BackgroundIn myasthenia crisis (MC), plasma exchange (PE) and intravenous immunoglobulin (IVIG) are confirmed effective treatment options, but PE may not be available in time, and the response rate to IVIG is not always satisfactory. This study aimed to investigate whether addition of efgartigimod confers benefits in patients with MC.MethodsThis real-world retrospective pilot study examined MC patients admitted to the First Affiliated Hospital of Sun Yat-sen University between August 2023 and May 2024, who were categorized into two groups: the traditional immunotherapy group (n = 14) and the add-on efgartigimod group (n = 9). In the efgartigimod group, patients received 20 mg/kg efgartigimod (n = 9), administered on the first and fifth days.ResultsTotally 23 patients were recruited in the study. Total hospital stays, MV duration, and non-invasive ventilation time were shorter in the efgartigimod group compared with the traditional immunotherapy group; however, these differences were not statistically significant (p > 0.05). We subsequently applied a generalized estimating equation (GEE) to the patients over an 8-week period and observed a reduction in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores in both groups; however, no significant differences were found within the groups (p > 0.05). Survival analysis was also conducted, revealing that the addition of efgrtigimod allowed patients to reach the MSE state more quickly, which is statistically significant (p = 0.0499). Additionally, three patients with MC who only received high-dose efgartigimod treatment all achieved favorable treatment outcomes.ConclusionThis suggests that efgartigimod may serve as an alternative option for MC patients or as a rescue treatment option for refractory individuals.

Hyperuricaemia (HUA) is a metabolic disorder resulting from the dysregulation of purine metabolism. It is closely associated with gout and various metabolic syndromes, representing an increasing global public health challenge. Current treatment approaches for HUA and gout generally involve the lifelong administration of urate-lowering agents to maintain optimal serum urate concentrations. However, poor patient adherence, often due to potential hepatorenal toxicity, frequently leads to disease relapse. Recent evidence indicates that the gut microbiota plays a significant role in maintaining urate homeostasis through multiple mechanisms, including the modulation of purine metabolism, urate catabolism and excretion, regulation of inflammatory responses, and preservation of intestinal barrier integrity. These findings highlight the gut microbiota as a promising novel therapeutic target. This review synthesizes recent progress in three key areas: (1) the relationship between the gut microbiota and HUA; (2) microbial mechanisms underlying urate-lowering effects, such as microbial purine and urate metabolism, regulation of urate transporters like ABCG2, and production of anti-inflammatory metabolites; and (3) microbiota-based therapeutic interventions, including probiotics, engineered bacterial strains, fecal microbiota transplantation, and pharmabiotic strategies. Additionally, we explore the translational potential of microbiota modulation in clinical settings and outline directions for future research. By integrating mechanistic understanding with therapeutic innovation, this review offers researchers and clinicians a comprehensive framework for advancing microbiota-targeted approaches in the management of hyperuricaemia.

INTRODUCTION:The aim of this study was to investigate the diagnostic utility of brain Magnetic resonance imaging (MRI) in anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDAR encephalitis) and analyze the relationship between clinical and brain MRI characteristics and disease prognosis. METHODS:A retrospective analysis was conducted on forty-six (59% female, median age: 24.5 years) clinically identified anti-NMDAR encephalitis patients from December 2012 to April 2022. All the patients underwent multiparametric MRI, with thirteen returning for follow-up. All the relevant clinical information was collected. The initial and follow-up brain MRI was sequentially analyzed for signal abnormalities, involvement of anatomy and structure, and brain/structure atrophy by two experienced neuroradiologists. Additionally, the relationship between clinical and brain MRI features and prognosis was examined. RESULTS:The most common symptom (33/46, 72%) in anti-NMDAR encephalitis was aberrant psychiatric behavior. Five (10%) cases combined with other positive antibodies. Although 91% of patients with mRS >2 before treatment, a statistically significant decrease mRS were observed after treatment (mRS: 3.50 ± 0.94 vs. mRS: 1.91 ± 1.53, p < 0.001). More than half of the patients had abnormal MRI findings. T2-weighted fluid-attenuated inversion recovery (FLAIR) hyperintense lesions that involve the frontal lobe and the limbic system are the characteristic imaging predilection of anti-NMDAR encephalitis. On follow-up MRI, we noticed 5 patients with significant hippocampal atrophy. Further analysis showed that the hippocampal involvement was a significant factor in predicting worse mRS scores both before and after treatment (p < 0.05). CONCLUSION:T2-FLAIR hyperintense lesions in the frontal lobe and the limbic system are indicative of anti-NMDAR encephalitis. The involvement of the hippocampus is a risk factor for a poor prognosis.

