Deciphering the molecular landscape of rheumatoid arthritis offers new insights into the stratified treatment for the condition.

Background: For Rheumatoid Arthritis (RA), a long-term chronic illness, it is essential to identify and describe patient subtypes with comparable goal status and molecular biomarkers. This study aims to develop and validate a new subtyping scheme that integrates genome-scale transcriptomic profiles of RA peripheral blood genes, providing a fresh perspective for stratified treatments. Methods: We utilized independent microarray datasets of RA peripheral blood mononuclear cells (PBMCs). Up-regulated differentially expressed genes (DEGs) were subjected to functional enrichment analysis. Unsupervised cluster analysis was then employed to identify RA peripheral blood gene expression-driven subtypes. We defined three distinct clustering subtypes based on the identified 404 up-regulated DEGs. Results: Subtype A, named NE-driving, was enriched in pathways related to neutrophil activation and responses to bacteria. Subtype B, termed interferon-driving (IFN-driving), exhibited abundant B cells and showed increased expression of transcripts involved in IFN signaling and defense responses to viruses. In Subtype C, an enrichment of CD8+ T-cells was found, ultimately defining it as CD8+ T-cells-driving. The RA subtyping scheme was validated using the XGBoost machine learning algorithm. We also evaluated the therapeutic outcomes of biological disease-modifying anti-rheumatic drugs. Conclusions: The findings provide valuable insights for deep stratification, enabling the design of molecular diagnosis and serving as a reference for stratified therapy in RA patients in the future.

Mendelian randomization analysis suggests no associations of herpes simplex virus infections with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) characterized by immune dysfunction is possibly more vulnerable to herpes simplex virus (HSV) infection. The infection has been intensively considered a common onset and exacerbation of SLE. This study is aimed at elucidating the causal association between SLE and HSV. A bidirectional two-sample Mendelian Randomization (TSMR) analysis was systematically conducted to explore the causal effect of SLE and HSV on each other. The causality was estimated by inverse variance weighted (IVW), MR-Egger and weighted median methods based on the summary-level genome-wide association studies (GWAS) data from a publicly available database. Genetically proxied HSV infection exhibited no causal association with SLE in the forward MR analysis using IVW method (odds ratio [OR] = 0.987; 95% confidence interval [CI]: 0.891-1.093; p = 0.798), nor did HSV-1 IgG (OR = 1.241; 95% CI: 0.874-1.762; p = 0.227) and HSV-2 IgG (OR = 0.934; 95% CI: 0.821-1.062; p = 0.297). Similar null results with HSV infection (OR = 1.021; 95% CI: 0.986-1.057; p = 0.245), HSV-1 IgG (OR = 1.003; 95% CI: 0.982-1.024; p = 0.788) and HSV-2 IgG (OR = 1.034; 95% CI: 0.991-1.080; p = 0.121) were observed in the reverse MR where SLE served as the exposure. Our study demonstrated no causal association between the genetically predicted HSV and SLE.

[Simulation for balanced effect of soil and water resources on cultivated land in Naoli River Basin, Northeast China under the RCPs climate scene]. / RCPsæ°”å€™æƒ æ™¯ä¸‹æŒ åŠ›æ²³æµåŸŸè€•åœ°æ°´åœŸèµ„æºå¹³è¡¡æ•ˆåº”æ¨¡æ‹Ÿ.

Under the scenarios of climate change, balancing the land and water resources is one of the key problems needed to be solved in land development. To reveal the water dynamics of the cultivated land in Naoli River Basin, we simulated the future scenarios by using the future land use simulation model based on Landsat Satellite images, the DEM data and the meteorological data. Results showed that the growth rate of cultivated land gradually decreased. It showed different changing characteristics in different time periods, which led to different balancing effect between land and water resources. In 1990, the water dynamics of the cultivated land resources was in good state, At the same time, the adjustment of crops structure caused the paddy fields increased dramatically. During 2002 to 2014, the cultivated land that in moderate and serious moisture shortage state increased slightly, the water deficit was deteriorating to a certain degree, and maintained sound development of water profit and loss situation gradually. By comparing the simulation accuracy with different spatial resolutions and time scales, we selected 200 m as the spatial resolution of the simulation, and simulated the land use status in 2038. The simulation results showed that the cultivated land's water profit and loss degree in the river basin showed significant polarization characteristic, in that the water profit and loss degree of the cultivated land would be further intensified, the area with the higher grades of moisture profit and loss degree would distribute more centralized, and partially high evaluated grades for the moisture shortage would expand. It is needed to develop the cultivated land irrigation schemes and adjust the cultivated land in Naoli River Basin to balance soil and water resources.

