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To investigate whether W' in the extreme-intensity domain is smaller, yet linked to the W' predicted by the severe-intensity time series. Twelve recreationally active participants (four females) completed 1) three extreme-intensity and three severe-intensity constant-power output (PO) trials to establish the PO duration series and to obtain W' within their respective domains (W'EXT and W'SVR, respectively); 2) two decremental protocols from extreme-to-severe (EXT1→SVR3) and from severe-to-severe POs (SVR2→SVR3); 3) one extreme- and one severe-intensity constant-PO trial preceded by priming exercise (EXT1P and SVR2P, respectively); and 4) control extreme- and severe-intensity constant-PO trials. Peak values for oxygen uptake (V̇O2peak), blood lactate concentration ([La-]b-peak), and minute ventilation (V̇Epeak) were also analyzed. W'EXT was significantly smaller than W'SVR (P < 0.001). There was no difference in W' between the composite EXT1→SVR3 and SVR2→SVR3 and SVR3 alone (all P > 0.05). Priming-induced increase in W'EXT and W'SVR was not different (P = 0.401). V̇O2peak, V̇Epeak, and [La-]b-peak were all greater in EXT1P compared with EXT1 (all P < 0.05). We showed that W'EXT is smaller than W'SVR during cycling. Following task failure during EXT1, more work could be performed at SVR3 until complete depletion of W'SVR. Additionally, heavy-intensity priming exercise increased W'EXT and W'SVR by a similar magnitude. Collectively, these findings suggest that performance within the extreme-intensity domain is limited by mechanisms, at least in part, different from those that limit performance within the severe-intensity domain. Show less

B-cell maturation antigen (BCMA) is the main target for chimeric antigen receptor (CAR)-T cells in multiple myeloma (MM), demonstrating promising outcomes. However, unlike what happens with CART19 in lymphoblastic leukemia and non-Hodgkin's lymphoma, a high proportion of patients will relapse after CAR-T BCMA therapy due to insufficient antigen expression, low CAR-T cell persistence and/or T-cell exhaustion. In other B cell malignancies, second-generation anti-CD19 4-1BB CARs with CD28-transmembrane domain (TMD) have shown high efficacy and a favorable toxicity profile. We have developed a second-generation CD8α-TM BCMA-4-1BBζ CAR-T product, ARI0002h (Cesnicabtagene-autoleucel) for patients with relapsed/refractory MM. We hypothesized that replacing the TMD of ARI0002h with a CD28-TMD could increase efficacy and reduce tumor escape while maintaining a tolerable toxicity profile. We generated CAR-T cells using T-cells isolated from buffy coats and evaluated the efficacy and fitness of CAR-Ts at day 8-10 of expansion against several MM cell lines. In vitro analyses included cytotoxicity, proliferation, cytokine secretion, T-cell subset markers, activation and exhaustion profiling, metabolomic assays, and RNA-seq after multiple tumor challenges. In in vivo xenograft studies using NSG mice, with tumor cells expressing GFP-ffLuc, disease progression was monitored weekly via bioluminescence imaging. Despite showing similar in vitro performance regarding cytotoxicity, proliferation and cytokine production, ARI2h-TM28 outperforms ARI0002h in a low BCMA expression setting and achieves superior in vivo tumor control and survival in relapse models with antigen downregulation. Furthermore, ARI2h-TM28 showed an optimized metabolic profile, more oxidative and energetic compared with ARI0002h, with downregulation of proinflammatory genes in CD8 T cells, contributing altogether both to reduced exhaustion and increased persistence of the CARs, improving their efficacy in preclinical models. Incorporating a CD28-TMD into the ARI0002h CAR enhances tumor control even in relapse models with downregulation of the target antigen, offering improved long-term disease management. This modification increases potency against MM tumor cell lines with both normal and reduced BCMA expression, demonstrating superior metabolic endurance and in vivo activity. Show less

