Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis.

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

The IL-15-AKT-XBP1s signaling pathway contributes to effector functions and survival in human NK cells.

Interleukin 15 (IL-15) is one of the most important cytokines that regulate the biology of natural killer (NK) cells1. Here we identified a signaling pathway-involving the serine-threonine kinase AKT and the transcription factor XBP1s, which regulates unfolded protein response genes2,3-that was activated in response to IL-15 in human NK cells. IL-15 induced the phosphorylation of AKT, which led to the deubiquitination, increased stability and nuclear accumulation of XBP1s protein. XBP1s bound to and recruited the transcription factor T-BET to the gene encoding granzyme B, leading to increased transcription. XBP1s positively regulated the cytolytic activity of NK cells against leukemia cells and was also required for IL-15-mediated NK cell survival through an anti-apoptotic mechanism. Thus, the newly identified IL-15-AKT-XBP1s signaling pathway contributes to enhanced effector functions and survival of human NK cells.

Neutral lysophosphatidylcholine mediates α-synuclein-induced synaptic vesicle clustering.

α-synuclein (α-Syn) is a presynaptic protein that is involved in Parkinson's and other neurodegenerative diseases and binds to negatively charged phospholipids. Previously, we reported that α-Syn clusters synthetic proteoliposomes that mimic synaptic vesicles. This vesicle-clustering activity depends on a specific interaction of α-Syn with anionic phospholipids. Here, we report that α-Syn surprisingly also interacts with the neutral phospholipid lysophosphatidylcholine (lysoPC). Even in the absence of anionic lipids, lysoPC facilitates α-Syn-induced vesicle clustering but has no effect on Ca2+-triggered fusion in a single vesicle-vesicle fusion assay. The A30P mutant of α-Syn that causes familial Parkinson disease has a reduced affinity to lysoPC and does not induce vesicle clustering. Taken together, the α-Syn-lysoPC interaction may play a role in α-Syn function.

Application of GWAS summary data and drug-induced gene expression profiles of neural progenitor cells in psychiatric drug prioritization analysis.

Common psychiatric disorders constitute one of the most substantial healthcare burdens worldwide. However, drug development in psychiatry remains hampered partially due to the lack of approaches to estimating drugs that can simultaneously modulate the expression of a nontrivial fraction of disease susceptibility genes. We proposed a new drug prioritization strategy under the framework of our previously proposed phenotype-associated tissues estimation approach (DESE) by investigating the drugs' selective perturbation effect on disease susceptibility genes. Based on the genome-wide association study summary data and drug-induced gene expression profiles of neural progenitor cells, we applied this strategy to prioritize candidate drugs for schizophrenia, depression and bipolar I disorder and identified several known therapeutic drugs among the top-ranked drug candidates. Also, our results revealed that the disease susceptibility genes involved in the selective gene perturbation analysis were enriched with many biologically sensible function terms and interacted with known therapeutic drugs. Our results suggested that selective gene perturbation analysis could be a promising starting point to prioritize biologically sensible drug candidates under the "one drug, multiple targets" paradigm for the drug development of common psychiatric disorders.

The Tox Gene Encodes Two Proteins with Distinct and Shared Roles in Gene Regulation.

Here we report that the murine Tox gene encodes two proteins from a single mRNA, and we investigate the mechanism of production and function of these proteoforms. The annotated thymocyte selection-associated HMG-box protein (TOX) coding sequence is predicted to produce a 526-aa protein (TOXFL). However, Western blots reveal two bands. We found that the lower band consists of an N-terminally truncated variant of TOX (TOXΔN), whereas the slower-migrating band is TOXFL. The TOXΔN proteoform is alternatively translated via leaky ribosomal scanning from an evolutionarily conserved translation initiation site downstream of the annotated translation initiation site. When expressed exogenously from a cDNA in murine CD8 T cells or HEK cells, or endogenously from the murine Tox locus, both forms are translated, although the ratio of TOXFL/TOXΔN significantly varies with cellular context. This includes regulation of proteoform production during development of murine CD4 T cells in the thymus, where the positive selection of CD4+CD8+ cells and subsequent differentiation to CD4+CD8lo transitional and CD4SP cell subsets is associated with both an increase in total TOX protein and increased TOXΔN production relative to TOXFL. Finally, we found that sole expression of TOXFL had a greater effect on gene regulation during chronic stimulation of murine CD8 T cells in culture mimicking exhaustion than did TOXΔN, including uniquely regulated cell cycle and other genes.

