Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice.

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.

Disentangling the coping process in White rural men who carry guns.

Affluent White rural men have the highest rates of gun ownership in the United States. However, few studies have specifically examined reasons and motivations for gun ownership and gun behaviors in this population. Therefore, this study sought to examine the relationship between stress variables, namely masculine gender role stress, adverse childhood experiences (ACEs), and income level, and subsequent pro-gun beliefs and amount of time an individual carried a gun within this population. Results indicated that only two measures of pro-gun beliefs (i.e., believing guns keep one safe, believing guns are present in one's social sphere) were correlated with percentage of time an individual carried. Additionally, ACEs were positively correlated with believing guns influence how others perceive oneself, levels of masculine gender role stress, and income. These results suggest that White rural gun owners who have increased ACEs have decreased income and tend to believe that owning guns impacts their social status with peers. However, increased ACEs do not influence belief about guns keeping one safe, believing guns are present in one's social sphere, or gun carriage. Instead, White rural gun owners without childhood adversity may be more susceptible to believing their safety depends on guns and belongingness within their social sphere. Future research should assess reasons why affluent White rural men find it important to maintain their safety in the context of gun ownership.

Morphology, genetic characterization and phylogeny of Moniliformis tupaia n. sp. (Acanthocephala: Moniliformidae) from the northern tree shrew Tupaia belangeri chinensis Anderson (Mammalia: Scandentia).

A new species of Moniliformis, M. tupaia n. sp. is described using integrated morphological methods (light and scanning electron microscopy) and molecular techniques (sequencing and analysing the nuclear 18S, ITS, 28S regions and mitochondrial cox1 and cox2 genes), based on specimens collected from the intestine of the northern tree shrew Tupaia belangeri chinensis Anderson (Scandentia: Tupaiidae) in China. Phylogenetic analyses show that M. tupaia n. sp. is a sister to M. moniliformis in the genus Moniliformis, and also challenge the systematic status of Nephridiacanthus major. Moniliformis tupaia n. sp. represents the third Moniliformis species reported from China.

Anti-synthetase syndrome is associated with a higher risk of hospitalization among patients with idiopathic inflammatory myopathy and COVID-19.

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.

Large-scale analysis of the N-terminal regulatory elements of the kinase domain in plant Receptor-like kinase family.

BACKGROUND: The N-terminal regulatory element (NRE) of Receptor-like kinases (RLKs), consisting of the juxtamembrane segment in receptor kinases (RKs) and the N-terminal extension segment in RLCKs, is a crucial component that regulates the activities of these proteins. However, the features and functions of the NRE have remained largely unexplored. Herein, we comprehensively analyze 510,233 NRE sequences in RLKs from 528 plant species, using information theory and data mining techniques to unravel their common characteristics and diversity. We also use recombinant RKs to investigate the function of the NRE in vitro. RESULTS: Our findings indicate that the majority of NRE segments are around 40-80 amino acids in length and feature a serine-rich region and a 14-amino-acid consensus sequence, 'FSYEELEKAT[D/N]NF[S/D]', which contains a characteristic α-helix and ST motif that connects to the core kinase domain. This conserved signature sequence is capable of suppressing FERONIA's kinase activity. A motif discovery algorithm identifies 29 motifs with highly conserved phosphorylation sites in RK and RLCK classes, especially the motif 'VGPWKpTGLpSGQLQKAFVTGVP' in LRR-VI-2 class. Phosphorylation of an NRE motif in an LRR-VI-2 member, MDIS1, modulates the auto-phosphorylation of its co-receptor, MIK1, indicating the potential role of NRE as a 'kinase switch' in RLK activation. Furthermore, the characterization of phosphorylatable NRE motifs improves the accuracy of predicting phosphorylatable sites. CONCLUSIONS: Our study provides a comprehensive dataset to investigate NRE segments from individual RLKs and enhances our understanding of the underlying mechanisms of RLK signal transduction and kinase activation processes in plant adaptation.

Curation, nomenclature, and topological classification of receptor-like kinases from 528 plant species for novel domain discovery and functional inference.