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults and can be seen in association with other diseases, including malignancy, drugs, infections, or autoimmune diseases. Over the last decade, great progress has been made in understanding the pathogenesis of the disease, resulting from the discovery of several target antigens by use of laser microdissection/mass spectrometry methodology. This technique has proven to be the most sensitive method available and has the advantage of testing for all the target antigens at one time. The discovery of these target antigens has now shifted the classification of MN from primary versus secondary to classification based on the target antigen identified. Each target antigen has its own specific clinical characteristics and known associated diseases. Identification of the target antigen can help further identify the underlying cause for a more targeted approach in looking for associated diseases. Progress has also been made in the treatment of patients with MN, with more standard risk stratification of the patients and a shift in using anti-CD20 drugs as the first line for those with moderate and high risk of progression. Trials are ongoing to further investigate the role of anti-plasma cell, anticomplement, and CAR-T (chimeric antigen receptor T-cell) therapies. Show less

Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG data sets. Unsupervised clustering categorized patients with HF into LacRG-based subgroups. An LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing expression patterns. HF mouse models were constructed and verified for LacRG expression. In 200 HF versus 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunologic features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (area under the curve: 0.999, 1.000, 0.744). Single-cell RNA sequencing (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T-cell, and NK-cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External data sets (GSE46224, GSE116250) identified 6 hub genes-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. In addition, analysis of HF dataset further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and 6 hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF through immune microenvironmental mechanisms. Show less

Valproic acid (VPA) is recognized for its neurotrophic properties and is widely used in psychiatric and peripheral disorders, while dextromethorphan (DM) has demonstrated anti-inflammatory and neuroprotective effects. This study examined whether adjunctive DM provides additional benefits on cognitive or immunomodulatory beyond standard VPA treatment in bipolar disorder (BD). BD aged 20-65 received open-label VPA (500-2500 mg/day; target blood level 50-100 μg/dl) for one week and were then randomized to VPA plus placebo (BDVPA) or VPA plus extended-release DM (BDVPA + DM; 30 or 60 mg/day) for twelve weeks. Neuropsychological measures (Continuous Performance Test, CPT; Wechsler Memory Scale-Revised, WMS-R), symptom severity, cytokines, and BDNF were assessed at baseline and post-treatment. A total of 109 participants (mean age 31.04 years, SD = 10.04) were enrolled; 96 completed cognitive testing and blood sampling (66 BD Show less

MicroRNAs, as key regulators in gene expression, may hold the key to understanding Alzheimer disease (AD) pathogenesis and diagnosis. To explore the expression level of miR-106b-3p in the serum of AD patients, and evaluate its diagnostic value for AD. A total of 250 AD patients and 200 healthy controls were enrolled. Real-time quantitative PCR with fluorescence detection was used to determine the relative expression level of miR-106b-3p. Correlation was analyzed by the Pearson linear correlation analysis. The receiver operating characteristic was used to evaluate the diagnostic efficacy of serum miR-106b-3p for AD. In vitro AD cellular models were established to explore the potential mechanism of miR-106b-3p in AD. The expression of miR-106b-3p in the serum of AD patients is significantly elevated, and its level is negatively correlated with the MMSE score. ROC curve analysis shows that it has certain diagnostic value. miR-106b-3p is a risk factor associated with AD. In addition, miR-106b-3p targets BDNF, affects the functions of SH-SY5Y cells, and promotes the occurrence and development of AD. Serum miR-106b-3p is significantly elevated in AD and may serve as a diagnostic biomarker. Preliminary evidence suggests it promotes AD progression by targeting BDNF, highlighting its potential as a therapeutic target for early intervention. Show less