Objective: This study was aimed at evaluating the efficacy of the "zipper method," a novel treatment strategy combining alternating plasma exchange (PLEX) and intravenous immunoglobulin (IVIG) pulse therapy, in adult patients with severe Guillain-Barr & eacute; syndrome (GBS) requiring mechanical ventilation.Methods: A retrospective analysis was conducted on seven adult patients diagnosed with severe GBS and treated with mechanical ventilation from June 2022 to August 2023. Three received the "zipper method" (alternating PLEX and IVIG pulse therapy), and the other four were treated with the classic method (PLEX followed by IVIG pulse therapy). Clinical outcomes, including duration of continuous mechanical ventilation (CMV), length of stay (LOS) in the ICU, total hospital stay, muscle strength recovery as measured by the Muscle Research Council (MRC) score, and Guillain-Barr & eacute; Syndrome Disability Scale (GBS-DS) and days to unaided walking, were compared between the two groups.Results: The "zipper method" group exhibited significant improvements in clinical outcomes compared to the classic method group. Specifically, the duration of CMV was reduced to 17.67 days, the LOS in the ICU was 22.33 days, the mean days to hospital discharge were 40.67 days, and the MRC score at 1 month was 43.67 and at 2 months was 56.67. Furthermore, the GBS-DS score at 2 months posttreatment was 1.00 and the mean days to unaided walking were 80.6 days, indicating a marked reduction in disability.Conclusion: The "zipper method" offers a promising new approach for the treatment of severe GBS in adults, leading to faster recovery of muscle strength and shorter ICU stays and length of hospital stay. This treatment strategy has the potential to improve patient outcomes and reduce the burden of severe GBS on healthcare systems. Further research, including prospective studies and randomized controlled trials, is warranted to validate these findings and explore the broader applicability of the "zipper method" in adult GBS treatment.

Background: Urinary tract infections (UTIs) rank among the most prevalent infectious diseases globally, with recurrent UTIs (rUTIs) posing substantial therapeutic challenges due to the lack of durable protective immunity. While trained immunity augments innate immune responses, its induction and functional significance in bladder-resident group 3 innate lymphoid cells (ILC3s) remain unknown. This study investigates whether ILC3s develop trained immunity following uropathogenic Escherichia coli (UPEC) exposure and how they contribute to mucosal defense against rUTIs. Methods: The ILC3 counts were detected in bladder sections from UTI patients and health controls (HC). A recurrent UTI mouse model was established through primary and secondary urethral UPEC inoculation. Bacterial loads in tissues were assessed, and single-cell suspensions were analyzed via flow cytometry. Bladder naïve- and UPEC-trained ILC3s were adoptively transferred, with evaluations of histopathology, epithelial barrier function, inflammation, and antimicrobial peptides. The in vitro ILC3 cell line MNK-3 was detected for IL-17A and IL-22 production following primary and secondary UPEC lysate stimulation. Results: We demonstrate that primary UPEC infection triggers ILC3 expansion in both human and murine bladders. Upon secondary challenge, these ILC3s develop trained immunity, characterized by enhanced proliferation, amplified IL-17A and IL-22 production, and improved pathogen clearance. Mechanistically, trained ILC3s reinforce urothelial barrier integrity through upregulation of antimicrobial peptides (Reg3b/Reg3g) and attenuate inflammatory pathology by suppressing pro-inflammatory cytokines (IL-6, TNF-α). Conclusions: We uncover an endogenous defense mechanism wherein UPEC primes bladder ILC3s via trained immunity, enabling amplified IL-17A- and IL-22-mediated protection against recurrent infections. These findings establish ILC3-trained immunity as a novel conceptual foundation, providing a basis for developing immunotherapies against rUTIs.