Receptor-like kinases (RLKs) are the most numerous signal transduction components in plants and play important roles in determining how different plants adapt to their ecological environments. Research on RLKs has focused mainly on a small number of typical RLK members in a few model plants. There is an urgent need to study the composition, distribution, and evolution of RLKs at the holistic level to increase our understanding of how RLKs assist in the ecological adaptations of different plant species. In this study, we collected the genome assemblies of 528 plant species and constructed an RLK dataset. Using this dataset, we identified and characterized 524 948 RLK family members. Each member underwent systematic topological classification and was assigned a gene ID based on a unified nomenclature system. Furthermore, we identified two novel extracellular domains in some RLKs, designated Xiao and Xiang. Evolutionary analysis of the RLK family revealed that the RLCK-XVII and RLCK-XII-2 classes were present exclusively in dicots, suggesting that diversification of RLKs between monocots and dicots may have led to differences in downstream cytoplasmic responses. We also used an interaction proteome to help empower data mining for inference of new RLK functions from a global perspective, with the ultimate goal of understanding how RLKs shape the adaptation of different plants to the environments/ecosystems. The assembled RLK dataset, together with annotations and analytical tools, forms an integrated foundation of multiomics data that is publicly accessible via the metaRLK web portal (http://metaRLK.biocloud.top).

Severe gastrointestinal involvements in patients with adult dermatomyositis with anti-NXP2 antibody.

OBJECTIVE: Gastrointestinal (GI) involvements were scarcely reported in adult anti-nuclear matrix protein 2 (NXP2) dermatomyositis (NXP2+DM). In this study, we investigated the clinical, pathological and molecular features as well as treatment options of this rare yet life-threatening disease. METHODS: We retrospectively collected the data of the cohort of NXP2+ DM from 2012 to 2022 in our hospital. RNA sequencing was performed in intestinal samples of perforated patients compared with healthy controls data set. RESULTS: A total of 56 patients with adult NXP2+DM were collected including 10 cases with GI involvements. Abdominal pain and melena were the initial manifestations for GI involvements with a median 10-month time lag after the diagnosis of NXP2+DM when myositis largely subsided. Within weeks, GI perforation occurred in 8 of 10 patients, while five patients underwent eight surgical interventions subsequently. The short-term mortality was observed in four patients. NXP2+DM with GI involvements presented with more extramuscular systemic manifestations such as interstitial lung disease and subcutaneous calcinosis. The GI pathological features encompassed vasculitis/vasculopathy with high MxA expression, intestinal smooth muscle necrosis and serosal calcinosis. Gene expression profile validated the type-I interferon activation and revealed that epithelial mesenchymal transition and focal adhesion pathway may also contribute. Finally, vedolizumab, an anti-α4ß7-integrin monoclonal antibody, exhibited promising therapeutic signals which should be further investigated. CONCLUSIONS: GI involvement is a unique complication in patients with adult NXP2+DM. Timely recognition and targeted therapy may turn out to be lifesaving.

Single-Cell Profiling of Bone Marrow B Cells and Early B Cell Developmental Disorders Associated With Systemic Lupus Erythematosus.

OBJECTIVE: The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown. METHODS: We performed single-cell RNA/B cell receptor (BCR) sequencing and immune profiling of BM B cells and classified patients with SLE into two groups: early B cell (Pro-B and Pre-B) normal (EBnor) and EB defective/low (EBlo) groups. RESULTS: The SLE-EBlo group exhibited more severe disease activity and proinflammatory status, overaction of type I interferon signaling and metabolic pathways within the B cell compartment, and aberrant BCR repertoires compared with the SLE-EBnor group. Moreover, in one patient with SLE who was initially classified in the SLE-EBlo group, early B cell deficiency and associated abnormalities were largely rectified in a second BM sample at the remission phase. CONCLUSION: In summary, this study suggests that early B cell loss in BM defines a unique pathological state in a subset of patients with SLE that may play an active role in the dysregulated autoimmune responses.

Pulmonary strongyloidiasis and hyperinfection in a Patient with idiopathic inflammatory myopathy：A case report.

Pulmonary strongyloidiasis is a rare infection in patients with autoimmune diseases, and immunosuppression can lead to the development of hyperinfection syndrome with a high mortality rate. We present a case of a 78-year-old male with previous idiopathic inflammatory myopathy (IIM) with interstitial lung disease. He developed hyperinfection syndrome and respiratory failure, and diagnostic metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) confirmed the presence of Strongyloides stercoralis. After treatment with ivermectin, the patient's symptoms improved. Therefore, adequate screening and prophylactic treatment are needed for people at risk of immunosuppression, which can reduce the occurrence of the devastating S. stercoralis hyperinfection syndrome. It also highlights mNGS as a highly accurate test for the detection of difficult to atypical pathogens.