A vitamin-C-derived DNA modification catalysed by an algal TET homologue.

Methylation of cytosine to 5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. Sequential oxidation of 5mC by ten-eleven translocation (TET) dioxygenases results in a cascade of additional epigenetic marks and promotes demethylation of DNA in mammals1,2. However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green alga Chlamydomonas reinhardtii contains a 5mC-modifying enzyme (CMD1) that is a TET homologue and catalyses the conjugation of a glyceryl moiety to the methyl group of 5mC through a carbon-carbon bond, resulting in two stereoisomeric nucleobase products. The catalytic activity of CMD1 requires Fe(II) and the integrity of its binding motif His-X-Asp, which is conserved in Fe-dependent dioxygenases3. However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate4, CMD1 uses L-ascorbic acid (vitamin C) as an essential co-substrate. Vitamin C donates the glyceryl moiety to 5mC with concurrent formation of glyoxylic acid and CO2. The vitamin-C-derived DNA modification is present in the genome of wild-type C. reinhardtii but at a substantially lower level in a CMD1 mutant strain. The fitness of CMD1 mutant cells during exposure to high light levels is reduced. LHCSR3, a gene that is critical for the protection of C. reinhardtii from photo-oxidative damage under high light conditions, is hypermethylated and downregulated in CMD1 mutant cells compared to wild-type cells, causing a reduced capacity for photoprotective non-photochemical quenching. Our study thus identifies a eukaryotic DNA base modification that is catalysed by a divergent TET homologue and unexpectedly derived from vitamin C, and describes its role as a potential epigenetic mark that may counteract DNA methylation in the regulation of photosynthesis.

CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis.

In addition to responding to environmental entrainment with diurnal variation, metabolism is also tightly controlled by cell-autonomous circadian clock. Extensive studies have revealed key roles of transcription in circadian control. Post-transcriptional regulation for the rhythmic gating of metabolic enzymes remains elusive. Here, we show that arginine biosynthesis and subsequent ureagenesis are collectively regulated by CLOCK (circadian locomotor output cycles kaput) in circadian rhythms. Facilitated by BMAL1 (brain and muscle Arnt-like protein), CLOCK directly acetylates K165 and K176 of argininosuccinate synthase (ASS1) to inactivate ASS1, which catalyzes the rate-limiting step of arginine biosynthesis. ASS1 acetylation by CLOCK exhibits circadian oscillation in human cells and mouse liver, possibly caused by rhythmic interaction between CLOCK and ASS1, leading to the circadian regulation of ASS1 and ureagenesis. Furthermore, we also identified NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 (NDUFA9) and inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as acetylation substrates of CLOCK. Taken together, CLOCK modulates metabolic rhythmicity by acting as a rhythmic acetyl-transferase for metabolic enzymes.

ONE-seq: epitranscriptome and gene-specific profiling of NAD-capped RNA.