This study aimed to investigate how nano curcumin (Nano-Cur) or nano-chromium chloride (Nano-CrCl) in comparison with metformin (Met), can reduce diabetic neuropathy caused by streptozotocin (STZ) in rats. Seventy Wistar albino male rats were randomly divided into seven groups (ten rats/group): control; STZ-induced diabetes; diabetic rats receiving daily oral doses of Nano-Cur, Cur, Nano-CrCl, CrCl, and Met. The present results show that all treated groups significantly alleviated diabetic neuropathy by restoring serum insulin and glucose levels, enhancing cerebral antioxidant activities and activating IR/PI3K/AKT, normalizing neurotransmitters, decreasing oxidative stress markers (MDA), and reducing inflammatory biomarkers and pyroptotic biomarkers. At the molecular level, the levels of GSK3B, JAK-2, STAT-3, AMPK, and BACE1 were significantly downregulated in all treated diabetic groups compared to the diabetic group, especially Nano-Cur and Met. However, Cur, Nano-CrCl, and CrCl did not cause any significant (p > 0.05) alteration in ACh levels compared to the diabetic group. Additionally, the Nano-Cur, Cur, and Met groups exhibited a marked increase in miRNA-223-3p and miRNA-124 levels, whereas Nano-CrCl and CrCl showed no significant changes in these miRNAs when compared to the diabetic group. Show less

Familial hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C), leading to a high risk of early onset atherosclerotic cardiovascular disease (ASCVD). This document provides an update to the National Lipid Association's 2011 clinical guidance, summarizing the remarkable progress in the field. With a global prevalence of approximately 1 in 311, FH remains severely underdiagnosed. This guidance reviews current diagnostic criteria, including the expanding role of genetic testing to complement diagnosis and to facilitate cascade screening, and emphasizes a thorough differential diagnosis. It provides recommendations for universal pediatric screening and systematic cascade screening in families to improve detection. Management strategies include intensified LDL-C treatment goals for both primary and secondary prevention of ASCVD. A stepwise approach to optimal therapy is outlined, beginning with lifestyle interventions and pharmacotherapy with maximally tolerated statins and ezetimibe. This update incorporates newer agents, including proprotein convertase subtilisin/kexin type 9 inhibitors and bempedoic acid. Additional therapies, such as lomitapide and evinacumab for homozygous FH and lipoprotein apheresis for heterozygous and homozygous FH, are discussed. Further topics include cardiovascular imaging for risk stratification, management in specific populations and circumstances, such as planning for and during pregnancy and in pediatrics, and recognition of health disparities. This guidance equips clinicians with evidence-based strategies to improve the identification and care of patients with FH, ultimately reducing the high morbidity and mortality associated with this condition. Show less

Metabolic side effects represent a major long-term concern in antipsychotic (AP)-treated early psychosis. We evaluated the weight gain and changes in related metabolic parameters in patients followed up for 12 months. We also explored DNA methylation of four genes associated with weight gain (ADRA2A, INSIG2, LEP, MC4R). We included patients aged 15-64 years followed in the Ribeirão Preto Early Intervention in Psychosis Program from two different cohorts (Clinical sample, n = 147; Epigenetic sample, n = 59). DNA methylation was analysed by pyrosequencing only at baseline, after several weeks of AP exposure. In both cohorts, 40% of patients initially received second-generation antipsychotics (SGAs), increasing to over 70% after one year. Clinical sample: At follow-up, patients exhibited significant increases in body mass index (p < 0.001), triglycerides (p < 0.001), HDL-c (p = 0.001) and LDL-c (p < 0.001). Patients predominantly on SGAs during the 12 months had almost three times higher chance of weight gain than those using haloperidol. Other factors associated with weight gain included non-white skin colour (OR = 2.6), fewer years of schooling (OR = 2.5) and a weight gain of at least 7% at three months (OR = 3.1). Epigenetic sample: Patients receiving SGA treatment (median = 23.4 weeks) at baseline showed hypermethylation within the MC4R promoter region in relation to patients using haloperidol (median = 18.6 weeks). No changes in the baseline methylation of other genes related to weight gain or AP drugs were observed longitudinally. MC4R promoter hypermethylation in SGA-treated patients suggests drug-induced metabolic alterations and a potential role of MC4R as a biomarker for predicting AP-related metabolic risk. Show less