Rare urachal mucinous cystic tumor of low malignant potential with peritoneal pseudomyxoma: A case report.

Mucinous cystic tumors of low malignant potential (MCTLMP) are rare urachal neoplasms. The morphological characteristics and clinical prognosis of MCTLMP is similar to that of mucinous cystic tumors occurring in the ovary and appendix. After complete resection, almost no cases of recurrence or metastasis have been reported. Because MCTLMP is rare, it may be missed in the clinic. MCTLMP can lead to the formation of pseudomyxoma peritonei (PMP), which manifests as the widespread production of mucus in the abdominal cavity and makes the disease complex or difficult to diagnose. At present, only 3 cases of MCTLMP with PMP have been reported in the literature. In the present study a fourth case of urachal MCTLMP in a 74-year-old male that resulted in widespread PMP is presented. Initially, a multilocular cystic lesion was revealed in the urachal duct area at the anterior upper margin of the bladder after a patient, experiencing lower abdominal pain, was imaged. As revealed using light microscopy, the cyst was lined with a mucous columnar epithelium, and part of the epithelium indicated pseudolamellar hyperplasia and papillary structures. The cells indicated mild atypia and low mitotic activity. There was no stromal infiltration of tumor cells, and a large amount of mucous exudate was observed. As preoperative computed tomography examination suggested the presence of a large amount of ascites and there were increased levels of blood tumor markers, carcinoembryonic antigen and carbohydrate antigen 125, clinicians considered that the diagnosis maybe a malignant tumor of the urachal gland with peripheral dissemination. However, the diagnosis of MCTLMP with PMP was confirmed by histopathological examination. The mass was completely removed, along with part of the peritoneum and bladder wall as these were within the tumor margin. The appendix appeared normal during surgery. A one off dose of intraperitoneal infusion chemotherapy with 1,000 mg 5-fluorouracil was performed after surgery. No recurrence was observed during the 8-month follow-up period.

The FERONIA-YUELAO module participates in translational control by modulating the abundance of tRNA fragments in Arabidopsis.

tRNA fragments (tRFs) are a recently identified class of small noncoding RNAs. To date, the regulation of tRF abundance and its functional mechanisms have been largely unclear in plants. We investigated how the Arabidopsis thaliana receptor kinase FERONIA (FER) regulates the abundance of tRFs to inhibit global mRNA translation. We demonstrate that FER regulates tRF abundance by directly phosphorylating the tRNA-binding protein YUELAO (YL) to modulate its function. Downregulation of FER and YL prevented the modification of tRNA via cytosine-5-methylation and 2'-O-methylation, thereby increasing tRF abundance. Furthermore, we show that YL acts as an important genetic downstream target of FER signaling, and knockdown of a specific tRF partially rescues the root hair growth defects of fer and yl mutants. Our findings shed light on the abundance and regulatory mechanisms of tRF and their role in inhibiting translation in plants.

SMARCA4­deficient non­small cell lung cancer with an EGFR mutation: A case report.

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4)-deficient non-small cell lung cancer (dNSCLC) is a rare malignant tumor that originates in the lungs. It occurs more frequently in male smokers, and the epidermal growth factor receptor (EGFR) gene is often mutation-free. In the present study, the case of a 60-year-old, non-smoking female patient diagnosed with SMARCA4-dNSCLC is reported. Biopsy of the tumor showed solid flaky, nest-like infiltrating growth. Immunohistochemistry revealed the following: SMARCA4/BRG1(-), SMARCB1/INI-1(+), cytokeratin7 (+), cytokeratin 5.2 (+), CK5/6(+) and calretinin(+). The Ki-67 positivity index was 75%, and the thyroid transcription factor-1, NapsinA, p40, nuclear protein in testis, CD34, Sal-like protein 4, SRY-box transcription factor 2 and synaptophysin were negative. Molecular analysis showed mutations in both EGFR and TP53. The pathological diagnosis was SMARCA4-dNSCLC with an EGFR gene mutation. The present case report could be used for broadening the pathological diagnosis of SMARCA4-dNSCLC and for selecting appropriate treatment approaches.