The hub metabolite, nicotinamide adenine dinucleotide (NAD), can be used as an initiating nucleotide in RNA synthesis to result in NAD-capped RNAs (NAD-RNA). Since NAD has been heightened as one of the most essential modulators in aging and various age-related diseases, its attachment to RNA might indicate a yet-to-be discovered mechanism that impacts adult life-course. However, the unknown identity of NAD-linked RNAs in adult and aging tissues has hindered functional studies. Here, we introduce ONE-seq method to identify the RNA transcripts that contain NAD cap. ONE-seq has been optimized to use only one-step chemo-enzymatic biotinylation, followed by streptavidin capture and the nudix phosphohydrolase NudC-catalyzed elution, to specifically recover NAD-capped RNAs for epitranscriptome and gene-specific analyses. Using ONE-seq, we discover more than a thousand of previously unknown NAD-RNAs in the mouse liver and reveal epitranscriptome-wide dynamics of NAD-RNAs with age. ONE-seq empowers the identification of NAD-capped RNAs that are responsive to distinct physiological states, facilitating functional investigation into this modification.

Metal-Organic Framework (MOF)-Based Clean Energy Conversion: Recent Advances in Unlocking its Underlying Mechanisms.

Carbon neutrality is an important goal for humanity . As an eco-friendly technology, electrocatalytic clean energy conversion technology has emerged in the 21st century. Currently, metal-organic framework (MOF)-based electrocatalysis, including oxygen reduction reaction (ORR), oxygen evolution reaction (OER), hydrogen evolution reaction (HER), hydrogen oxidation reaction (HOR), carbon dioxide reduction reaction (CO2RR), nitrogen reduction reaction (NRR), are the mainstream energy catalytic reactions, which are driven by electrocatalysis. In this paper, the current advanced characterizations for the analyses of MOF-based electrocatalytic energy reactions have been described in details, such as density function theory (DFT), machine learning, operando/in situ characterization, which provide in-depth analyses of the reaction mechanisms related to the above reactions reported in the past years. The practical applications that have been developed for some of the responses that are of application values, such as fuel cells, metal-air batteries, and water splitting have also been demonstrated. This paper aims to maximize the potential of MOF-based electrocatalysts in the field of energy catalysis, and to shed light on the development of current intense energy situations.

Head-to-head comparison of magnetic resonance elastography-based liver stiffness, fat fraction, and T1 relaxation time in identifying at-risk NASH.

BACKGROUND AND AIMS: The presence of at-risk NASH is associated with an increased risk of cirrhosis and complications. Therefore, noninvasive identification of at-risk NASH with an accurate biomarker is a critical need for pharmacologic therapy. We aim to explore the performance of several magnetic resonance (MR)-based imaging parameters in diagnosing at-risk NASH. APPROACH AND RESULTS: This prospective clinical trial (NCT02565446) includes 104 paired MR examinations and liver biopsies performed in patients with suspected or diagnosed NAFLD. Magnetic resonance elastography-assessed liver stiffness (LS), 6-point Dixon-derived proton density fat fraction (PDFF), and single-point saturation-recovery acquisition-calculated T1 relaxation time were explored. Among all predictors, LS showed the significantly highest accuracy in diagnosing at-risk NASH [AUC LS : 0.89 (0.82, 0.95), AUC PDFF : 0.70 (0.58, 0.81), AUC T1 : 0.72 (0.61, 0.82), z -score test z >1.96 for LS vs any of others]. The optimal cutoff value of LS to identify at-risk NASH patients was 3.3 kPa (sensitivity: 79%, specificity: 82%, negative predictive value: 91%), whereas the optimal cutoff value of T1 was 850 ms (sensitivity: 75%, specificity: 63%, and negative predictive value: 87%). PDFF had the highest performance in diagnosing NASH with any fibrosis stage [AUC PDFF : 0.82 (0.72, 0.91), AUC LS : 0.73 (0.63, 0.84), AUC T1 : 0.72 (0.61, 0.83), |z| <1.96 for all]. CONCLUSION: Magnetic resonance elastography-assessed LS alone outperformed PDFF, and T1 in identifying patients with at-risk NASH for therapeutic trials.

Association of gum treatment with cognitive decline and dementia risk among older adults with periodontal symptoms: a 12-year prospective cohort study.