Pain is one of the leading causes of disability worldwide. Despite the various pharmacological treatments available, patients with chronic pain often remain with significant disabilities and unsatisfactory pain control. Cannabis and cannabinoids are sometimes used in the treatment of chronic pain as they have been shown to be useful in a subset of patients. Some of the adverse effects associated with cannabis use, such as cannabis use disorder (CUD) and cannabis-induced psychosis, have been associated with several genetic variants. Despite this, the paucity of the data or the contradictory results for reported variants limits our ability to use them as genetic markers to personalize cannabis treatment tailored to patients’ genetic background. The aim of this genetic association study was to investigate the link between previously reported genes and cannabinoid response in terms of pain response, CUD and risk of psychotic adverse events in patients with chronic pain. Phone or in person interviews were conducted to document participants’ characteristics, cannabis use and effects, concurrent pharmacotherapy and comorbid conditions. Screening for CUD was performed using the Cannabis Use Disorders Identification Test – Revised. Blood or saliva samples were collected for the genotyping of 18 variants in 11 genes ( One hundred participants were recruited, with blood or saliva samples collected from 77 of them. Two single-nucleotide polymorphisms (SNP) in cannabinoid receptor 1 ( These results suggest alternative allele carriers of rs1049353 and rs2023239 could be at an increased risk of psychotic adverse events related to cannabis use, although additional investigation is required to replicate and confirm these findings. The online version contains supplementary material available at 10.1186/s42238-026-00408-w. Show less

The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases. Show less

Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE Show less

Imaging studies showed early atrophy of the cholinergic basal forebrain (BF) already at prodromal stages of sporadic Alzheimer's disease (AD). Women and carriers of the ApoE epsilon 4 (ApoE ε4) allele are more likely to develop the disease; however, the underlying mechanisms are still unclear. Here we aimed at exploring the impact of sex and ApoE ε4 genotype in the AD spectrum on longitudinal measures of the basal forebrain and hippocampus, as a comparison region. We leveraged the German multi-centered study DELCODE and analyzed 712 individuals (median age: 71.25 years, interquartile range [IQR] = 9.22) with follow-up MRI scans (median time: 2.8 years, [IQR] = 1.75). Diagnostic groups comprised cognitively normal ( The hippocampus, but not the basal forebrain, showed significant atrophy over time (Hipp: Our findings did not show the anticipated longitudinal effects of sex and ApoE ε4 on longitudinal basal forebrain volume. Only hippocampal atrophy progressed significantly faster in ApoE ε4 homozygote carriers. This dissociation may reflect stage-dependent neurodegenerative processes, with early basal forebrain vulnerability followed by more rapid hippocampal decline, as well as methodological and sample-related constraints. If replicated, these findings suggest that hippocampal measures may be more sensitive longitudinal biomarkers in ApoE ε4 homozygotes, while sex- and ApoE ε4-related effects on the cholinergic system may be more prominent at earlier disease stages. Show less

Atherosclerotic cardiovascular diseases (ASCVDs) remain the primary cause of morbidity and mortality. Macrophages are involved in the progression and regression of atherosclerosis, and macrophage amino acid metabolism is important during this process. Here, we identified that the expression of cystine/glutamate antiporter Slc7a11 was upregulated by oxidized low-density lipoprotein, and specifically enhanced in the macrophages of atherosclerotic plaques. Macrophage-specific Show less

Methodological challenges diminish the number and reliability of longitudinal studies on executive functions (EFs) starting in infancy. To address this, the current study used latent profile analysis (LPA) to examine EF task performance across three age points: 8 months, 2.5 years, and 5 years. Participants were children (N = 830; 55.5% boys; > 95% White) from the FinnBrain Birth Cohort Study. Three profiles were identified: constant below average EF profile (14.2%), and two average EF profiles differentiated by Spin the Pots performance (working memory) at 5 years (above average 29.8%, below average 56%). Expected associations between the below average EF profile, male sex, and lower general cognitive performance were found, further supporting the validity of the profiles. Show less