The CHAMP1 complex, a little-known but highly conserved protein complex consisting of CHAMP1, POGZ, and HP1α, is enriched in heterochromatin though its cellular function in these regions of the genome remain unknown. Here we show that the CHAMP complex promotes heterochromatin assembly at multiple chromosomal sites, including centromeres and telomeres, and promotes homology-directed repair (HDR) of DNA double strand breaks (DSBs) in these regions. The CHAMP1 complex is also required for heterochromatin assembly and DSB repair in highly-specialized chromosomal regions, such as the highly-compacted telomeres of ALT (Alternative Lengthening of Telomeres) positive tumor cells. Moreover, the CHAMP1 complex binds and recruits the writer methyltransferase SETDB1 to heterochromatin regions of the genome and is required for efficient DSB repair at these sites. Importantly, peripheral blood lymphocytes from individuals with CHAMP1 syndrome, an inherited neurologic disorder resulting from heterozygous mutations in CHAMP1, also exhibit defective heterochromatin clustering and defective repair of DSBs, suggesting that a defect in DNA repair underlies this syndrome. Taken together, the CHAMP1 complex has a specific role in heterochromatin assembly and the enhancement of HDR in heterochromatin.

Background: Balamuthia mandrillaris is a free-living amoebic parasite that primarily causes rare opportunistic infections in immunocompromised hosts. Balamuthia amoebic encephalitis (BAE) is a rare yet severe parasitic infection affecting the central nervous system. It has an extremely low incidence in China but can have a mortality rate as high as 98%. The clinical manifestations of amebic infections are similar to those of bacterial and tuberculous meningitis, lacking specificity, which makes accurate diagnosis challenging in the clinical setting. Case Presentation: A 61-year-old immunocompetent woman experienced worsening headache and a moderate fever over the course of five days, initially treated as a common cold. On 25 February 2025, she exhibited behavioral abnormalities, dysphagia, and a high fever of 40.2 °C, which progressed to a coma. On 26 February, her cranial CT scan revealed multifocal hemorrhagic lesions in the right frontotemporoparietal lobes. The MRI revealed similar lesions with slight enhancement and herniation. She underwent an emergency decompressive craniectomy, yet her condition continued to deteriorate following the surgery. On 27 February, serum targeted next-generation sequencing (tNGS) detected B. mandrillaris. Additionally, metagenomic NGS (mNGS) of the cerebrospinal fluid (CSF) sample confirmed the presence on 28 February. Finally, B. mandrillaris was identified through a brain tissue biopsy on 3 March. However, due to the delayed diagnosis and lack of effective drugs, her condition rapidly deteriorated and became irreversible. Her family ultimately chose to withdraw treatment. Conclusions: This study highlights the application of NGS for early diagnosis of patients with severe CNS infection. Both tNGS and mNGS can be considered for the rapid detection of rare or novel pathogens and for facilitating diagnosis.

OBJECTIVE:Limited evidence has led to ongoing debate about the benefits of thymectomy for late-onset myasthenia gravis (LOMG). This study aims to compare the outcomes of patients with LOMG who underwent thymectomy versus those who received medical treatment alone, and evaluate the incidence of surgical adverse events. METHODS:Non-thymomatous acetylcholine-receptor antibody positive patients with LOMG were selected from a multi-center longitudinal clinical database. Rates of and time to response (remission and minimal manifestations status) were compared between 2 groups by propensity score matching (PSM), Kaplan-Meier analysis, and Cox regression models. Additionally, the incidence of adverse events about thymectomy was compared between LOMG and younger patients with myasthenia gravis (MG) aged 40 to 50 years old. RESULTS:A total of 55 and 210 patients with LOMG were enrolled in the thymectomy and medical treatment groups, respectively. The thymectomy group exhibited significantly younger onset age (56.31 ± 6.15 vs. 62.04 ± 7.83, p < 0.001). After PSM adjustment, thymectomy demonstrated a greater cumulative probability (p < 0.001), and the 2.356-fold (95% confidence interval [CI] = 1.537-3.612, p < 0.001) higher chance of better outcomes compared to medical treatment. In subgroup analysis, thymectomy showed significantly higher response rates compared to medical treatment alone at 24 ± 2 months (48.9%, 95% CI = 33.7-64.1% vs 23.8%, 95% CI = 14.2-33.3%, p = 0.004), and 36 ± 2 months (59.5%, 95% CI = 42.9-76.1% vs 28.9%, 95% CI = 18.5-39.4%, p = 0.002). The incidences of adverse events were comparable between patients with LOMG and younger patients with MG (32.0% vs 22.4%, p = 0.286). INTERPRETATION:Thymectomy may be an effective therapeutic option for LOMG. Our findings highlight the need for further development of a randomized trial targeting patients with LOMG. ANN NEUROL 2026;99:629-638.

