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Activin A, a critical member of the transforming growth factor-β (TGF-β) superfamily, is a pluripotent factor involved in allergies, autoimmune diseases, cancers and other diseases with immune disorder. Similar to its family member, TGF-β, activin A also transmits signals through SMAD2/SMAD3, however, they bind to distinct receptors. Recent studies have uncovered that activin A plays a pivotal role in both innate and adaptive immune systems. Here we mainly focus its effects on activation, differentiation, proliferation and function of cells which are indispensable in the immune system and meanwhile make some comparisons with those of TGF-β.

With programmed death 1/ligand 1 (PD-1/PD-L1) as the cornerstone, anti-PD antibodies have pioneered revolutionary immunotherapies for malignancies. But most patients struggled to respond to anti-PD owing to primary or acquired resistance or even hyperprogression, pointing to more efforts needed to explore this axis. PD-1 constrains T-cell immunoreactivity via engaging with PD-L1 of tumor/myeloid cells is the canonical PD-1/PD-L1 axis function mode. Studies are increasingly aware of the impact of noncanonical PD-1/PD-L1 expression in various cancers. PD-L1 induced on activated T-cells ligates to PD-1 to mediate self-tolerance or acts on intratumoral myeloid cells and other T-cells, affecting their survival, differentiation and immunophenotyping, leading to tumor immunosuppression. Myeloid PD-1 interferes with their proliferation, differentiation, cytokine secretion and phagocytosis, mediating remarkable pro-tumor effects. Tumor cell intrinsic PD-1 signaling has diverse functions in different tumors, resulting in pro-proliferation or proliferation inhibition. These nonclassical PD-1/PD-L1 functions may be novel anti-PD mechanisms or causes of treatment resistance. This review highlights the nonnegligible role of T-cell-intrinsic PD-L1 and tumor/myeloid PD-1 in the cell interplay network and the complex impact on the efficacy of anti-PD antibodies. Reconsidering and rational utilization of the comprehensive PD-1/PD-L1 axis could cumulate breakthroughs in precision treatment and combination for anti-PD therapies.

Fibroblast-like synoviocytes (FLSs) are the prominent non-immune cells in synovium and play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Searching for natural compounds that may suppress the pathological phenotypes of FLSs is important for the development of RA treatment. Tomatidine (Td), a steroidal alkaloid derived from the solanaceae family, has been reported to have anti-inflammatory, anti-tumor and immunomodulatory effects. However, its effect on RA remains unknown. Here, we examined the inhibitory effect of Td on TNFα-induced arthritic FLSs, and subsequently investigated its therapeutic effect on collagen-induced arthritis (CIA) rats. Our results revealed that Td significantly inhibited TNFα-induced proliferation and migration of arthritic FLSs. In addition, we found that Td treatment could efficaciously ameliorate synovial inflammation and joint destruction of rats with CIA. Both in vitro and in vivo studies showed that Td significantly suppressed the production of pro-inflammatory cytokines including IL-1β, IL-6 and TNFα, and downregulated the expression of MMP-9 and RANKL. Further molecular mechanism studies revealed that the inhibitory effect of Td on RA might attribute to the decreased activations of MAPKs (ERK and JNK) and NF-κB. These findings provide evidence that Td has the potential to be developed into a complementary or alternative agent for RA therapy.

As the sole cell type responsible for bone resorption, osteoclasts play a pivotal role in a variety of lytic bone diseases. Suppression of osteoclast formation and activation has been proposed as an effective protective therapy for new bone. In this study, we reported for the first time that phillyrin (Phil), an active ingredient extracted from forsythia, significantly inhibited RANKL-induced osteoclastogenesis and bone resorption in vitro and protected against lipopolysaccharide-induced osteolysis in vivo. Further molecular investigations demonstrated that Phil effectively blocked RANKL-induced activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase, which suppressed the expression of c-Fos and nuclear factor of activated T-cells cytoplasmic 1. Taken together, these data suggested that Phil might be a potential antiosteoclastogenesis agent for treating osteoclast-related bone lytic diseases.