ß1 -Adrenoceptor autoantibodies increase the susceptibility to ventricular arrhythmias involving abnormal repolarization in guinea-pigs.

NEW FINDINGS: What is the central question of this study? High titres of autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AAs) can be detected in the sera of patients with ventricular arrhythmias, but a causal relationship between ß1 -AAs and ventricular arrhythmias has not been established. What is the main finding and its importance? Monoclonal ß1 -AAs (ß1 -AR mAbs) were used in the experiments. We showed that ß1 -AR mAbs increased susceptibility to ventricular arrhythmias and induced repolarization abnormalities. Antibody adsorption of ß1 -AAs will be a potential new therapeutic strategy for ventricular arrhythmias in patients with high titres of ß1 -AAs. High titres of autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AAs) can be detected in sera from patients with ventricular arrhythmias, but a causal relationship between ß1 -AAs and ventricular arrhythmias has not been established. In this work, ECGs of guinea-pigs and isolated guinea-pig hearts were recorded. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were evoked by programmed electrical stimulation of the left ventricular epicardium of isolated guinea-pig hearts. The monophasic action potential and effective refractory period of the left ventricle were recorded in paced isolated guinea-pig hearts. Furthermore, to increase the specificity, monoclonal autoantibodies against the second extracellular loop of the ß1 -adrenergic receptor (ß1 -AR mAbs) were used in all experiments. The results showed that ß1 -AR mAbs induced premature ventricular contractions in guinea-pigs and isolated guinea-pig hearts. In addition, ß1 -AR mAbs decreased the threshold of VT/VF and prolonged the duration of VT/VF. Furthermore, ß1 -AR mAbs shortened the corrected QT interval and effective refractory period, and prolonged late-phase repolarization of the monophasic action potential (MAPD90-30 ). These changes in electrophysiological parameters might be attributed, at least in part, to the arrhythmogenicity of ß1 -AR mAbs.

Lipidomics Biomarkers of Diet-Induced Hyperlipidemia and Its Treatment with Poria cocos.

Hyperlipidemia is a major cause of atherosclerotic cardiovascular disease. Poria cocos (PC) is a medicinal product widely used in Asia. This study was undertaken to define the alterations of lipid metabolites in rats fed a high-fat diet to induce hyperlipidemia and to explore efficacy and mechanism of action of PC in the treatment of diet-induced hyperlipidemia. Plasma samples were then analyzed using UPLC-HDMS. The untreated rats fed a high-fat diet exhibited significant elevation of plasma triglyceride and total and low-density lipoprotein (LDL) cholesterol concentrations. This was associated with marked changes in plasma concentrations of seven fatty acids (palmitic acid, hexadecenoic acid, hexanoylcarnitine, tetracosahexaenoic acid, cervonoyl ethanolamide, 3-hydroxytetradecanoic acid, and 5,6-DHET) and five sterols [cholesterol ester (18:2), cholesterol, hydroxytestosterone, 19-hydroxydeoxycorticosterone, and cholic acid]. These changes represented disorders of biosynthesis and metabolism of the primary bile acids, steroids, and fatty acids and mitochondrial fatty acid elongation pathways in diet-induced hyperlipidemia. Treatment with PC resulted in significant improvements of hyperlipidemia and the associated abnormalities of the lipid metabolites.

Endothelial progenitor cells: therapeutic perspective for ischemic stroke.

