Synergistic Effect of Ubiquitin-Specific Protease 14 and Poly(ADP-Ribose) Glycohydrolase Co-Inhibition in BRCA1-Mutant, Poly(ADP-Ribose) Polymerase Inhibitor-Resistant Triple-Negative Breast Cancer Cells.

Purpose: The clinical benefits of poly(ADP-ribose) polymerase (PARP) inhibitors are limited to triple-negative breast cancer (TNBC) with BRCA deficiency due to primary and acquired resistance. Thus, there is a pressing need to develop alternative treatment regimens to target BRCA-mutated TNBC tumors that are resistant to PARP inhibition. Similar to PARP, poly(ADP-ribose) glycohydrolase (PARG) plays a role in DNA replication and repair. However, there are conflicting reports on the vulnerability of BRCA1-deficient tumor cells to PARG inhibition. This study aims to investigate the synergistically lethal effect of the PARG inhibitor COH34 and the ubiquitin-specific protease (USP) 14 inhibitor IU1-248 and the underlying mechanisms in BRCA1-mutant, PARP inhibitor-resistant TNBC cells. Methods: The cytotoxicity of PARG inhibition alone or in combination with USP14 inhibition in the BRCA-mutant, PARP inhibitor-resistant TNBC cell lines, HCC1937 and SUM149PT, was analyzed using cell viability and proliferation assays and flow cytometry. The molecular mechanisms underlying the synergistic effects of IU1-248 and COH34 were evaluated by immunofluorescence staining, DNA repair reporter assays and Western blot analysis. Results: It was found that HCC1937 and SUM149PT cells exhibited moderate responsiveness to PARG inhibition alone. To the best of our knowledge, this research is the first to demonstrate that the combination of IU1-248 and COH34 produces synergistic effects against TNBC cells in the same setting. Mechanistically, the blockade of USP14 by IU1-248 was shown to increase DNA damage and promote error-prone non-homologous end joining (NHEJ), as evidenced by the accumulation of γH2AX and 53BP1 in the nucleus and the activation of a reporter assay. Additionally, it was demonstrated that the inhibition of NHEJ repair activity attenuates the synergistic effects of concomitant PARG and USP14 inhibition. IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc. Conclusion: USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.

Navigating Complexity in Postural Orthostatic Tachycardia Syndrome.

Postural Orthostatic Tachycardia Syndrome (POTS) affects up to 1% of the US population, predominantly women, and is characterized by a complex, elusive etiology and heterogeneous phenotypes. This review delves into the intricate physiology and etiology of POTS, decoding the roles of the sinoatrial node, the autonomic nervous system, fluid dynamics, and the interplay between the immune and endocrine systems. It further examines key contributing factors such as dysautonomia, thoracic hypovolemia, autonomic neuropathies, sympathetic denervation, autoimmune responses, and associations with conditions such as small-fiber neuropathy and mast cell activation syndrome. Given the numerous mysteries surrounding POTS, we also cautiously bring attention to sinoatrial node and myocardial function, particularly in how the heart responds to stress despite exhibiting a normal cardiac phenotype at rest. The potential of genomic research in elucidating the underlying mechanisms of POTS is emphasized, suggesting this as a valuable approach that is likely to improve our understanding of the genetic underpinnings of POTS. The review introduces a tentative classification system for the etiological factors in POTS, which seeks to capture the condition's diverse aspects by categorizing various etiological factors and acknowledging co-occurring conditions. This classification, while aiming to enhance understanding and optimize treatment targets, is presented as a preliminary model needing further study and refinement. This review underscores the ongoing need for research to unravel the complexities of POTS and to develop targeted therapies that can improve patient outcomes.

Copy number variations contribute to malignant tumor development in children with serious birth defects.

