CHD4, DDIT4, EP300, EPHA5, FGFRL1, FXN, HMGCR, HVCN1, KCNK5, MRGPRE, NLGN2, NR1D1, PLXNB1, TGFB1, TGFB3, THRA, TLN1 and TP53), two of which were significant in both blood and brain (HMGCR and TGFB3). The results of phenome-wide research showed that HMGCR was highly correlated with low-density lipoprotein, and TGFB3 was primarily associated with insulin-like growth factor 1 levels. CONCLUSIONS: This study utilized MR and colocalization analysis to identify 21 potential drug targets for migraine, two of which were significant in both blood and brain. These findings provide promising leads for more effective migraine treatments, potentially reducing drug development costs.

Residual biliary intraepithelial neoplasia without malignant transformation at resection margin for perihilar cholangiocarcinoma does not require expanded resection: a dual center retrospective study.

BACKGROUND: Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN). METHOD: Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics. RESULTS: 306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup. CONCLUSION: For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin.

SIG: Graph-Based Cancer Subtype Stratification With Gene Mutation Structural Information.

Somatic tumors have a high-dimensional, sparse, and small sample size nature, making cancer subtype stratification based on somatic genomic data a challenge. Current methods for improving cancer clustering performance focus on dimension reduction, integrating multi-omics data, or generating realistic samples, yet ignore the associations between mutated genes within the patient-gene matrix. We refer to these associations as gene mutation structural information, which implicitly includes cancer subtype information and can enhance subtype clustering. We introduce a novel method for cancer subtype clustering called SIG(Structural Information within Graph). As cancer is driven by a combination of genes, we establish associations between mutated genes within the same patient sample, pair by pair, and use a graph to represent them. An association between two mutated genes corresponds to an edge in the graph. We then merge these associations among all mutated genes to obtain a structural information graph, which enriches the gene network and improves its relevance to cancer clustering. We integrate the somatic tumor genome with the enriched gene network and propagate it to cluster patients with mutations in similar network regions. Our method achieves superior clustering performance compared to SOTA methods, as demonstrated by clustering experiments on ovarian and LUAD datasets. The code is available at https://github.com/ChangSIG/SIG.git.

Human angiotensin converting enzyme 2 specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants.

BACKGROUND: The Spike protein mutation of SARS-CoV-2 led to decreased protective effect of various vaccines and monoclonal antibodies, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Down-regulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed based on sequence data, require no delivery system, and can be administered locally. OBJECTIVE: We sought to design ASOs that can block SARS-CoV-2 by down-regulating ACE2 in human airway. METHODS: ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASOs pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels. RESULTS: ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore they efficiently suppressed virus replication of three different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also down-regulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathological changes in lungs, and they increased survival of mice. CONCLUSION: ACE2-targeting ASOs can effectively block SARS-COV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations.

Cu-Pd bimetal-decorated siloxene nanosheets for semi-hydrogenation of acetylene.

Metallic Pd has been proved highly promising when paired with Cu for industrially important acetylene semi-hydrogenation. Herein, we demonstrate that high-surface-area siloxene can feasibly enable alloying between Pd and Cu via room-temperature reduction with Si-H bonds. Unprecedentedly small Cu nanoparticles with isolated Pd were in situ loaded on siloxene, addressing the core problem of low selectivity of Pd and low activity of Cu. This devised structure outclassed the traditional impregnated SiO2 in every aspect of the catalytic performance for the semi-hydrogenation of acetylene under industry conditions, with a 91% acetylene conversion and an impressive 93% selectivity to ethylene at 200 °C, and showed long-term stability with negligible activity decay at this harsh temperature. This work provides new insights for the design of economic bimetallic loaded catalysts for balancing the activity-selectivity dilemma, demonstrating the viability of siloxene as both a synthetic reagent and a carrier material for efficient catalysis.

Material basis and pharmacodynamic mechanism of YangshenDingzhi granules in the intervention of viral pneumonia: Based on serum pharmacochemistry and network pharmacology.