INTRODUCTION: This study examines the associations of gum treatment with cognitive decline and dementia risk among older adults with periodontal symptoms in the US. METHODS: A cohort of 866 adults aged ≥50 with periodontal symptoms was recruited for the 2008 Health and Retirement Study "Dental Health Experimental Module" and followed until 2020. Cognitive function was assessed with the Telephone Interview for Cognitive Status (TICS). Dementia status was ascertained with the Langa-Weir algorithm based on TICS scores and proxy assessments. Linear mixed-effects model and multivariable Cox regression models were utilized to analyze the associations of gum treatment with cognitive decline and the risk of dementia, respectively. RESULTS: Of 866 participants (mean age 67.7, 61.4% women), 105 (12.1%) developed dementia with a median 9 (IQR, 6-10) years follow-up. The dementia incidence rates were lower in the group with gum treatment (7.4 vs. 12.9 per 1,000 person-years). Compared with participants who did not have gum treatment, those with gum treatment experienced a decline in TICS score that was on average 0.025 (95% CI, 0.005-0.044) points less per year and a 38% lower incidence of dementia (Hazard Ratio, 0.62; 95% CI, 0.41-0.93). These associations were consistent across participants with different severity of periodontal symptoms and sociodemographic characteristics (age, sex, race, ethnicity, and education) except for income levels. CONCLUSION: Prompt gum treatment for older adults with periodontal symptoms may be beneficial for their cognitive health.

3D-CEUS/MRI-CEUS fusion imaging vs 2D-CEUS after locoregional therapies for hepatocellular carcinoma: a multicenter prospective study of therapeutic response evaluation.

OBJECTIVES: To compare the diagnostic accuracy of 3D contrast-enhanced ultrasound (CEUS)/MRI-CEUS fusion imaging with 2D-CEUS in assessing the response of hepatocellular carcinoma (HCC) to locoregional therapies in a multicenter prospective study. MATERIALS AND METHODS: A consecutive series of patients with HCC scheduled for locoregional treatment were enrolled between April 2021 and March 2023. Patients were randomly divided into 3D-CEUS/MRI-CEUS fusion imaging group (3D/fusion group) or 2D-CEUS group (2D group). CEUS was performed 1 week before and 4-6 weeks after locoregional treatment. Contrast-enhanced MRI (CE-MRI) 4-6 weeks after treatment was set as the reference standard. CEUS images were evaluated for the presence or absence of viable tumors. Diagnostic performance criteria, including sensitivity, specificity, accuracy, and area under the curve (AUC), were determined for each modality. RESULTS: A total of 140 patients were included, 70 patients in the 2D group (mean age, 60.2 ± 10.4 years) and 70 patients in the 3D/fusion group (mean age, 59.8 ± 10.6 years). The sensitivity of the 3D/fusion group was 100.0% (95% CI: 75.9, 100.0), higher than that of the 2D group (55.6%, 95% CI: 22.7, 84.7; p = 0.019). The specificity of the 3D/fusion group was 96.3% (95% CI: 86.2, 99.4), which was comparable to that of the 2D group (98.4%, 95% CI: 90.0, 99.9; p = 0.915). The AUC of the 3D/fusion group was 0.98 (95% CI: 0.95, 1.00), higher than that of the 2D group (0.77, 95% CI: 0.56, 0.98; p = 0.020). CONCLUSION: 3D-CEUS/MRI-CEUS fusion imaging exhibits superior diagnostic accuracy in evaluating the treatment response to locoregional therapies for HCC. CLINICAL RELEVANCE STATEMENT: 3D-CEUS/MRI-CEUS fusion imaging can be applied for post-treatment assessment of residual tumors in HCC undergoing locoregional treatment, offering potential benefits in terms of accurate diagnosis and clinical management. KEY POINTS: Evaluating for HCC recurrence following locoregional therapy is important. 3D-CEUS/MRI-CEUS fusion imaging achieved a higher sensitivity than 2D-CEUS in assessing residual tumors after locoregional therapies. 3D-CEUS/MRI-CEUS fusion imaging can help clinicians intervene early in residual HCC lesions after locoregional treatment.