Cowpea [Vigna unguiculata (L.) Walp.] is an annual legume of economic importance and widely grown in the semi-arid tropics. However, high-density genetic maps of cowpea are still lacking. Here, we identified 34,868 SNPs (single nucleotide polymorphisms) that were distributed in the cowpea genome based on the RAD sequencing (restriction-site associated DNA sequencing) technique using a population of 170 individuals (two cowpea parents and 168 F2:3 progenies). Of these, 17,996 reliable SNPs were allotted to 11 consensus linkage groups (LGs). The length of the genetic map was 1,194.25 cM in total with a mean distance of 0.066 cM/SNP marker locus. Using this map and the F2:3 population, combined with the CIM (composite interval mapping) method, eleven quantitative trait loci (QTL) of yield-related trait were detected on seven LGs (LG4, 5, 6, 7, 9, 10, and 11) in cowpea. These QTL explained 0.05–17.32% of the total phenotypic variation. Among these, four QTL were for pod length, four QTL for thousand-grain weight (TGW), two QTL for grain number per pod, and one QTL for carpopodium length. Our results will provide a foundation for understanding genes related to grain yield in the cowpea and genus Vigna.

The battery thermal management system (BTMS) utilizing phase change materials (PCM) has shown promising performance in high heat flux heat dissipation. However, conventional PCM systems do not fully exploit the latent thermal properties of paraffin wax to enhance battery cooling efficiency. To address this issue, this paper proposes a novel multilayer composite material for BTMS, aiming to improve the thermal performance of the battery and overcome the low thermal conductivity of paraffin wax. The preparation process involves positioning the battery at the center of a triangular container, melting paraffin wax and pouring it into a 100 mm high container to form a 20 mm paraffin layer, placing copper foils and graphite layers on the paraffin surface, and repeating this step once. Finally, pour the 40 mm paraffin wax into the container, resulting in a sandwich-like structure with two layers of graphite. The cooling performance of the multilayer composite structure was experimentally tested at different ambient temperatures (15°C and 20°C) and discharge rates, and compared with a conventional BTMS based on pure paraffin wax. The results demonstrate that the multilayer composite structure exhibits superior heat dissipation compared to the pure paraffin structure, significantly reducing battery temperature rise, particularly at higher discharge rates. At an ambient temperature of 20°C and a discharge rate of 5°C, the battery temperature rise is only 14.97°C, with a remarkable cooling effect of 32.6%. Moreover, optimization of the number and thickness of graphite layers in the composite structure reveals that the 6-layer graphite structure outperforms the 2-layer, 4-layer, 8-layer, and 10-layer graphite structures. Additionally, a relatively lower battery surface temperature is observed with a graphite thickness of 0.5 mm on the basis of the 6-layer graphite structure. These findings indicate that the proposed novel layout structure exhibits excellent thermal performance, effectively addressing the low thermal conductivity limitation of traditional paraffin cooling systems, and providing a new approach for thermal management of lithium batteries.

BackgroundFNDC5 is a novel and important player in energy regulation related to glucose metabolism and insulin levels. Thus, it may affect the incidence of type 2 diabetes mellitus (T2DM). Nevertheless, the association between FNDC5 single nucleotide polymorphisms (SNPs) and susceptibility to T2DM remains unclear. The aim of this meta-analysis was to explore whether the SNPs, rs3480 and rs16835198, are associated with the risk of T2DM.MethodsStudies published before February 1st, 2022 were screened to identify the included studies. R software was also applied for calculation of odds ratio (OR), 95% confidence interval (95% CI), heterogeneity, and sensitivity analysis.ResultsSeven studies for rs3480 (involving 5475 patients with T2DM and 4855 healthy controls) and five studies for rs16835198 (involving 4217 patients with T2DM and 4019 healthy controls) were included in this meta-analysis. The results revealed a statistically significant association of rs3480 with T2DM under homozygote (GG vs AA: OR = 1.76, 95% CI = 1.31–2.37, P = 0.0002, I2 = 59%) genetic model. However, there was no statistically significant correlation between rs16835198 and susceptibility to T2DM under allelic (G vs T: OR = 1.33, 95% CI = 0.94–1.89, P = 0.11, I2 = 84%), heterozygote (GT vs TT: OR = 1.17, 95% CI = 0.80–1.69, P = 0.42, I2 = 71%), homozygote (GG vs TT: OR = 1.35, 95% CI = 0.95–1.94, P = 0.10, I2 = 62%), recessive (GG+GT vs TT: OR = 1.25, 95% CI = 0.88–1.79, P = 0.22, I2 = 72%), and dominant (GG vs GT+GG: OR = 1.20, 95% CI = 0.96–1.50, P = 0.11, I2 = 46%) genetic models.ConclusionsThe present meta-analysis revealed that rs3480 in FNDC5 is significantly associated with susceptibility to T2DM, while rs16835198 does not show such an association.