There are two key signatures of pediatric cancers: (a) higher prevalence of germline alterations and (b) heterogeneity in alteration types. Recent population-based assessments have demonstrated that children with birth defects (BDs) are more likely to develop cancer even without chromosomal anomalies; therefore, explorations of genetic alterations in children with BDs and cancers could provide new insights into the underlying mechanisms for pediatric tumor development. We performed whole-genome sequencing (WGS) on blood-derived DNA for 1556 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumor, 757 cancer-free children with BDs, and 345 healthy individuals, focusing on copy number variation (CNV) analysis. Roughly half of the children with BD-cancer have CNVs that are not identified in BD-only/healthy individuals, and CNVs are not evenly distributed among these patients. Strong heterogeneity was observed, with a limited number of cancer predisposition genes containing CNVs in more than three patients. Moreover, functional enrichments of genes with CNVs showed that dozens of patients have variations related to the same biological pathways, such as deletions of genes with neurological functions and duplications of immune response genes. Phenotype clustering uncovered recurrences of patients with sarcoma: A notable enrichment was observed involving non-coding RNA regulators, showing strong signals related to growth and cancer regulations in functional analysis. In conclusion, we conducted one of the first genomic studies exploring the impact of CNVs on cancer development in children with BDs, unveiling new insights into the underlying biological processes.

[Analysis of the relationship between epistaxis and homocysteine and climatic factors in ultra-high altitude area].

Objective:To analyze the related influencing factors of epistaxis in extremely high altitude area, and to provide evidence for the prevention and treatment of epistaxis in extremely high altitude area. Methods:From January 2021 to December 2022, 206 outpatients with epistaxis, 54 inpatients with epistaxis and 69 inpatients withoutepistaxis in theDepartment of Otorhinolarygology, Naqu People's Hospital were collected. The previous history, drinking history, smoking history, serum homocysteine（Hcy）, white blood cell count（WBC）, red blood cell count（RBC）, hematocrit（HCT）, hemoglobin（HGB） and mean hemoglobin concentration（MCHC） were compared between inpatients with or without epistaxis. The factors with significant differences were analyzed by binary Logistic regression. The monthly average temperature,air pressure, humidity and 2-minute wind speed were collected from January 2021 to December 2022 in Naqu City to analyze the correlation between epistaxis and climate factors. Results:The number of patients with hypertension in the case group was more than that in the control group, and the difference was significant（P=0.013）. Serum Hcy level in the case group was higher than that in the control group（P<0.001）. RBC, HCT, HGB and MCHC were lower than that in the control group（P=0.001, 0.001, 0.001, 0.039）, and the difference was significant. History of hypertension and Hcy were risk factors for epistaxis. Patients with a history of hypertension were 3.713 times more likely to suffer from epistaxis than those without a history of hypertension（P=0.022）. Each 1 increase in Hcy concentration increased the risk of epistaxis by 13.1%（P=0.001）. Conclusion:Patients with epistaxis in Naqu area had higher serum Hcy level and lower RBC, HCT, HGB and MCHC. History of hypertension and Hcy were risk factors for epistaxis. Patients with a history of hypertension were 3.713 times more likely to suffer from epistaxis than those without a history of hypertension. Every 1 increase in Hcy concentration increased the risk of epistaxis by 13.1%. Active intervention of hypertension and serum Hcy can effectively prevent the incidence of epistaxis.

Host selection by thrips is affected by the floral volatile profile of sunflower.

Thrips, Frankliniella intonsa, is a highly polyphagous pest with a worldwide distribution. F. intonsa-infested sunflower seeds show marked visual damage. The study findings revealed that significantly more F. intonsa infested confection sunflower compared to oilseed sunflower, via olfactometer bioassay studies, we found that compared with the flower and pollen of oilseed sunflowers, those of confection sunflowers attract F. intonsa. Considering this discrepancy in the preference of F. intonsa on oilseed and confection sunflowers, the volatiles of the flower and pollens of two sunflowers were analysed by gas chromatography-mass spectroscopy. The behavioural responses of F. intonsa were assessed for these compounds using Y-tube bioassays. Geranyl bromide, a unique volatile component of oilseed sunflowers, induced an assertive approach-avoidance behaviour in F. intonsa, whereas the unique component ethyl isovalerate in confection sunflowers attracted F. intonsa. F. intonsa adults demonstrated significant attraction to the blends of confection sunflowers. Furthermore, field verification revealed that intercropping confection and oilseed sunflowers could effectively control F. intonsa. The study provided insights into the chemical cues used by F. intonsa in locating hosts. Therefore, oilseed sunflowers can be used as repellent plants to prevent F. intonsa invasion.

Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis.

Gastric cancer (GC) is a substantial global health concern, and the development of liver metastasis (LM) in GC represents a critical stage linked to unfavorable patient prognoses. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the immune landscape of GC liver metastasis, revealing several immuno-suppressive components within the tumor immune microenvironment (TIM). Our findings unveiled an increased presence of cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cell (MDSC)-like macrophages, tumor-associated macrophage (TAM)-like macrophages, and naive T cells, while conventional dendritic cells (cDCs) and effector CD8 T cells declined in LM. Additionally, we identified two distinct natural killer (NK) cell clusters exhibiting differential cytotoxicity-related gene expression, with cytotoxic NK cells notably reduced in LM. Strikingly, TGFß was identified as an inducer of NK cell dysfunction, potentially contributing to immune evasion and tumor metastasis. In preclinical LM models, the combined approach of inhibiting TGFß and transferring NK cells exhibited a synergistic impact, resulting in a significant reduction in liver metastasis. This work highlights the importance of understanding the complex immune dynamics within GC liver metastasis and presents a promising strategy combining TGFß inhibition and NK-based immunotherapy to improve patient outcomes.

Nrf2 mediated signaling axis in heart failure: Potential pharmacological receptor.

Heart failure (HF) has emerged as the most pressing health concerns globally, and extant clinical therapies are accompanied by side effects and patients have a high burden of financial. The protein products of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes have a variety of cardioprotective effects, including antioxidant, metabolic functions and anti-inflammatory. By evaluating established preclinical and clinical research in HF to date, we explored the potential of Nrf2 to exert unique cardioprotective functions as a novel therapeutic receptor for HF. In this review, we generalize the progression, structure, and function of Nrf2 research in the cardiovascular system. The mechanism of action of Nrf2 involved in HF as well as agonists of Nrf2 in natural compounds are summarized. Additionally, we discuss the challenges and implications for future clinical translation and application of pharmacology targeting Nrf2. It's critical to developing new drugs for HF.

ZL006 mitigates anxiety-like behaviors induced by closed head injury through modulation of the neural circuit from the medial prefrontal cortex to amygdala.

Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.

A new mechanism of thyroid hormone receptor ß agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles.

Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor ß (THRß) agonist and the first approved drug for NASH treatment. It is well known that the THRß activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl4 (HFD+CCl4)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg-1·d-1, i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THRß activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THRß agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRß activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRß agonists in NASH treatment.

Single-Cell Omics for Transcriptome CHaracterization (SCOTCH): isoform-level characterization of gene expression through long-read single-cell RNA sequencing.

The advent of long-read single-cell transcriptome sequencing (lr-scRNA-Seq) represents a significant leap forward in single-cell genomics. With the recent introduction of R10 flowcells by Oxford Nanopore, we propose that previous computational methods designed to handle high sequencing error rates are no longer relevant, and that the prevailing approach using short reads to compile "barcode space" (candidate barcode list) to de-multiplex long reads are no longer necessary. Instead, computational methods should now shift focus on harnessing the unique benefits of long reads to analyze transcriptome complexity. In this context, we introduce a comprehensive suite of computational methods named Single-Cell Omics for Transcriptome CHaracterization (SCOTCH). Our method is compatible with the single-cell library preparation platform from both 10X Genomics and Parse Biosciences, facilitating the analysis of special cell populations, such as neurons, hepatocytes and developing cardiomyocytes. We specifically re-formulated the transcript mapping problem with a compatibility matrix and addressed the multiple-mapping issue using probabilistic inference, which allows the discovery of novel isoforms as well as the detection of differential isoform usage between cell populations. We evaluated SCOTCH through analysis of real data across different combinations of single-cell libraries and sequencing technologies (10X + Illumina, Parse + Illumina, 10X + Nanopore_R9, 10X + Nanopore_R10, Parse + Nanopore_R10), and showed its ability to infer novel biological insights on cell type-specific isoform expression. These datasets enhance the availability of publicly available data for continued development of computational approaches. In summary, SCOTCH allows extraction of more biological insights from the new advancements in single-cell library construction and sequencing technologies, facilitating the examination of transcriptome complexity at the single-cell level.