Endothelial progenitor cells (EPCs), which can be cultured in vitro from mononuclear cells in peripheral blood or bone marrow, express both hematopoietic stem cell and endothelial cell markers on their surface. They are believed to participate in endothelial repair and postnatal angiogenesis due to their abilities of differentiating into endothelial cells and secreting protective cytokines and growth factors. Mounting evidence suggests that circulating EPCs are reduced and dysfunctional in various diseases including hypertension, diabetes, coronary heart disease, and ischemic stroke. Therefore, EPCs have been documented to be a potential biomarker for vascular diseases and a hopeful candidate for regenerative medicine. Ischemic stroke, as the major cause of disability and death, still has limited therapeutics based on the approaches of vascular recanalization or neuronal protection. Emerging evidence indicates that transplantation of EPCs is beneficial for the recovery of ischemic cerebral injury. EPC-based therapy could open a new avenue for ischemic cerebrovascular disease. Currently, clinical trials for evaluating EPC transfusion in treating ischemic stroke are underway. In this review, we summarize the general conceptions and the characteristics of EPCs, and highlight the recent research developments on EPCs. More importantly, the rationale, perspectives, and strategies for using them to treat ischemic stroke will be discussed.

Isolation and enrichment of human genomic CpG islands by methylation-sensitive mirror orientation selection.

CpG islands (CGIs) in human genomic DNA are GC-rich fragments whose aberrant methylation is associated with human disease development. In the current study, methylation-sensitive mirror orientation selection (MS-MOS) was developed to efficiently isolate and enrich unmethylated CGIs from human genomic DNA. The unmethylated CGIs prepared by the MS-MOS procedure subsequently were used to construct a CGI library. Then the sequence characteristics of cloned inserts of the library were analyzed by bioinformatics tools, and the methylation status of CGI clones was analyzed by HpaII PCR. The results showed that the MS-MOS method could be used to isolate up to 0.001% of differentially existed unmethylated DNA fragments in two complex genomic DNA. In the CGI library, 34.1% of clones had insert sequences satisfying the minimal criteria for CGIs. Excluding duplicates, 22.0% of the 80,000 clones were unique CGI clones, representing 60% of all the predicted CGIs (about 29,000) in human genomic DNA, and most or all of the CGI clones were unmethylated in human normal cell DNA based on the HpaII PCR analysis results of randomly selected CGI clones. In conclusion, MS-MOS was an efficient way to isolate and enrich human genomic CGIs. The method has powerful potential application in the comprehensive identification of aberrantly methylated CGIs associated with human tumorigenesis to improve understanding of the epigenetic mechanisms involved.

[The distribution of ATPase during the pollen development of Allium cepa L].

The distribution of ATPase in pollen of Allium cepa L. was studied using Pb3 precipitation technique during pollen development. Only some ATPase precipitates were located in the nucleus of microspore mother cells (MMC) and a few in its cytoplasm. After meiosis of MMC,many ATPase precipitates appeared in the exine of pollen wall of microspore even it was in tetrad, suggesting that ATPase from tapetum is necessary during pollen wall construction. The intine of pollen wall of microspore was synthesized at its late stage and consisted of cellular material which was from microspore. There were also many ATPase precipitates in intine,and the ATPase came from microspore. Then ATPase precipitates in vegetative cell increased and that in generative cell decreased during the development of 2-cellular pollen,suggesting the differentiation of vigor between both cells. The physiological functions of ATPase in developing pollen of Allium cepa L. were analyzed.

[Substance P regulates function of osteoclasts via neurokinin-1 receptor].

OBJECTIVE: To investigate the effects of substance P on cultured rat osteoclasts. METHODS: Neurokinin-1 (NK1) receptor expression in osteoclasts was examined by immunohitochemical method, and changes of bone resorption activity caused by substance P and NK1 receptor antagonists were detected by pit formation assay. RESULTS: Immunoreactivity for NK1 receptor was distributed in the cytoplasm of osteoclasts. The average of pit formation areas significantly increased with addition of substance P (10(-7)-10(-4) mol/L) (P < 0.05), but the number of pitformations did not change (P > 0.05). NK1 receptor antagonists inhibited the enhancement of the bone resorption by substance P addition. CONCLUSION: The findings suggested that substance P may stimulate osteoclasts and result in bone resorption by the mediation of NK1 receptor.