Myasthenic crisis (MC) refers to rapid deterioration of myasthenia gravis (MG), affecting lung and bulbar muscles and causing breathing difficulties. Currently, efgartigimod has shown good therapeutic effects in patients with generalized myasthenia gravis (GMG). This retrospective real-world study explored the effectiveness of efgartigimod in patients with MC. Reviewing the clinical data of five patients (including four patients with refractory MC) with MC who received efgartigimod at the First Affiliated Hospital of Sun Yat-sen University, all of these patients were admitted from September 2023 to December 2023. Each patient received 20 mg/kg of efgartigimod on the first and fifth day. After discharge, all patients showed a clinically meaningful decrease in Myasthenia Gravis Activities of Daily Living (MG-ADL) scale (a decrease of ≥ 2 points) and an improvement in their lung function. Additionally, all patients had a decrease in IgG levels (58.59 ± 18.48

BACKGROUND As a non-coding RNA molecule, circular RNAs (circRNAs) have significant specificity, and existing data suggest a close relationship between them and the prognosis of patients with gastric cancer (GC). However, this mechanism has no evidence yet. This article explores the functions of hsa_circRNA_102415 in the malignant behavior and potential downstream signaling of GC cells. The chosen approach is loss of signal and functional gain. AIM To investigate and analyze the relationship between hsa_circRNA_102415 and GC and explore its specific role. Results provide reference for other researchers to develop targeted treatment plans. METHODS The gene expression omnibus (GEO) database can be used to obtain the microarray dataset GSE83521. Data were analyzed using the GEO2R tool to identify differences in circRNAs between normal and GC samples. Quantitative real-time polymerase chain reaction was used to detect differentially expressed genes in GC tissue samples and adjacent cancer tissue samples. GC cells were transfected with small interfering-hsa_circRNA_104415 and plasmid DNA (pcDNA)-hsa_ircRNA_102415. Multiple detection methods, such as Transwell and cell counting kit 8, were used to evaluate cellular physiological activities, including cell invasion and proliferation. The relationship between Wnt family members 2B, microRNA (miR)-4529-5p, etc. , including argonaute 2-RNA immunoprecipitation and luciferase reporter genes was analyzed. Rescue experiments were conducted to analyze and explore the relationship between the malignant behavior of GC cells and hsa_circRNA_102415. RESULTS GEO2R analysis confirmed that hsa_circRNA_102415 had significantly higher expression levels in disease tissues. hsa_circRNA_102415 and miR-4529-5p showed a negative correlation in disease cells, suggesting that hsa_ circRNA_102415 upregulated WNT2B expression in GC cells as a competing endogenous RNA for miR-4529-5p. miR-4529-5p mimic or small interfering-WNT2B reversed the effects of pcDNA-hsa_circRNA_102415 or miR-4529-5p inhibitor on cell malignant functions. CONCLUSION miR-4529-5p was used to successfully activate the potential of WNT2B , clarify the role of hsa_circRNA_102415 in GC cells, and provide reference for other researchers to develop targeted treatment plans.