Sex Differences in the Dual Antiplatelet Therapy Versus Alteplase for Patients with Minor Nondisabling Acute Ischemic Stroke: A Secondary Analysis of the ARAMIS Study.

BACKGROUND AND PURPOSE: Sex is associated with clinical outcome in stroke. The present study aimed to determine the effect of sex on efficacy of dual antiplatelet (DAPT) versus alteplase in ischemic stroke based on Antiplatelet versus recombinant tissue plasminogen activator (R-tPA) for Acute Mild Ischemic Stroke (ARAMIS) trial. METHODS: In this secondary analysis of the ARAMIS study, eligible patients aged 18 years or older with minor nondisabling stroke who received dual antiplatelet therapy or intravenous alteplase within 4.5 h of stroke onset were divided into two groups: men and women. The primary endpoint was an excellent functional outcome, defined as a modified Rankin Scale (mRS) 0-1 at 90 days. Binary logistic regression analyses and generalized linear models were used. RESULTS: Of the 719 patients who completed the study, 31% (223) were women, and 69% (496) were men. There were no significant sex differences in excellent functional outcome (unadjusted p = 0.304 for men and p = 0.993 for women; adjusted p = 0.376 for men and p = 0.918 for women) and favorable functional outcome (mRS score of 0-2; unadjusted p = 0.968 for men and p = 0.881 for women; adjusted p = 0.824 for men and p = 0.881 for women). But for the secondary outcomes, compared with alteplase, DAPT was associated with a significantly decreased proportion of early neurological deterioration within 24 h in men {unadjusted odds ratio [OR] = 0.440 [95% confidence interval (CI), 0.221-0.878]; p = 0.020; adjusted OR = 0.436 [95% CI, 0.216-0.877]; p = 0.020}, but not in women [unadjusted OR = 0.636 (95% CI, 0.175-2.319), p = 0.490; adjusted OR = 0.687 (95% CI, 0.181-2.609), p = 0.581]. For the safety outcomes, compared with the DAPT group, alteplase was associated with a significantly increased proportion of any bleeding events in men [unadjusted OR = 3.110 (95% CI, 1.103-8.770); p = 0.032], but not in women [unadjusted OR = 5.333 (95% CI, 0.613-46.407), p = 0.129; adjusted OR = 5.394 (95% CI, 0.592-49.112), p = 0.135]. CONCLUSION: Sex did not influence the effect of dual antiplatelet therapy versus intravenous alteplase in minor nondisabling stroke, but more early neurological deterioration and bleeding events occurred in men who received alteplase.

Deep Learning Model for Predicting Proliferative Hepatocellular Carcinoma Using Dynamic Contrast-Enhanced MRI: Implications for Early Recurrence Prediction Following Radical Resection.

RATIONALE AND OBJECTIVES: The proliferative nature of hepatocellular carcinoma (HCC) is closely related to early recurrence following radical resection. This study develops and validates a deep learning (DL) prediction model to distinguish between proliferative and non-proliferative HCCs using dynamic contrast-enhanced MRI (DCE-MRI), aiming to refine preoperative assessments and optimize treatment strategies by assessing early recurrence risk. MATERIALS AND METHODS: In this retrospective study, 355 HCC patients from two Chinese medical centers (April 2018-February 2023) who underwent radical resection were included. Patient data were collected from medical records, imaging databases, and pathology reports. The cohort was divided into a training set (n = 251), an internal test set (n = 62), and external test sets (n = 42). A DL model was developed using DCE-MRI images of primary tumors. Clinical and radiological models were generated from their respective features, and fusion strategies were employed for combined model development. The discriminative abilities of the clinical, radiological, DL, and combined models were extensively analyzed. The performances of these models were evaluated against pathological diagnoses, with independent and fusion DL-based models validated for clinical utility in predicting early recurrence. RESULTS: The DL model, using DCE-MRI, outperformed clinical and radiological feature-based models in predicting proliferative HCC. The area under the curve (AUC) for the DL model was 0.98, 0.89, and 0.83 in the training, internal validation, and external validation sets, respectively. The AUCs for the combined DL and clinical feature models were 0.99, 0.86, and 0.83 in these sets, while the AUCs for the combined DL, clinical, and radiological model were 0.99, 0.87, and 0.8, respectively. Among models predicting early recurrence, the DL plus clinical features model showed superior performance. CONCLUSION: The DL-based DCE-MRI model demonstrated robust performance in predicting proliferative HCC and stratifying patient risk for early postoperative recurrence. As a non-invasive tool, it shows promise in enhancing decision-making for individualized HCC management strategies.

