A Role for the IgH Intronic Enhancer E mu in Enforcing Allelic Exclusion

The intronic enhancer (E mu) of the immunoglobulin heavy chain (IgH) locus is critical for V region gene assembly. To determine E mu\u27s subsequent functions, we created an Igh allele with assembled V(H) gene but with E mu removed. In mice homozygous for this E mu-deficient allele, B cell development was normal and indistinguishable from that of mice with the same V(H) knockin and E mu intact. In mice heterozygous for the E mu-deficient allele, however, allelic exclusion was severely compromised. Surprisingly, this was not a result of reduced suppression of V-DJ assembly on the second allele. Rather, the striking breakdown in allelic exclusion took place at the pre-B to immature B cell transition. These findings reveal both an important role for E mu in influencing the fate of newly arising B cells and a second checkpoint for allelic exclusion

Dietary Flaxseed Oil Prevents Western-Type Diet-Induced Nonalcoholic Fatty Liver Disease in Apolipoprotein-E Knockout Mice

The prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased globally during recent decades. Intake of n-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), is believed to be beneficial to the development of NAFLD. However, little information is available with regard to the effect of flaxseed oil rich in α-linolenic acid (ALA, C18:3n-3), a plant-derived n-3 PUFA, in improving NAFLD. This study was to gain the effect of flaxseed oil on NAFLD and further investigate the underlying mechanisms. Apolipoprotein-E knockout (apoE-KO) mice were given a normal chow diet, a western-type high-fat and high-cholesterol diet (WTD), or a WTD diet containing 10% flaxseed oil (WTD + FO) for 12 weeks. Our data showed that consumption of flaxseed oil significantly improved WTD-induced NAFLD, as well as ameliorated impaired lipid homeostasis, attenuated oxidative stress, and inhibited inflammation. These data were associated with the modification effects on expression levels of genes involved in de novo fat synthesis (SREBP-1c, ACC), triacylglycerol catabolism (PPARα, CPT1A, and ACOX1), inflammation (NF-κB, IL-6, TNF-α, and MCP-1), and oxidative stress (ROS, MDA, GSH, and SOD)

Liveness-Based RRT Algorithm for Autonomous Underwater Vehicles Motion Planning

Motion planning is a crucial, basic issue in robotics, which aims at driving vehicles or robots towards to a given destination with various constraints, such as obstacles and limited resource. This paper presents a new version of rapidly exploring random trees (RRT), that is, liveness-based RRT (Li-RRT), to address autonomous underwater vehicles (AUVs) motion problem. Different from typical RRT, we define an index of each node in the random searching tree, called “liveness” in this paper, to describe the potential effectiveness during the expanding process. We show that Li-RRT is provably probabilistic completeness as original RRT. In addition, the expected time of returning a valid path with Li-RRT is obviously reduced. To verify the efficiency of our algorithm, numerical experiments are carried out in this paper

Impact Assessment of New Energy Characteristics on Regional Power Grid Considering Multiple Time Scales

[Introduction] With the development of new energy, the influence of new energy uncertainty and time characteristics on power grid is increasing day by day. Traditional new energy indexes are difficult to describe the interaction between power grid and new energy. It is necessary to establish evaluation system and index to quantify the impact of new energy on power grid. [Method] Construct the evaluation system from multi-dimensional and multi-scale and establish new energy output characteristic index, electric quantity characteristic index, peak regulation characteristic index and flexibility demand index to analyze the new energy output characteristics, the relationship between new energy output and electric quantity, the influence of new energy on peak regulation and the influence of new energy fluctuation on power grid at critical moments. Typical scene features were mined by applying indexes from different time scales such as year, season, month, day and hour. [Result] All kinds of indexes of the evaluation system has been calculated by taking the actual wind power, PV power and load in a certain area as an example. The results show quantitatively the influence of regional new energy on power grid and its distribution characteristics at different time scales. The engineering practicability of the proposed index system is verified. [Conclusion] The proposed index calculation method is quick and simple and the physical meaning of indexes is clear and intuitive and helpful to guide the planning and dispatching of new energy