This study aimed to investigate changes in brain structure and function of hippocampus in aged type 2 diabetes mellitus (T2DM) rats and the effects of tea polyphenol (TP) intervention using magnetic resonance imaging (MRI) and tissue-level molecular analyses. Rats were randomly assigned to six groups: Control, Aged, Aged T2DM, Aged T2DM + TP, Aged T2DM + rosiglitazone, and Aged T2DM + piracetam intervention groups. Anxiety- and depression-like behaviors were assessed using the open field test, the forced swimming test and elevated plus maze. Brain structure, blood flow and neuro-associated metabolites were evaluated via MRI. The number of nerve cells, neurons, microglia and astrocytes, the expression of BDNF/CREB/p-CREB protein, the levels of inflammatory factors, and the integrity of the myelin sheath in the hippocampus were evaluated. Relationships between behavioral, cellular and molecular changes and MRI-derived indicators were evaluated by Pearson correlation analysis. Aged T2DM rats exhibited severe anxiety- and depression-like behaviors accompanied by brain atrophy, reduced blood flow and decreased brain metabolites. At the microstructural level, the number of hippocampal neurons in the Aged T2DM group was significantly reduced, accompanied by increased counts of microglia and astrocytes. Meanwhile, the expression levels of hippocampal p-CREB and BDNF were decreased, the concentration of the inflammatory factor IL-1β, IL-6, TNF-α was elevated, and myelin integrity was impaired. Intervention with TP alleviated anxiety- and depression-like behavior, with MRI-detected abnormalities and in vitro histopathological molecular changes improved (except for myelin integrity). TP intervention mitigated alterations in brain structure and function as well as anxiety and depression-like behaviors in aged T2DM rats. Show less

The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology. We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold ( Show less

Gibberellins have been reported to play both positive and negative roles in arbuscular mycorrhizal (AM) symbioses. Despite extensive characterisation of the role of DELLAs in AM colonisation, studies of gibberellin function have largely been restricted to chemical interventions. Few studies have examined how disruption to gibberellin biosynthesis affects AM symbioses. To explore this further, we obtained Show less

Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer's disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with Show less

Personality traits are associated with cognitive resilience to dementia-related neuropathology. This study examines whether personality traits are related to cognitive resilience to accelerated epigenetic aging. Participants were adults aged from 50 to 98 years (N = 2926, 58% female, Mean age = 68.72, SD = 9.57) from the Health and Retirement Study (HRS). Data on cognition and epigenetic aging measures (GrimAge and DunedinPoAM38) were obtained in 2016. Data on personality, demographic factors, and clinical, behavioral, and psychological covariates were obtained in 2014/2016. Cognitive resilience was defined as the residual from the regression of cognition on epigenetic aging measures. Controlling for demographic factors, linear regression analyses indicated that higher neuroticism was associated with worse-than-expected cognition relative to one's epigenetic aging for both GrimAge and DunedinPoAM38 epigenetic measures. Higher conscientiousness and openness were related to better-than-expected cognition relative to one's epigenetic aging across the two measures. Logistic regression further indicated that higher neuroticism was associated with a lower likelihood of cognitive resilience to accelerated epigenetic aging, whereas higher conscientiousness and openness were related to a higher likelihood of cognitive resilience. These associations were partially accounted for by disease burden, sleep quality, physical activity, smoking, depressive symptoms, childhood adversity, lifetime trauma, and APOE e4 status, and persisted when participants with cognitive impairment were excluded. There was little evidence that age or sex moderated the associations. The present study expands the literature on resilience from neuropathology to a broader systemic impact of aging to provide novel evidence that personality traits are associated with cognitive resilience to accelerated epigenetic aging. Show less