BACKGROUND: YangshenDingzhi granules (YSDZ) are clinically effective in preventing and treating COVID-19. The present study elucidates the underlying mechanism of YSDZ intervention in viral pneumonia by employing serum pharmacochemistry and network pharmacology. METHODS: The chemical constituents of YSDZ in the blood were examined using ultra-performance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry (UPLC-Q-Exactive Orbitrap MS). Potential protein targets were obtained from the SwissTargetPrediction database, and the target genes associated with viral pneumonia were identified using GeneCards, DisGeNET, and Online Mendelian Inheritance in Man (OMIM) databases. The intersection of blood component-related targets and disease-related targets was determined using Venny 2.1. Protein-protein interaction networks were constructed using the STRING database. The Metascape database was employed to perform enrichment analyses of Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways for the targets, while the Cytoscape 3.9.1 software was utilized to construct drug-component-disease-target-pathway networks. Further, in vitro and in vivo experiments were performed to establish the therapeutic effectiveness of YSDZ against viral pneumonia. RESULTS: Fifteen compounds and 124 targets linked to viral pneumonia were detected in serum. Among these, MAPK1, MAPK3, AKT1, EGFR, and TNF play significant roles. In vitro tests revealed that the medicated serum suppressed the replication of H1N1, RSV, and SARS-CoV-2 replicon. Further, in vivo testing analysis shows that YSDZ decreases the viral load in the lungs of mice infected with RSV and H1N1. CONCLUSION: The chemical constituents of YSDZ in the blood may elicit therapeutic effects against viral pneumonia by targeting multiple proteins and pathways.

Relationship between immune cells and the development of chronic lung allograft dysfunction.

A major cause of death for lung transplant recipients (LTRs) is the advent of chronic lung allograft dysfunction (CLAD), which has long plagued the long-term post-transplant prognosis and quality of survival of transplant patients. The intricacy of its pathophysiology and the irreversibility of its illness process present major obstacles to the clinical availability of medications. Immunotherapeutic medications are available, but they only aim to slow down the course of CLAD rather than having any therapeutic impact on the disease's development. For this reason, understanding the pathophysiology of CLAD is essential for both disease prevention and proven treatment. The immunological response in particular, in relation to chronic lung allograft dysfunction, has received a great deal of interest recently. Innate immune cells like natural killer cells, eosinophils, neutrophils, and mononuclear macrophages, as well as adaptive immunity cells like T and B cells, play crucial roles in this process through the release of chemokines and cytokines. The present review delves into changes and processes within the immune microenvironment, with a particular focus on the quantity, subtype, and characteristics of effector immune cells in the peripheral and transplanted lungs after lung transplantation. We incorporate and solidify the documented role of immune cells in the occurrence and development of CLAD with the advancements in recent years.

A new mechanism of antibody diversity: formation of the natural antibodies containing LAIR1 and LILRB1 extracellular domains.

The recent discovery of public antibodies targeting Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), which contain extracellular immunoglobulin-like domains from LAIR1 or LILRB1, constitutes a significant step forward in comprehending the reactivity of the Plasmodium parasite. These antibodies arise from unique B cell clones and demonstrate extensive cross-reactivity through their interaction with P. falciparum RIFINs. LAIR1 and LILRBs are specialized type I transmembrane glycoproteins, classified as immune inhibitory receptors, restricted to primates and mainly found on hematopoietic cells. They are instrumental in modulating interactions within the tumor microenvironment and across the immune system, and are increasingly recognized as important in anti-cancer immunotherapy and pathogen defense. The presence of LAIR1/LILRB1-containing antibodies offers new insights into malaria parasite evasion strategies and the immune system's response. Additionally, the innovative method of integrating extra exons into the antibody switch region is a noteworthy advancement, enriching the strategies for the generation of a varied array of bispecific and multispecific antibodies.

[Morphological characteristics and reduction techniques of sagittal beak-like deformity of head-neck fragment in femoral intertrochanteric fractures].