Glutaredoxin2 reduces age-associated B cell differentiation through maintaining redox homeostasis

BackgroundThe redox system plays a pivotal role in autoimmune diseases and cancer, with oxidative stress and antioxidant adaptations driving pathological processes. Age/autoimmunity-associated B cells (ABCs), characterized by elevated ROS levels, are implicated in autoimmune disorders such as systemic lupus erythematosus (SLE). However, the mechanisms linking ROS to ABC differentiation remain unclear. Glutaredoxin 2 (Grx2), a key oxidoreductase, regulates redox homeostasis, but its role in autoimmune B cell biology is underexplored.MethodsUsing wild-type and Grx2-knockout mice, we examined ROS levels and ABC differentiation. In vitro, ABC differentiation was induced with IL-21 and TLR7 agonist, and the effect of the antioxidant N-Acetyl-L-Cysteine (NAC) was assessed. The SLE-prone ShipΔB model crossed with Grx2−/− mice was used to evaluate autoimmune pathology.ResultsABCs exhibited higher ROS levels than follicular B cells, and NAC reduced ABC differentiation rate by 50%, demonstrating ROS dependency. Grx2 deficiency amplified ROS levels and ABC proportions in aged mice, correlating with accelerated autoimmunity. In ShipΔB mice, Grx2 deletion exacerbated ABC differentiation, CD4+ T cell activation, and anti-dsDNA autoantibody titers.ConclusionsGrx2 acts as a redox checkpoint that limits ABC-driven autoimmunity by modulating ROS. The Grx2–ROS axis represents a potential therapeutic target for SLE and related chronic inflammatory diseases

The Modulatory Properties of Astragalus membranaceus Treatment on Triple-Negative Breast Cancer: An Integrated Pharmacological Method.

Background: Studies have shown that the natural products of Astragalus membranaceus (AM) can effectively interfere with a variety of cancers, but their mechanism of action on breast cancer remains unclear. Triple-negative breast cancer (TNBC) is associated with a severely poor prognosis due to its invasive phenotype and lack of biomarker-driven-targeted therapies. In this study, the potential mechanism of the target composition acting on TNBC was explored by integrated pharmacological models and in vitro experiments. Materials and Methods: Based on the Gene Expression Omnibus (GEO) database and the relational database of Traditional Chinese Medicines (TCMs), the drug and target components were initially screened to construct a common network module, and multiattribute analysis was then used to characterize the network and obtain key drug-target information. Furthermore, network topology analysis was used to characterize the betweenness and closeness of key hubs in the network. Molecular docking was used to evaluate the affinity between compounds and targets and obtain accurate combination models. Finally, in vitro experiments verified the key component targets. The cell counting kit-8 (CCK-8) assay, invasion assay, and flow cytometric analysis were used to assess cell viability, invasiveness, and apoptosis, respectively, after Astragalus polysaccharides (APS) intervention. We also performed western blot analysis of key proteins to probe the mechanisms of correlated signaling pathways. Results: We constructed "compound-target" (339 nodes and 695 edges) and "compound-disease" (414 nodes and 6458 edges) networks using interaction data. Topology analysis and molecular docking were used as secondary screens to identify key hubs of the network. Finally, the key component APS and biomarkers PIK3CG, AKT, and BCL2 were identified. The in vitro experimental results confirmed that APS can effectively inhibit TNBC cell activity, reduce invasion, promote apoptosis, and then counteract TNBC symptoms in a dose-dependent manner, most likely by inhibiting the PIK3CG/AKT/BCL2 pathway. Conclusion: This study provides a rational approach to discovering compounds with a polypharmacology-based therapeutic value. Our data established that APS intervenes with TNBC cell invasion, proliferation, and apoptosis via the PIK3CG/AKT/BCL2 pathway and could thus offer a promising therapeutic strategy for TNBC

Identifying the Antiproliferative Effect of Astragalus Polysaccharides on Breast Cancer: Coupling Network Pharmacology With Targetable Screening From the Cancer Genome Atlas