Background: In recent years, the impact of visceral fat accumulation on renal damage has garnered significant attention. However, whether visceral fat accumulation contributes to the incidence of both albuminuria and chronic kidney disease (CKD) is still uncertain. Our objective is to look into the possible correlation between visceral adiposity accumulation and incident increased urinary albumin excretion and CKD. Methods: We analyzed data from a cohort of 9916 subjects aged 40 years and above. As an innovative and convenient biomarker of visceral adiposity distribution, visceral adiposity index (VAI) was calculated in accordance with a gender‐specific equation using measurement of blood lipids and anthropometric parameters of obesity. Albuminuria was determined by urine albumin‐to‐creatinine ratio (UACR) ≥ 30 mg/g. CKD was determined by establishment of either of the following: (1) estimated glomerular filtration rate (eGFR) 60 mL/min per 1.73 m 2 or less; (2) UACR ≥ 30 mg/g. Results: During an average follow‐up period of 3.6 ± 0.7 years, 245 (4.7%) subjects developed albuminuria and 332 (6.3%) participants developed CKD. Incidence of albuminuria and CKD had a tendency to advance along with ascending VAI levels in both genders. According to multiple stepwise linear regression analysis, γ‐glutamyltransferase (γ‐GGT), fasting insulin, fasting plasma glucose (FPG), low‐density lipoprotein cholesterol (LDL‐C), and systolic blood pressure (SBP) were independent determinants for VAI. Multivariate‐adjusted hazard ratios (HRs) of albuminuria with 95% confidence intervals (CIs) in Cox regression analysis were 1 (reference), 0.82 (0.53–1.29), 1.50 (1.01–2.23), and 1.52 (1.02–2.26) in ascending quartiles of VAI. Similarly, the HRs with 95% CI of CKD in ascending quartiles of VAI were 1 (reference), 0.96 (0.66–1.41), 1.51 (1.07–2.15), and 1.56 (1.10–2.20). For subgroup analyses, VAI significantly correlated with risk of both albuminuria and CKD in older subjects (age ≥ 58 years), nondiabetes subjects, and non‐ASCVD subjects (all p < 0.05). Conclusions: The greater deposition of visceral fat assessed by VAI is independently associated with risk of increased urinary albumin excretion and CKD in middle‐aged and aged Chinese.

Background:Neutrophil-to-lymphocyte ratio (NLR) and Lymphocyte-to-monocyte ratio (LMR) have been reported to be associated with outcomes in acute ischemic stroke. However, research on elderly populations remains relatively scarce. We investigated the prognosis of NLR and LMR in elderly with acute ischemic stroke(AIS). Methods:Based on the modified Rankin Score (mRS) on the 90th day after stroke, patients were divided into group and bad prognosis groups. Multivariate logistic regression analysis and receiver operating curves were used to identify prognostic factors and their predictive powers. Results:In total, 824 elderly patients with AIS were enrolled between November 2021 and December 2023. Significant differences emerged in the NLR, LMR, and lymphocyte count between the two groups (P<0.05). Binary logistic regression identified NLR, LMR and neutrophil count as independent risk factors for an unfavorable prognosis in elderly patients with AIS. The areas under the curve (AUCs) of NLR, LMR, and the combination of NLR and LMR to discriminate poor function prognosis were 0.703, 0.672, and 0.706, respectively. ROC analysis also showed that combination of NLR and LMR was superior to NLR and LMR alone for predicting AIS. Conclusion:NLR and LMR independently contribute to an unfavorable prognosis in elderly patients with AIS. The area under the ROC curve (AUC) for the combined NLR and LMR was higher than that for NLR and LMR individually, suggesting that combining these two indicators can improve the predictive ability for clinical outcomes in elderly patients with AIS.

Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues—like the kidneys—remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.