Objective: To summarize the morphological characteristics of sagittal beak-like deformity of head-neck fragment in femoral intertrochanteric fractures and to investigate the technical skills in fracture reduction. Methods: A clinical data of 31 patients with femoral intertrochanteric fractures between May 2021 and April 2023 was retrospectively analyzed. The fractures had sagittal beak-like deformity of head-neck fragment in all patients. There were 13 males and 18 females, with an average age of 76.2 years (range, 68-83 years). The time from injury to operation was 36-76 hours (mean, 51.2 hours). Fractures were classified as type A1.2 in 10 cases, type A1.3 in 11 cases, type A2.2 in 6 cases, and type A2.3 in 4 cases according to the AO/Orthopaedic Trauma Association (AO/OTA)-2018 classification; and as type A1.3 in 10 cases, type A2.1 in 11 cases, type A2.2 in 6 cases, type A2.3 in 2 cases, and type A2.4 in 2 cases according to a novel comprehensive classification for femoral intertrochanteric fractures proposed by the "Elderly Hip Fracture" Research Group of the Reparative and Reconstructive Surgery Committee of the Chinese Rehabilitation Medical Association. Based on preoperative X-ray films, CT scan and three-dimensional reconstruction, the fractures were classified into two types: type 1 (14 cases), with uncomplicated fracture morphology, severe bone interlocking and (or) soft tissue incarceration; type 2 (17 cases), with severe fracture crushing, obvious dissociation between bone blocks, and severe soft tissue hinge destruction. After the failure of the closed reduction, all patients underwent fracture reduction assisted with instrument via anterior minimal incision and proximal femoral nail antirotation nails internal fixation. The operation time, intraoperative fluoroscopy, intraoperative visible blood loss, length of hospital stay, and incidence of complications were recorded. The fracture reduction quality and stability score were assessed at immediate after operation under fluoroscopy. The fracture healing was evaluated and healing time was recorded by X-ray films. The pain visual analogue scale (VAS) score was performed at 48 hours after operation and Parker-Palmer activity score at 3 months after operation for function evaluation. Results: The operation time was 39-58 minutes (mean, 46.3 minutes); fluoroscopy was performed 13-38 times (mean, 23.5 times) during operation; the intraoperative visible blood loss was 45-90 mL (mean, 65.3 mL). The fracture reduction quality and stability score were rated as good in 29 cases and acceptable in 2 cases. The pain VAS score was 2-6 (mean, 3.1) at 48 hours after operation. Eleven patients developed deep vein thrombosis of the lower limbs after operation. Patients were hospitalized for 6-10 days (mean, 7.3 days). All patients were followed up 5-8 months (mean, 6.5 months). All fractures healed at 3.5-8.0 months after operation (mean, 4.5 months). Parker-Palmer activity score at 3 months after operation was 9 in 28 cases and 6 in 3 cases. Conclusion: The femoral intertrochanteric fracture with sagittal beak-like deformity of head-neck fragment is difficult to manually reduce. The pin combined with cannulated screw insertion to the neck cortex can hold the fragment and assist fracture reduction, which is a simple and effective technique.

Associations between frailty, depression and risk of hospitalisation for infection: A large prospective cohort study.

BACKGROUND: There is a considerable lack of epidemiological evidence on whether frailty, and frailty comorbid depression could increase the risk of infections in older adults. This study aimed to examine the prospective association between frailty, depression, and risk of infections. METHODS: A total of 308,892 eligible participants were included. Linked hospital admission records (HES) were used to identify a primary or secondary diagnosis of depression, and infection. Frailty was assessed by Fried frailty phenotype indicators. Cox proportional hazard model was conducted to examine the associated risk between frailty, depression, comorbid frailty and depression and risk of incident infections. Results were stratified by age and gender. RESULTS: During the follow-up, 74,749 (24.19 %) incident any infection cases were identified, the incidence density of any infection was 17.29/1000 person years. Frailty alone (HR = 1.38, 95 % CI: 1.33-1.43), depression alone (HR = 1.90, 95 % CI: 1.86-1.94), and comorbid frailty and depression (HR = 1.91, 95 % CI: 1.82-1.99) were associated with greater risks of any infections relative to participants with neither frailty nor depression. The associations between frailty alone, depression alone, comorbid frailty and depression, and any infections/most infection subtypes were significant for all age strata in both male and female. LIMITATIONS: Frailty phenotype was assessed through the adapted Fried criteria, based on a mix of self-reported and objective measurements. CONCLUSION: Frailty, depression, and comorbid frailty and depression were significantly associated with increased risk of incident infections.

Mendelian randomization analysis of the brain, cerebrospinal fluid, and plasma proteome identifies potential drug targets for attention deficit hyperactivity disorder.