Shared molecular mechanisms and transdiagnostic potential of neurodevelopmental disorders and immune disorders.

The co-occurrence and familial clustering of neurodevelopmental disorders and immune disorders suggest shared genetic risk factors. Based on genome-wide association summary statistics from five neurodevelopmental disorders and four immune disorders, we conducted genome-wide, local genetic correlation and polygenic overlap analysis. We further performed a cross-trait GWAS meta-analysis. Pleotropic loci shared between the two categories of diseases were mapped to candidate genes using multiple algorithms and approaches. Significant genetic correlations were observed between neurodevelopmental disorders and immune disorders, including both positive and negative correlations. Neurodevelopmental disorders exhibited higher polygenicity compared to immune disorders. Around 50%-90% of genetic variants of the immune disorders were shared with neurodevelopmental disorders. The cross-trait meta-analysis revealed 154 genome-wide significant loci, including 8 novel pleiotropic loci. Significant associations were observed for 30 loci with both types of diseases. Pathway analysis on the candidate genes at these loci revealed common pathways shared by the two types of diseases, including neural signaling, inflammatory response, and PI3K-Akt signaling pathway. In addition, 26 of the 30 lead SNPs were associated with blood cell traits. Neurodevelopmental disorders exhibit complex polygenic architecture, with a subset of individuals being at a heightened genetic risk for both neurodevelopmental and immune disorders. The identification of pleiotropic loci has important implications for exploring opportunities for drug repurposing, enabling more accurate patient stratification, and advancing genomics-informed precision in the medical field of neurodevelopmental disorders.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways.

BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

CRISPR/Cas9 screenings unearth protein arginine methyltransferase 7 as a novel essential gene in prostate cancer metastasis.

Due to the limited effectiveness of current treatments, the survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC) is significantly reduced. Consequently, it is imperative to identify novel therapeutic targets for managing these patients. Since the invasive ability of cells is crucial for establishing and maintaining metastasis, the aim of this study was to identify the essential regulators of invasive abilities of mCRPC cells by conducting two independent high-throughput CRISPR/Cas9 screenings. Furthermore, some of the top hits were validated using siRNA technology, with protein arginine methyltransferase 7 (PRMT7) emerging as the most promising candidate. We demonstrated that its inhibition or depletion via genetic or pharmacological approaches significantly reduces invasive, migratory and proliferative abilities of mCRPC cells in vitro. Moreover, we confirmed that PRMT7 ablation reduces cell dissemination in chicken chorioallantoic membrane and mouse xenograft assays. Molecularly, PRMT7 reprograms the expression of several adhesion molecules by methylating various transcription factors, such as FoxK1, resulting in the loss of adhesion from the primary tumor and increased motility of mCRPC cells. Furthermore, PRMT7 higher expression correlates with tumor aggressivity and poor overall survival in prostate cancer patients. Thus, this study demonstrates that PRMT7 is a potential therapeutic target and potential biomarker for mPCa.

Revealing novel genomic insights and therapeutic targets for juvenile idiopathic arthritis through omics.

BACKGROUND: The genetic architecture of JIA remains only partially comprehended. There is a clear imperative for continued endeavours to uncover insights into the underlying causes of JIA. METHODS: This study encompassed a comprehensive spectrum of endeavours, including conducting a JIA genome-wide association study (GWAS) meta-analysis that incorporated data from 4550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritizing target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. RESULTS: Fourteen genome-wide significant non-HLA loci were identified, including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and BMD traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for the affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized. CONCLUSIONS: Our identification of four novel JIA-associated genes, CD247, RHOH, COLEC10 and IRF8, broadens the novel potential drug repositioning opportunities. We established a new genetic link between COLEC10, TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms.