Chronic Kidney Disease (CKD) has emerged as a significant global public health concern, with membranous Nephropathy (MN) being the most prevalent pathological type of nephrotic syndrome in adults. MN is classified as an antibody-mediated autoimmune disease. There is a growing interest in the research of MN-related antigens. Furthermore, the treatment of MN predominantly relies on the administration of immunosuppressants, with traditional regimens such as corticosteroids and cyclophosphamide, which have significant side effects, and rituximab, having a 35-40% failure rate, highlighting the critical need for the development of specific and effective immunotherapy strategies. In this review, we summarized the research progress on newly discovered MN-related antigens, including exostosin 1/exostosin 2(EXT1/EXT2), Neural Cell Adhesion Molecule 1 (NCAM-1), Neural Epidermal Growth Factor-like 1 (NELL-1), Contactin 1 (CNTN1), Semaphorin 3B, High-Temperature Recombinant Protein A1 (HTRA1), protocadherin FAT atypical cadherin 1(FAT1) and Protocadherin 7(PCDH7). Among them, NELL-1 and HTRA1 primarily serve as target antigens for primary MN, and their serum antibody titers show a strong correlation with disease activity. While EXT1/EXT2, NCAM1, CNTN-1, and FAT1 mainly act as target antigens for secondary MN. In addition, we evaluated the clinical applications and efficacy of novel immunosuppressants and therapeutic approaches, including new anti-CD20 antibodies, proteasome inhibitors, anti-plasma cell therapies, belimumab, complement inhibitors, and immunoadsorption. The new anti-CD20 agents represented by obalimumab and obinutuzumab, along with anti-plasma cell therapies such as daratumumab, have emerged as ideal alternatives for patients with rituximab resistance. Other therapeutic approaches, including complement inhibitors, immunoadsorption, and belimumab, have also exhibited their unique advantages. Show less

Depression is one of the most prevalent and disabling non-motor symptoms in Parkinson's disease (PD), forming a bidirectional relationship with motor dysfunction that worsens quality of life. Pharmacological treatments exhibit limited and inconsistent efficacy, and may lead to adverse interactions. Acupuncture may improve both depressive and motor symptoms by regulating the neuro-immune-endocrine network, but high-quality evidence remains insufficient. This study aims to evaluate the efficacy and safety of acupuncture as an adjunctive therapy for depression in PD and to explore potential biological correlates of clinical changes using predefined serum biomarkers. In this single-center, evaluator-blinded, randomized controlled trial, 88 patients with PD and comorbid depression will be randomly assigned to an acupuncture group or a waitlist control group. The primary outcome is the change in the Montgomery-Asberg Depression Rating Scale (MADRS) score. Secondary outcomes include motor function, anxiety, sleep quality, and overall quality of life. Exploratory analyses will assess serum inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and kynurenine/tryptophan (KYN/TRP) ratio. We hypothesize that adjunctive acupuncture may improve depressive and motor symptoms compared with the control. Exploratory analyses will examine whether clinical changes are associated with changes in relevant biomarkers. This study will provide rigorous evidence for acupuncture as an adjunctive therapy, offering a non-pharmacological strategy to optimize the comprehensive management of PD and disrupt the bidirectional emotion-motor interplay. https://www.chictr.org.cn/, identifier ChiCTR2500113443. Show less

The gut microbiome and the central nervous system are intricately connected through a bidirectional communication system that plays a vital role in maintaining gut homeostasis and overall health. Disruptions in this interaction are linked to gastrointestinal and neuropsychiatric disorders, including anxiety. This review aims to provide a comprehensive analysis of the gut microbiota's role in anxiety and evaluate the therapeutic potential of prebiotics. This review synthesizes recent literature from databases including PubMed, Scopus, Web of Science, and Google Scholar, focusing on the gut microbiota's role in anxiety and the therapeutic potential of prebiotics. The microbiota-gut-brain axis communicates through multiple pathways, including the vagus nerve, immune signaling, microbial metabolites, and the hypothalamic-pituitary-adrenal (HPA) axis. Prebiotics modulate these pathways by enhancing beneficial microbial populations and influencing the production of neuroactive compounds. Key molecular targets implicated in this communication include brain-derived neurotrophic factor (BDNF), glucocorticoid receptors, and shortchain fatty acids, which modulate neurotransmitters such as GABA and serotonin, and influence neuroinflammatory pathways implicated in anxiety pathophysiology. The findings highlight the immunological, neurochemical, and endocrine mechanisms through which the gut microbiota interacts with neurophysiological systems. These mechanisms underscore the pharmacological potential of prebiotics in the management of psychiatric illnesses. The interplay between the gastrointestinal microbiota and neurophysiological systems provides key pharmacological insights into the potential of prebiotics as a therapeutic approach for managing psychiatric illnesses, detailing their mechanistic pathways and translational applications in clinical practice. Show less

Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the treatment of HS is of critical importance. Using summary statistics from the eQTLGen Consortium, Decode database, and FinnGen cohort, we conducted transcriptome-wide and proteome-wide Mendelian randomization (MR) to discover potential pharmacological targets against HS, with subsequent validation via RNA sequencing. Upstream regulators and downstream mechanisms were further investigated to better understand the roles of the pathogenic gene. Drug prediction, molecular docking, and molecular dynamics (MD) simulation were employed to estimate the value of potential drugs for HS. A high level of fibroblast growth factor receptor 1 (FGFR1) significantly increased the risk of HS according to transcriptome-wide (P = 0.011) and proteome-wide MR (P = 0.002) analyses. RNA-seq further validated the high expression of FGFR1 in HS. Gene-gene interaction network and enrichment analysis identified FGFR1 as the core gene driving the progression of HS, highlighting multiple biosynthetic processes. Pharmacological evaluation of candidate drugs predicted stable binding between Ro-4396686 and FGFR1. Our findings suggest that FGFR1 can serve as promising target for optimizing HS treatments, potentially reducing the costs of drug development. Show less

Mammalian genomes harbor hundreds of thousands of RNA polymerase II (RNA Pol II) landing pads, enhancers, and promoters from which transcription initiates bidirectionally. Nevertheless, processive transcription is largely restricted to the small gene-containing fraction of the genome. An essential metazoan complex, Restrictor, composed of WDR82 and ZC3H4, restrains processive RNA Pol II activity at extragenic transcription units, thus representing a critical enforcer of genome utilization. However, because of the widespread recruitment of Restrictor to both genic and non-genic transcription sites, the mechanistic basis for its selectivity for extragenic transcription is unclear. Here, we show that while WDR82 tethers Restrictor to transcription initiation sites, the C3H1-type zinc fingers of ZC3H4 make sequence-specific interactions with motifs enriched at the 5' end of extragenic transcripts, with such interactions being required for transcription termination. Hence, although Restrictor recruitment requires WDR82-dependent tethering to the initiating RNA Pol II, its selectivity mainly arises from sequence-specific RNA recognition. Show less

This study aimed to analyze the clinical features, genetic basis, and management of late-onset carbamoyl phosphate synthetase 1 deficiency (CPS1D) through a pediatric case report and literature review, highlighting diagnostic challenges and therapeutic strategies. We present a 19-year-old female with recurrent neurological symptoms since age 8. She underwent comprehensive metabolic screening, neuroimaging, and whole-exome sequencing of theCPS1gene. Identified variants were assessed for pathogenicity using multiple orthogonalin silicoprediction tools. The patient's initial hyperammonemic crisis at age 8 was misdiagnosed as encephalitis. Workup at age 13 confirmed hyperammonemia (peak 168 µmol/L), hypocitrullinemia, and elevated glutamine. Genetic analysis identified compound heterozygousCPS1variants: a novel c.1058 T > C (p.F353S) and known pathogenic c.1145C > T (p.P382L). A self-selected low-protein diet controlled acute crises but led to severe growth failure (height 145 cm, weight 30 kg). Late-onset CPS1D's nonspecific neurological symptoms often lead to misdiagnosis. Diagnosis requires a high index of suspicion, integrating metabolic profiling with genetic confirmation. This case expands the pathogenic genotypic spectrum of CPS1D. It crucially highlights that while dietary management is life-saving, it requires expert multidisciplinary oversight to prevent devastating consequences like growth failure, especially in resource-limited settings. Routine ammonia testing in unexplained encephalopathy is paramount. Show less