BACKGROUND: The need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal genetic evidence could represent potential drug targets. However, a comprehensive screen of the proteome has not yet been conducted. METHODS: We employed a three-pronged approach using Mendelian Randomization (MR) and Bayesian colocalization analysis. Firstly, we studied 608 brains, 214 CSF, and 612 plasma proteins as potential causal mediators of ADHD using MR analysis. Secondly, we analysed the consistency of the discovered biomarkers across three distinct subtypes of ADHD: childhood, persistent, and late-diagnosed ADHD. Finally, we extended our analysis to examine the correlation between identified biomarkers and Tourette syndrome and pervasive autism spectrum disorder (ASD), conditions often linked with ADHD. To validate the MR findings, we conducted sensitivity analysis. Additionally, we performed cell type analysis on the human brain to identify risk genes that are notably enriched in various brain cell types. FINDINGS: After applying Bonferroni correction, we found that the risk of ADHD was increased by brain proteins GMPPB, NAA80, HYI, CISD2, and HYI, TIE1 in CSF and plasma. Proteins GMPPB, NAA80, ICA1L, CISD2, TIE1, and RMDN1 showed overlapped loci with ADHD risk through Bayesian colocalization. Overexpression of GMPPB protein was linked to an increase in the risk for all three ADHD subtypes. While ICA1L provided protection against both ASD and ADHD, CISD2 increased the probability of both disorders. Cell-specific studies revealed that GMPPB, NAA80, ICA1L, and CISD2 were predominantly present on the surface of excitatory-inhibitory neurons. INTERPRETATION: Our comprehensive MR investigation of the brain, CSF, and plasma proteomes revealed seven proteins with causal connections to ADHD. Particularly, GMPPB and TIE1 emerged as intriguing targets for potential ADHD therapy. FUNDING: This work was partly funded by the Key R & D Program of Zhejiang (T.L. 2022C03096); the National Natural Science Foundation of China Project (C.Z. 82001413); Postdoctoral Foundation of West China Hospital (C.Z. 2020HXBH163).

Whole-genome analysis, evaluation and regulation of in vitro and in vivo GABA production from Levilactobacillus brevis YSJ3.

Gamma-aminobutyric acid (GABA) produced by lactic acid bacteria (LAB) is safe and has several health benefits. Levilactobacillus brevis YSJ3 was selected from 110 LAB. It exhibited the highest in vitro GABA production level of 970.10 µg/mL. Whole-genome analysis revealed that L. brevis YSJ3 contained gadR, gadC, gadB and gadA. Furthermore, the Luedeking-Piret model was fitted, which indicated that GABA production was divided into three stages. The gadR 0079, gadC 0080, and gadB 0081 were confirmed to promote GABA synthesis. Moreover, 55 metabolites, particularly those involved in arginine metabolism, were significantly different at 6 and 20 h of cultivation. Notably, L. brevis YSJ3 significantly improved sleep in mice and increased GABA levels in the mice's gut compared with the control group. This suggests that the oral administration of L. brevis YSJ3 improves sleep quality, probably by increasing intestinal GABA levels. Overall, L. brevis YSJ3 was confirmed as a GABA-producing strain in vitro and in vivo, making it a promising probiotic candidate for its application in food and medicine.

Acupuncture plus topiramate placebo versus topiramate plus sham acupuncture for the preventive treatment of chronic migraine: A single-blind, double-dummy, randomized controlled trial.

BACKGROUND: Acupuncture has been used for the treatment of chronic migraine, but high-quality evidence is scarce. We aimed to evaluate acupuncture's efficacy and safety compared to topiramate for chronic migraine. METHODS: This double-dummy randomized controlled trial included participants aged 18-65 years diagnosed with chronic migraine. They were randomly assigned (1:1) to receive acupuncture (three sessions/week) plus topiramate placebo (acupuncture group) or topiramate (50-100 mg/day) plus sham acupuncture (topiramate group) over 12 weeks, with the primary outcome being the mean change in monthly migraine days during weeks 1-12. RESULTS: Of 123 screened patients, 60 (mean age 45.8, 81.7% female) were randomly assigned to acupuncture or topiramate groups. Acupuncture demonstrated significantly greater reductions in monthly migraine days than topiramate (weeks 1-12: -2.79 [95% CI: -4.65 to -0.94, p = 0.004]; weeks 13-24: -3.25 [95% CI: -5.57 to -0.92, p = 0.007]). No severe adverse events were reported. CONCLUSIONS: Acupuncture may be safe and effective for treating chronic migraine. The efficacy of 12 weeks of acupuncture was sustained for 24 weeks and superior to that of topiramate. Acupuncture can be used as an optional preventive therapy for chronic migraine. TRIAL REGISTRATION: ISRCTN.org Identifier 13563102.

Unraveling NEK4 as a Potential Drug Target in Schizophrenia and Bipolar I Disorder: A Proteomic and Genomic Approach.