The effect of metformin on urate metabolism: Findings from observational and Mendelian randomization analyses.

AIM: To evaluate the effect of metformin on urate metabolism. MATERIALS AND METHODS: Using the UK Biobank, we first performed association analyses of metformin use with urate levels, risk of hyperuricaemia and incident gout in patients with diabetes. To explore the causal effect of metformin on urate and gout, we identified genetic variants proxying the glycated haemoglobin (HbA1c)-lowering effect of metformin targets and conducted a two-sample Mendelian randomization (MR) utilizing the urate and gout genetic summary-level data from the CKDGen (n = 288 649) and the FinnGen cohort. We conducted two-step MR to explore the mediation effect of body mass index and systolic blood pressure. We also performed non-linear MR in the UK Biobank (n = 414 055) to show the results across HbA1c levels. RESULTS: In 18 776 patients with type 2 diabetes in UK Biobank, metformin use was associated with decreased urate [ß = -4.3 µmol/L, 95% confidence interval (CI) -7.0, -1.7, p = .001] and reduced hyperuricaemia risk (odds ratio = 0.87, 95% CI 0.79, 0.96, p = .004), but not gout. Genetically proxied averaged HbA1c-lowering effects of metformin targets, equivalent to a 0.62% reduction in HbA1c, was associated with reduced urate (ß = -12.5 µmol/L, 95% CI -21.4, -4.2, p = .004). Body mass index significantly mediated this association (proportion mediated = 33.0%, p = .002). Non-linear MR results suggest a linear trend of the effect of metformin on urate reduction across various HbA1c levels. CONCLUSIONS: The effect of metformin may reduce urate levels but not incident gout in the general population.

Electrochemical Cross-Coupling between N-(4-Hydroxyphenyl)-sulfonamides and 2-Naphthols: Synthesis of 2,2'-Bis(arenol)s.

We herein present an electrochemical method for the dehydrogenative cross-coupling of N-(4-hydroxyphenyl)-sulfonamides and 2-naphthols. This transformation provides a direct and scalable approach to a wide range of C1-symmetric 2,2'-bis(arenol)s with moderate to high yields under mild conditions. Preliminary attempts with the asymmetric variant of this reaction were also performed with ≤55% ee for the synthesis of 2,2'-bis(arenol)s. Control experiments were conducted to propose a plausible mechanism for the reaction.

Different Anti-inflammatory Drugs on High-Sensitivity C-Reactive Protein in Patients After Percutaneous Coronary Intervention: A Pilot Randomized Clinical Trial.

ABSTRACT: Colchicine reduces atherothrombotic cardiovascular events in coronary artery disease because of its anti-inflammatory effect. However, the effects of the other anti-inflammatory drugs in coronary artery disease remain unclear. This study included 132 patients aged 18-80 years who completed the planned percutaneous coronary interventions and were treated with aggressive secondary prevention strategies for 4 weeks. The subjects were randomly assigned to 1 of the following treatment groups for 4 weeks: (1) control: no additional intervention; (2) colchicine: 0.5 mg once a day; (3) tranilast: 0.1 g thrice a day; or (4) oridonin: 0.5 g thrice a day. The primary outcome was the percentage change in high-sensitivity C-reactive protein (hsCRP) levels at the end of 4 weeks. In total, 109 patients completed the study. The mean age was 58.33 years, 81 (74.31%) were male, and 28 (25.69%) were female. The percentage changes in hsCRP after 4 weeks of treatment were -11.62%, -48.28%, -21.60%, and -7.81%, in the control, colchicine, tranilast, and the oridonin groups, respectively. Compared with the control group, only the colchicine group showed significantly greater reduction in hsCRP levels ( P = 0.022). In targeted proteomic analysis, proteins associated with neutrophil activation (azurocidin, myeloperoxidase, and myeloblastin), platelet aggregation (glycoprotein VI), and endothelial damage (galectin-3) were reduced with colchicine therapy. These results show that of 3 anti-inflammatory drugs only colchicine could reduce hsCRP in patients after percutaneous coronary interventions.