Erucic acid improves the progress of pregnancy complicated with systemic lupus erythematosus by inhibiting the effector function of CD8+ T cells.

Pathogenic CD8+ T cells are pivotal contributors to the onset of systemic lupus erythematosus (SLE). Erucic acid (EA) has been proven to have anti-inflammatory activity. However, the capacity of EA to regulate pathogenic CD8+ T cells in the context of pregnancy complicated with SLE (pSLE) remains unclear. In our investigation, we observed augmented CD8+ T cell effector function juxtaposed with diminished EA levels in pSLE patients relative to healthy pregnant controls. Significantly, plasma EA levels exhibited a negative correlation with the severity of pSLE-associated complications. In blood from patients with pSLE, EA inhibited the effector function of CD8+ T cells, concurrently dampening the maintenance of stem cell-like memory CD8+ T cells. Mechanistically, EA orchestrated the inhibition of CD8+ T cell effector function by impeding signal transducer and activator of transcription 3 phosphorylation and promoting ferroptosis. Moreover, EA supplementation in pregnant MRL/lpr mice manifested as the attenuation of uterine CD8+ T cell effector function, culminating in the mitigation of placental pathological damage. Our findings uncover the immune response modulatory effects of EA upon pathogenic CD8+ cells, thereby unveiling new perspectives for therapeutic strategies targeting pSLE patients.

Iguratimod attenuated fibrosis in systemic sclerosis via targeting early growth response 1 expression.

BACKGROUND: The early growth response 1 (EGR1) is a central transcription factor involved in systemic sclerosis (SSc) pathogenesis. Iguratimod is a synthesized anti-rheumatic disease-modifying drug, which shows drastic inhibition to EGR1 expression in B cells. This study is aiming to investigate the anti-fibrotic effect of iguratimod in SSc. METHODS: EGR1 was detected by immunofluorescence staining real-time PCR or western blot. Iguratimod was applied in EGR1 overexpressed or knockdown human dermal fibroblast, bleomycin pre-treated mice, tight skin 1 mice, and SSc skin xenografts. RNA sequencing was performed in cultured fibroblast and xenografts to identify the iguratimod regulated genes. RESULTS: EGR1 overexpressed predominantly in non-immune cells of SSc patients. Iguratimod reduced EGR1 expression in fibroblasts and neutralized changes of EGR1 response genes regulated by TGFß. The extracellular matrix (ECM) production and activation of fibroblasts were attenuated by iguratimod while EGR1 overexpression reversed this effect of iguratimod. Iguratimod ameliorated the skin fibrosis induced by bleomycin and hypodermal fibrosis in TSK-1 mice. Decreasing in the collagen content as well as the density of EGR1 or TGFß positive fibroblasts of skin xenografts from naïve SSc patients was observed after local treatment of iguratimod. CONCLUSION: Targeting EGR1 expression is a probable underlying mechanism for the anti-fibrotic effect of iguratimod.

Social Functioning Outcomes of a High School-Based Treatment Program for Adolescents with ADHD.

OBJECTIVE: We evaluated the extent to which receiving the multi-component treatment of the Challenging Horizons Program (CHP) would lead to significant improvements in social functioning, as well as in inattention, internalizing symptoms, parent stress, and emotion dysregulation for high-school-aged adolescents with attention-deficit hyperactivity disorder (ADHD). METHOD: Participants were 186 high-school-aged adolescents (74% White) with a diagnosis of ADHD who were randomly assigned to either CHP (n = 92; 80% boys; M age = 15.0; SD = 0.8) or Community Care (CC; n = 94; 78% boys; M age = 15.1; SD = 0.9) within each of 12 participating schools. Parent and adolescent reports of social functioning were the primary outcome measures. Secondary outcomes included ratings of symptoms of ADHD and related disorders, parent stress, and emotion regulation. RESULTS: Intent-to-treat analyses using hierarchical linear modeling revealed significant group-by-time interactions of medium magnitude (d range = .40 to .52) on parent-rated social skills. Significant group-by-time benefits were also identified for adolescent self-rated social skills as well as the secondary outcomes of parent-rated inattention symptoms, emotion regulation, and parenting stress. DISCUSSION: CHP appears to benefit social skills along with related characteristics for adolescents with ADHD. Understanding these unique findings for this population informs additional research related to treatment mechanisms and effectiveness trials.