Rituximab is recommended as the preferred second-line immunotherapy for autoimmune encephalitis (AE). However, Ofatumumab (OFA), a novel fully human anti-CD20 antibody, has been reported infrequently in patients with AE. Among the various forms of AE, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common and severe. This study presents three cases of severe anti-NMDAR encephalitis treated with OFA following the failure of first-line immunotherapy. The results indicated that the patients experienced no significant adverse reactions after receiving OFA, and their clinical symptoms improved markedly within one week of treatment. One month post-treatment with OFA, scores on the Glasgow Coma Scale (GCS) and the Barthel Index of Activities of Daily Living (Barthel-ADL) increased, while scores on the modified Rankin Scale (mRS), Clinical Assessment Scale in Autoimmune Encephalitis (CASE), and Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) decreased. During the three-month and six-month follow-up periods, patients exhibited further symptomatic improvement, suggesting that OFA is a safe and effective treatment option for anti-NMDAR encephalitis. These findings propose a novel therapeutic strategy for severe refractory anti-NMDAR encephalitis.

Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

Background The prevalence of patients positive for muscle-specific kinase antibody (hereafter, MuSK-Ab) accounts for 5-8% of all myasthenia gravis (MG) cases. Currently, efgartigimod has shown good therapeutic effects in MUSK-Ab-positive MG patients in a phase III clinical trial. However, phase III clinical trials tend to exclude MG patients in exacerbation, and there are only few real-world studies on the efficacy of efgartigimod in MuSK-Ab-positive myasthenic crisis (MC) patients. This retrospective, real-world study aimed to explore the efficacy of efgartigimod in MuSK-Ab-positive MG with exacerbation.Methods We reviewed the clinical data of four MuSK-Ab-positive patients with exacerbation of MG who received efgartigimod at the First Affiliated Hospital of Sun Yat-sen University, including two patients with MC. All patients were admitted between September 2023 and May 2024. Most patients are simultaneously undergoing rituximab treatment.Results Each patient completed one cycle of efgartigimod. After the first administration, four patients showed a clinically meaningful decrease in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score (a reduction of more than 4 points compared to baseline), and all patients showed a decrease in IgG levels after one cycle of efgartigimod. Regarding safety, none of the patients experienced any obvious adverse effects. At the final follow-up, all patients achieved the minimal symptom expression status (an MG-ADL score of 0 or 1) following the first administration of efgartigimod for 8.75 +/- 5.56 weeks. This article presents a case involving a patient who exhibited prompt alleviation of symptoms following the administration of a high dose of efgartigimod (20 mg/kg, given on days 1 and 5), without the use of any other fast-acting treatment.Conclusion This retrospective real-world study demonstrates the effectiveness and safety of efgartigimod in these four MuSK-Ab-positive, female Asian patients with exacerbation of MG, as well as in patients experiencing MC. It is important to note that efgartigimod should not be viewed as a substitute for foundational immunotherapy; rather, it is intended as a rescue treatment during exacerbations and as an adjunctive therapy in the context of long-term immunotherapy. This non-invasive approach has the potential to become another treatment option for MuSK-Ab-positive MG patients.

Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3β (p-GSK-3β), thereby promoting β-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic β-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.

Background: Although obesity and heart rate (HR) were closely related to the prevalence and development of type 2 diabetes mllitus (T2DM), few studies have shown a co-association effect of them on T2DM. We aimed at assessing the interactive effects of HR and obesity with prevalence of T2DM in Chinese population, providing the exact cutpoint of the risk threshold for blood glucose with high HR. Materials and Methods: In the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal study (REACTION) cohorts (N = 8398), the relationship between HR and T2DM was explored by linear regression, logistic regression, and restricted cubic spline, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Interaction terms between HR and body mass index (BMI) and HR and waist circumference (WC) were introduced into the logistic regression model. Result: sIn those with HR > 88.0 beats/min, fasting plasma glucose and oral glucose tolerance tests were significantly correlated with HR, and the prevalence of T2DM was highly correlated with HR (all p < .05). There were interactive associations of HR and obesity in patients with T2DM with HR < 74 beats/min. Conclusion: High HR was in interaction with obesity, associating with prevalence of T2DM. The newly subdivided risk threshold for HR with T2DM might be HR > 88 beats/minute. image

Integrin αvβ6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvβ6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvβ6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvβ6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvβ6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvβ6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvβ6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvβ6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvβ6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvβ6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvβ6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvβ6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvβ6 in renal inflammation, providing a solid rationale for the use of αvβ6 inhibition to treat kidney inflammation and fibrosis.