Gender differences in symptom burden among people living with HIV/AIDS receiving antiretroviral therapy in Yunnan, China.

ABSTRACTLittle is known about gender differences in the symptom burden of people living with HIV/AIDS (PLWHA) on antiretroviral therapy in China. This study was conducted based on a biopsychosocial-medical model to describe gender differences in symptom burden among 1035 PLWHA in Yunnan Province, China. After propensity score matching, 798 PLWHA were included in this analysis. Feeling stressed, poor sleep, and memory loss were the most burdensome symptoms among men, while feeling stressed, memory loss, and dizziness were the most burdensome symptoms among women. Among men PLWHA, factors associated with symptom burden were being of the ethnic minority, CD4 count ≥ 500 cells/mm3, physical functioning, and social support. Among women PLWHA, factors associated with symptom burden were being an inpatient, physical functioning, psychological functioning, and social support. Our findings suggest that healthcare providers need to take into account gender differences when developing optimal prevention, treatment, and care programs that provide individualized care to reduce patients' symptom burden.

Grouper OTUB1 and OTUB2 promote red-spotted grouper nervous necrosis virus (RGNNV) replication by inhibiting the host innate immune response.

Red-spotted grouper nervous necrosis virus (RGNNV) is a major viral pathogen of grouper and is able to antagonize interferon responses through multiple strategies, particularly evading host immune responses by inhibiting interferon responses. Ovarian tumor (OTU) family proteins are an important class of DUBs and the underlying mechanisms used to inhibit interferon pathway activation are unknown. In the present study, primers were designed based on the transcriptome data, and the ovarian tumor (OTU) domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) and OTUB2 genes of Epinephelus coioides (EcOTUB1 and EcOTUB2) were cloned and characterized. The homology alignment showed that both EcOTUB1 and EcOTUB2 were most closely related to E. lanceolatus with 98 % identity. Both EcOTUB1 and EcOTUB2 were distributed to varying degrees in grouper tissues, and the transcript levels were significantly up-regulated following RGNNV stimulation. Both EcOTUB1 and EcOTUB2 promoted replication of RGNNV in vitro, and inhibited the promoter activities of interferon stimulated response element (ISRE), nuclear transcription factors kappaB (NF-κB) and IFN3, and the expression levels of interferon related genes and proinflammatory factors. Co-immunoprecipitation experiments showed that both EcOTUB1 and EcOTUB2 could interact with TRAF3 and TRAF6, indicating that EcOTUB1 and EcOTUB2 may play important roles in interferon signaling pathway. The results will provide a theoretical reference for the development of novel disease prevention and control techniques.

OsMKK1 is a novel element that positively regulates the Xa21-mediated resistance response to Xanthomonas oryzae pv. oryzae in rice.

KEY MESSAGE: OsMKK1, a MAPK gene, positively regulates rice Xa21-mediated resistance response and also plays roles in normal growth and development process of rice. The mitogen-activated protein kinase (MAPK) cascade was highly conserved among eukaryotes, which played crucial roles in plant responses to pathogen infection. Bacterial blight is the most devastating bacterial disease. Xa21 confers broad-spectrum resistance to Xanthomonas oryzae pv. Oryzae (Xoo). This study identified that the transcription level of OsMKK1 was up-regulated in resistant response against Xoo, thus overexpression (OsMKK1-OX) and RNA interference (OsMKK1-RNAi) transgenic rice lines under the background of Xa21 was constructed. Compared with recipient control plants 4021, the OsMKK1-OX lines significantly enhanced disease resistance to Xoo, on the contrary, the resistance of OsMKK1-RNAi lines was weakened, demonstrated that OsMKK1 played a positive role in Xa21-mediated disease resistance pathway. A number of pathogenesis-related proteins, including PR1A, PR2 and PR10A showed enhanced expression in OsMKK1-OX lines, supported that these PR genes may be regulated by OsMKK1 to participate in the defense responses. In addition, the agronomic traits of OsMKK1 transgenic plants were affected. Overall, these results revealed the role of OsMKK1 in Xa21-mediated resistance against Xoo and in the normal growth and development process in rice.