Background: Apoptosis is a type of cell death, which can produce abundant mediators to modify the tumor microenvironment. However, relationships between apoptosis, immunosuppression, and immunotherapy resistance of gastric cancer (GC) remain unclear.Methods: Gene expression data and matching clinical information were extracted from TCGA-STAD, GSE84437, GSE34942, GSE15459, GSE57303, ACRG/GSE62254, GSE29272, GSE26253, and IMvigor210 datasets. A consensus clustering analysis based on six apoptosis-related genes (ARGs) was performed to determine the molecular subtypes, and then an apoptosisScore was constructed based on differentially expressed and prognostic genes between molecular subtypes. Estimate R package was utilized to calculate the tumor microenvironment condition. Kaplan-Meier analysis and ROC curves were performed to further confirm the apoptosisScore efficacy.Results: Based on six ARGs, two molecular subgroups with significantly distinct survival and immune cell infiltration were identified. Then, an apoptosisScore was built to quantify the apoptosis index of each GC patient. Next, we investigated the correlations between the clinical characteristics and apoptosisScore using logistic regression. Multivariate Cox analysis shows that low apoptosisScore was an independent predictor of poor overall survival in TCGA and ACRG datasets, and was associated with the higher pathological stage. Meanwhile, low apoptosisScore was associated with higher immune cell, higher ESTIMATEScore, higher immuneScore, higher stromalScore, higher immune checkpoint, and lower tumorpurity, which was consistent with the “immunity tidal model theory”. Importantly, low apoptosisScore was sensitive to immunotherapy. In addition, GSEA indicated that several gene ontology and Kyoto Encyclopedia of Genes and Genomes items associated with apoptosis, several immune-related pathways, and JAK–STAT signal pathway were considerably enriched in the low apoptosisScore phenotype pathway.Conclusion: Our findings propose that low apoptosisScore is a prognostic biomarker, correlated with immune infiltrates, and sensitivity to immunotherapy in GC.

BackgroundAlthough emerging evidence supports the relationship between necroptosis (NEC) related genes and hepatocellular carcinoma (HCC), the contribution of these necroptosis-related genes to the development, prognosis, and immunotherapy of HCC is unclear.MethodsThe expression of genes and relevant clinical information were downloaded from TCGA-LIHC, LIRI-JP, GSE14520/NCI, GSE36376, GSE76427, GSE20140, GSE27150, and IMvigor210 datasets. Next, we used an unsupervised clustering method to assign the samples into phenotype clusters base on 15 necroptosis-related genes. Subsequently, we constructed a NEC score based on NEC phenotype-related prognostic genes to quantify the necroptosis related subtypes of individual patients.ResultsWe divided the samples into the high and low NEC score groups, and the high NEC score showed a poor prognosis. Simultaneously, NEC score is an effective and stable model and had a good performance in predicting the prognosis of HCC patients. A high NEC score was characterized by activation of the stroma and increased levels of immune infiltration. A high NEC score was also related to low expression of immune checkpoint molecules (PD-1/PD-L1). Importantly, the established NEC score would contribute to predicting the response to anti-PD-1/L1 immunotherapy.ConclusionsOur study provide a comprehensive analysis of necroptosis-related genes in HCC. Stratification based on the NEC score may enable HCC patients to benefit more from immunotherapy and help identify new cancer treatment strategies.