Influence on the fermentation quality, microbial diversity, and metabolomics in the ensiling of sunflower stalks and alfalfa.

With the rapid development of the livestock industry, finding new sources of feed has become a critical issue that needs to be addressed urgently. China is one of the top five sunflower producers in the world and generates a massive amount of sunflower stalks annually, yet this resource has not been effectively utilized. Therefore, in order to tap into the potential of sunflower stalks for animal feed, it is essential to explore and develop efficient methods for their utilization.In this study, various proportions of alfalfa and sunflower straw were co-ensiled with the following mixing ratios: 0:10, 2:8, 4:6, 5:5, 6:4, and 8:2, denoted as A0S10, A2S8, A4S6, A5S5, A6S4, and A8S2, respectively. The nutrient composition, fermentation quality, microbial quantity, microbial diversity, and broad-spectrum metabolomics on the 60th day were assessed. The results showed that the treatment groups with more sunflower straw added (A2S8, A4S6) could start fermentation earlier. On the first day of fermentation, Weissella spp.dominated overwhelmingly in these two groups. At the same time, in the early stage of fermentation, the pH in these two groups dropped rapidly, which could effectively reduce the loss of nutrients in the early stage of fermentation.In the later fermentation period, a declining trend in acetic acid levels was observed in A0S10, A2S8, and A4S6, while no butyric acid production was detected in A0S10 and A2S8 throughout the process. In A4S6, butyric acid production was observed only after 30 days of fermentation. From the perspective of metabolites, compared with sunflower ensiling alone, many bioactive substances such as flavonoids, alkaloids, and terpenes are upregulated in mixed ensiling.

Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency.

BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

Differentiation Between the Low and High Trans-Stenotic Pressure Gradient in Patients With Idiopathic Intracranial Hypertension Using 4D Flow MRI-Derived Hemodynamic Parameters.

BACKGROUND: Trans-stenotic pressure gradient (TPG) measurement is essential for idiopathic intracranial hypertension (IIH) patients with transverse sinus (TS) stenosis. Four-D flow MRI may provide a noninvasive imaging method for differentiation of IIH patients with different TPG. PURPOSE: To investigate the associations between 4D flow parameters and TPG, and to evaluate the diagnostic performance of 4D flow parameters in differentiating patients with high TPG (GroupHP) from low TPG (GroupLP). STUDY TYPE: Prospective. POPULATION: 31 IIH patients with TS stenosis (age, 38 ± 12 years; 23 females) and 5 healthy volunteers (age, 25 ± 1 years; 2 females). FIELD STRENGTH/SEQUENCE: 3T, 3D phase contrast MR venography, and gradient recalled echo 4D flow sequences. ASSESSMENT: Scan-rescan reproducibility of 4D flow parameters were performed. The correlation between TPG and flow parameters was analyzed. The netflow and velocity difference between inflow plane, outflow plane, and the stenosis plane were calculated and compared between GroupHP and GroupLP. STATISTICAL TESTS: Pearson's correlation or Spearman's rank correlation coefficient, Independent samples t-test or Wilcoxon rank-sum test, Intra-class correlation coefficient (ICC), Bland-Altman analyses, Receiver operating characteristic curves. A P value <0.05 was considered significant. RESULTS: Significant correlations were found between TPG and netflow parameters including Favg,out-s, Favg,in-s, Fmax,out-s, and Fmax,in-s (r = 0.525-0.565). Significant differences were found in Favg,out-s, Fmax,out-s, Favg,in-s, and Fmax,in-s between GroupHP and GroupLP. Using the cut-off value of 2.19 mL/sec, the Favg,out-s showed good estimate performance in distinguishing GroupHP from GroupLP (AUC = 0.856). The ICC (ranged 0.905-0.948) and Bland-Altman plots indicated good scan-rescan reproducibility. DATA CONCLUSIONS: 4D flow MRI derived flow parameters showed good correlations with TPG in IIH patients with TS stenosis. Netflow difference between outflow and stenosis location at TS shows the good performance in differentiating GroupHP and GroupLP cases. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.