Comprehensive Analysis of Sphingolipid Metabolism-Related Genes in Osteoarthritic Diagnosis and Synovial Immune Dysregulation.

BACKGROUND Osteoarthritis (OA) is a chronic degenerative disease characterized by synovitis and has been implicated in sphingolipid metabolism disorder. However, the role of sphingolipid metabolism pathway (SMP)-related genes in the occurrence of OA and synovial immune dysregulation remains unclear. MATERIAL AND METHODS In this study, we obtained synovium-related databases from GEO (n=40 for both healthy controls and OA) and analyzed the expression levels of SMP-related genes. Using 2 algorithms, we identified hub genes and developed a diagnostic model incorporating these hub genes to predict the occurrence of OA. Subsequently, the hub genes were further validated in peripheral blood samples from OA patients. Additionally, CIBERSORT and MCP-counter analyses were employed to explore the correlation between hub genes and immune dysregulation in OA synovium. WGCNA was used to determine enriched modules in different clusters. RESULTS Overall, the expression levels of SMP genes were upregulated in OA synovium. We identified 6 hub genes of SMP and constructed an excellent diagnostic model (AUC=0.976). The expression of re-confirmed hub genes showed associations with immune-related cell infiltration and levels of inflammatory cytokines. Furthermore, we observed heterogeneity in the expression patterns of hub genes across different clusters of OA. Notably, older patients displayed increased susceptibility to elevated levels of pain-related inflammatory cytokines and infiltration of immune cells. CONCLUSIONS The SMP-related hub genes have the potential to serve as diagnostic markers for OA patients. Moreover, the 4 hub genes of SMP demonstrate wide participation in immune dysregulation in OA synovium. The activation of different pathways is observed among different populations of patients with OA.

Relationship between abnormal pelvic floor electromyography and obstetric factors in postpartum women: a cross-sectional study.

OBJECTIVE: To evaluate the surface electromyography (sEMG) of pelvic floor muscles (PFMs), compare between vaginal birth and cesarean section and correlate with maternity and obstetrics characteristics in primiparous 6-8 weeks postpartum. METHODS: PFMs surface electromyography screening data of primiparous postpartum women in our hospital at 6-8 weeks postpartum from 2018 to 2021 were selected and analyzed. The study collected data on delivery activities of 543 postpartum women totally. RESULTS: In general, the abnormal incidence of pelvic floor electromyography in postpartum women mainly occurred in slow muscle (type I fiber) stage and endurance testing stage. Compared to vaginal birth postpartum women, the incidence of abnormal pelvic floor electromyography in cesarean section postpartum women is lower. There were statistical differences in measurement values of pelvic floor electromyography in several different stages between cesarean section and vaginal birth (P < 0.005). Regarding the influence on pelvic floor electromyography, there were more influencing factors on vaginal birth postpartum women including age, height, weight, weight gain during pregnancy, gestational week, and first and second stage of labor than on cesarean section postpartum women whose influencing factors included age, weight gain during pregnancy, and newborn weight. CONCLUSION: Effects on surface electromyography (sEMG) of pelvic floor muscles (PFMs) at 6-8 weeks postpartum differed based on the different modes of delivery. The high-risk obstetric factors closely related to abnormal surface electromyography (sEMG) of pelvic floor muscles (PFMs) were maternal age, height, weight, and second stage of labor.