BACKGROUND AND HYPOTHESIS: Investigating the shared brain protein and genetic components of schizophrenia (SCZ) and bipolar I disorder (BD-I) presents a unique opportunity to understand the underlying pathophysiological processes and pinpoint potential drug targets. STUDY DESIGN: To identify overlapping susceptibility brain proteins in SCZ and BD-I, we carried out proteome-wide association studies (PWAS) and Mendelian Randomization (MR) by integrating human brain protein quantitative trait loci with large-scale genome-wide association studies for both disorders. We utilized transcriptome-wide association studies (TWAS) to determine the consistency of mRNA-protein dysregulation in both disorders. We applied pleiotropy-informed conditional false discovery rate (pleioFDR) analysis to identify common risk genetic loci for SCZ and BD-I. Additionally, we performed a cell-type-specific analysis in the human brain to detect risk genes notably enriched in distinct brain cell types. The impact of risk gene overexpression on dendritic arborization and axon length in neurons was also examined. STUDY RESULTS: Our PWAS identified 42 proteins associated with SCZ and 14 with BD-I, among which NEK4, HARS2, SUGP1, and DUS2 were common to both conditions. TWAS and MR analysis verified the significant risk gene NEK4 for both SCZ and BD-I. PleioFDR analysis further supported genetic risk loci associated with NEK4 for both conditions. The cell-type specificity analysis revealed that NEK4 is expressed on the surface of glutamatergic neurons, and its overexpression enhances dendritic arborization and axon length in cultured primary neurons. CONCLUSIONS: These findings underscore a shared genetic origin for SCZ and BD-I, offering novel insights for potential therapeutic target identification.

A Novel tsRNA, m7G-3' tiRNA LysTTT, Promotes Bladder Cancer Malignancy Via Regulating ANXA2 Phosphorylation.

Emerging evidence indicates that transfer RNA (tRNA)-derived small RNAs (tsRNAs), originated from tRNA with high abundance RNA modifications, play an important role in many complex physiological and pathological processes. However, the biological functions and regulatory mechanisms of modified tsRNAs in cancer remain poorly understood. Here, it is screened for and confirmed the presence of a novel m7G-modified tsRNA, m7G-3'-tiRNA LysTTT (mtiRL), in a variety of chemical carcinogenesis models by combining small RNA sequencing with an m7G small RNA-modified chip. Moreover, it is found that mtiRL, catalyzed by the tRNA m7G-modifying enzyme mettl1, promotes bladder cancer (BC) malignancy in vitro and in vivo. Mechanistically, mtiRL is found to specifically bind the oncoprotein Annexin A2 (ANXA2) to promote its Tyr24 phosphorylation by enhancing the interactions between ANXA2 and Yes proto-oncogene 1 (Yes1), leading to ANXA2 activation and increased p-ANXA2-Y24 nuclear localization in BC cells. Together, these findings define a critical role for mtiRL and suggest that targeting this novel m7G-modified tsRNA can be an efficient way for to treat BC.

Deciphering the Genetic Variation: A Comparative Analysis of Parental and Attenuated Strains of the QXL87 Vaccine for Infectious Bronchitis.

The QXL87 live attenuated vaccine strain for infectious bronchitis represents the first approved QX type (GI-19 lineage) vaccine in China. This strain was derived from the parental strain CK/CH/JS/2010/12 through continuous passage in SPF chicken embryos. To elucidate the molecular mechanism behind its attenuation, whole-genome sequencing was conducted on both the parental and attenuated strains. Analysis revealed 145 nucleotide mutations in the attenuated strain, leading to 48 amino acid mutations in various proteins, including Nsp2 (26), Nsp3 (14), Nsp4 (1), S (4), 3a (1), E (1), and N (1). Additionally, a frameshift mutation caused by a single base insertion in the ORFX resulted in a six-amino-acid extension. Subsequent comparison of post-translational modification sites, protein structure, and protein-protein binding sites between the parental and attenuated strains identified three potential virulence genes: Nsp2, Nsp3, and S. The amino acid mutations in these proteins not only altered their conformation but also affected the distribution of post-translational modification sites and protein-protein interaction sites. Furthermore, three potential functional mutation sites-P106S, A352T, and L472F, all located in the Nsp2 protein-were identified through PROVEAN, PolyPhen, and I-Mutant. Overall, our findings suggest that Nsp2, Nsp3, and S proteins may play a role in modulating IBV pathogenicity, with a particular focus on the significance of the Nsp2 protein. This study contributes to our understanding of the molecular mechanisms underlying IBV attenuation and holds promise for the development of safer live attenuated IBV vaccines using reverse genetic approaches.