Background:Astragalus polysaccharides (APS), natural plant compounds, have recently emerged as a promising strategy for cancer treatment, but little is known concerning their effects on breast cancer (BC) tumorigenesis.Methods: We obtained breast cancer genetic data from The Cancer Genome Atlas (TCGA) database, network pharmacology to further clarify its biological properties. Survival analysis and molecular docking techniques were implemented for the final screening to obtain key target information. Our experiments focused on the detection of intervention effects of APS on BC cells (MCF-7 and MDA-MB-231), and quantitative RT-PCR (qRT-PCR) was used to assess the expression of key targets.Results: A total of 1,439 differentially expressed genes (DEGs) were identified by TCGA and used to build disease networks. Module analysis, gene ontology and pathway analysis revealed characteristic of the DEGs network. Topological properties were used to identify key targets, survival analysis and molecular docking finally found that the targets of APS regulation of BC cells may be CCNB1, CDC6, and p53. Through cell viability, migration and invasion assays, we found that APS interferes with the development of breast cancer in MCF7 and MDA-MB-231 cells in a dose-dependent manner. Furthermore, qRT-PCR verification suggested that the expression of CCNB1 and CDC6 in breast cancer cells was significantly downregulated in response to APS, while expression of the tumor suppressor gene P53 was significantly increased.Conclusion: Results of this study suggest therapeutic potential for APS in BC treatment, possibly through interventions with CCNB1, CDC6, and P53. Furthermore, these findings illustrate the feasibility of using network pharmacology to connect large-scale target data as a way to discover the mechanism of natural products interfering with disease

A role for the IgH intronic enhancer Eμ in enforcing allelic exclusion

The intronic enhancer (Eμ) of the immunoglobulin heavy chain (IgH) locus is critical for V region gene assembly. To determine Eμ's subsequent functions, we created an Igh allele with assembled VH gene but with Eμ removed. In mice homozygous for this Eμ-deficient allele, B cell development was normal and indistinguishable from that of mice with the same VH knockin and Eμ intact. In mice heterozygous for the Eμ-deficient allele, however, allelic exclusion was severely compromised. Surprisingly, this was not a result of reduced suppression of V-DJ assembly on the second allele. Rather, the striking breakdown in allelic exclusion took place at the pre-B to immature B cell transition. These findings reveal both an important role for Eμ in influencing the fate of newly arising B cells and a second checkpoint for allelic exclusion

Fine mapping and candidate gene analysis of proportion of four-seed pods by soybean CSSLs

Soybean yield, as one of the most important and consistent breeding goals, can be greatly affected by the proportion of four-seed pods (PoFSP). In this study, QTL mapping was performed by PoFSP data and BLUE (Best Linear Unbiased Estimator) value of the chromosome segment substitution line population (CSSLs) constructed previously by the laboratory from 2016 to 2018, and phenotype-based bulked segregant analysis (BSA) was performed using the plant lines with PoFSP extreme phenotype. Totally, 5 ICIM QTLs were repeatedly detected, and 6 BSA QTLs were identified in CSSLs. For QTL (qPoFSP13-1) repeated in ICIM and BSA results, the secondary segregation populations were constructed for fine mapping and the interval was reduced to 100Kb. The mapping results showed that the QTL had an additive effect of gain from wild parents. A total of 14 genes were annotated in the delimited interval by fine mapping. Sequence analysis showed that all 14 genes had genetic variation in promoter region or CDS region. The qRT−PCR results showed that a total of 5 candidate genes were differentially expressed between the plant lines having antagonistic extreme phenotype (High PoFSP > 35.92%, low PoFSP< 17.56%). The results of haplotype analysis showed that all five genes had two or more major haplotypes in the resource population. Significant analysis of phenotypic differences between major haplotypes showed all five candidate genes had haplotype differences. And the genotypes of the major haplotypes with relatively high PoFSP of each gene were similar to those of wild soybean. The results of this study were of great significance to the study of candidate genes affecting soybean PoFSP, and provided a basis for the study of molecular marker-assisted selection (MAS) breeding and four-seed pods domestication