To guarantee the quality and survival rate of their offspring, ovoviviparous teleost evolved special characteristics of in vivo fertilization and embryo development. Maternal black rockfish, having over 50 thousand embryos developing within the ovary simultaneously, provided around 40% nutrition throughout oocyte development, while the capillaries around each embryo contributed the rest 60% during pregnancy. Since fertilization, capillaries started to proliferate and developed into a placenta-like structure that covered over half of each embryo. Aimed to characterize the potential mechanism behind, comparative transcriptome analysis of samples collected according to the process of pregnancy. Three important time point in the process, including mature oocyte stage, fertilization and sarcomere period, were chosen for the transcriptome sequencing. Our study identified key pathways and genes involved in the cell cycle as well as DNA replication and repair, cell migration and adhesion, immune, and metabolic functions. Notably, several of the semaphoring gene family members were differently expressed. To confirm the accuracy of these genes, total of 32 sema genes were identified from the whole genome and distinct expression pattern of sema genes was observed in different pregnant stages. Our results revealed a novel insight for further investigating the functions of sema genes in reproduction physiology and embryo processes in ovoviviparous teleost.

UNASSIGNED: Allergen-specific immunotherapy (AIT) has been employed in the treatment of allergic diseases for many years. However, the effectiveness of AIT requires improvement. Substance P (SP) can interact with immune cells, modulate immune cell activity, and regulate immune reaction. The purpose of this study is to use SP as an immune regulator to enhance the therapeutic efficacy of AIT.
UNASSIGNED: An established mouse model of the airway allergy disorder (AAD) was employed with ovalbumin as a specific antigen. The AAD response was evaluated through established procedures. AAD mice were treated with AIT employing SP as an immune regulator. Dendritic cells were isolated from the airway tissues by magnetic cell sorting, and were analyzed by RNA sequencing (RNAseq).
UNASSIGNED: We observed that after sensitization with ovalbumin, mice exhibited AAD-like symptoms, serum specific IgE, and Th2 polarization. The presence of SP in the course of sensitization prevented the development of AAD. Treating mice with SP by nasal instillations induced IL-10, but not TGF-β, in dendritic cells of the airway tissues. The most differentially expressed genes (DEG) in the dendritic cells were those related to the IL-10 expression, including Il10, Tac1r, and Mtor. The gene ontology analysis showed that these DEGs mainly mapped to the tachykinin-PI3K-AKT-mTOR pathway. The addition of SP substantially enhanced the therapeutic efficacy of AIT for AAD by inducing antigen specific type 1 regulatory T cells (Tr1 cells).
UNASSIGNED: Acting as an immune regulator, SP promotes the therapeutic efficacy for AAD by inducing antigen specific Tr1 cells in the airway tissues.

Semaphorins (Semas), which belongs to the axonal guidance molecules, include 8 classes and could affect axon growth in the nervous system. Recently, semaphorins were found to regulate other pathophysiological processes, such as immune response, oncogenesis, tumor angiogenesis, and bone homeostasis, through binding with their plexin and neuropilin receptors. In this review, we summarized the detailed role of semaphorins and their receptors in the pathological progression of various cardiovascular diseases (CVDs), highlighting that semaphorins may be potential therapeutic targets and novel biomarkers for CVDs.

Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, inflammatory and anti-cancer immune responses. Semaphorins comprise secreted and cell surface-exposed molecules and their receptors are mainly found in the Plexin and Neuropilin families, which are further implicated in a signaling network controlling the tumor microenvironment. Accumulating evidence indicates that semaphorins may be considered as novel clinical biomarkers for cancer, especially for the prediction of patient survival and responsiveness to therapy. Moreover, preclinical experimental studies have demonstrated that targeting semaphorin signaling can interfere with tumor growth and/or metastatic dissemination, suggesting their relevance as novel therapeutic targets in cancer; this has also prompted the development of semaphorin-interfering molecules for application in the clinic. Here we will survey, in diverse human cancers, the current knowledge about the relevance of semaphorin family members, and conceptualize potential lines of future research development in this field.

Nerve endings and terminal Schwann cells (TSCs) specifically and densely surround hair follicle at isthmus area, forming a neuromuscular-junction-like structure called lanceolate complex. The interplay between neuronal components and epidermis in this specialized structure enables hair to properly sense complex stimuli from environments. However, how nerves precisely attach to and innervate this specific region during development remains to be elucidated. Here, we demonstrate that SEMA3C, a secreted protein member of semaphorin family responsible for axonal guidance, is localized right below sebaceous gland and in close approximation with nerve endings and TSCs processes all through the entire hair cycle. SEMA3C protein is deposited outside of epithelial cells and its expression is independent on the presence of nerve endings/TSCs. SEMA3C is also found in portions of dermal papilla at growth phase. The tight spatial association of SEMA3C with lanceolate complex suggests that it might play roles in establishment and/or maintenance of the lanceolate complex in hair follicle.

Small vessel diseases, such as ischemic retinopathy and cerebral small vessel disease (CSVD), are increasingly recognized in patients with diabetes, dementia and cerebrovascular disease. The mechanisms of small vessel diseases are poorly understood, but the latest studies suggest a role for semaphorins. Initially identified as axon guidance cues, semaphorins are mainly studied in neuronal morphogenesis, neural circuit assembly, and synapse assembly and refinement. In recent years, semaphorins have been found to play important roles in regulating vascular growth and development and in many pathophysiological processes, including atherosclerosis, angiogenesis after stroke and retinopathy. Growing evidence indicates that semaphorins affect the occurrence, perfusion and regression of both the macrovasculature and microvasculature by regulating the proliferation, apoptosis, migration, barrier function and inflammatory response of endothelial cells, vascular smooth muscle cells (VSMCs) and pericytes. In this review, we concentrate on the regulatory effects of semaphorins on the cell components of the vessel wall and their potential roles in microvascular diseases, especially in the retina and cerebral small vessel. Finally, we discuss potential molecular approaches in targeting semaphorins as therapies for microvascular disorders in the eye and brain.

Objective: To explore the correlation between Semaphorin 4D (Sema4D) and rheumatoid arthritis (RA) clinical manifestations, laboratory indexes, bone destruction and rheumatoid arthritis related interstitial lung disease(RA-ILD), and to analyze its significance in evaluating the severity of patients with rheumatoid arthritis. Methods: A total of 108 RA patients and 50 healthy controls from September 2018 to October 2019 were collected from the Department of Rheumatology and Immunology, Peking University People\'s Hospital and Beijing Haidian Hospital. According to the DAS 28 score, RA patients were divided into active disease group (DAS28>2.6) and stable disease group (DAS28 ≤ 2.6). Fifty healthy controls. The levels of Sema4D in serum were detected by enzyme-linked immunoassay method (ELISA), and their correlation with clinical manifestations of RA, laboratory indicators, degree of bone damage and RA-ILD were analyzed. Results: The level of serum Sema4D in RA active group was significantly higher than that in stable group and healthy control group (P<0.05). The concentration serum Sema4D was positively correlated with C-reactive protein(CRP) (r=0.28, P<0.05), rheumatoid factor(RF) (r=0.25, P<0.05) and the 28-joint disease activity score (DAS28) (r=0.45, P<0.01). The concentration serum Sema4D was positively correlated with β-Crosslaps(r=0.20, P<0.05) and Sharp-van der Heijde score (SHS)(r=0.13, P<0.05). The concentration serum Sema4D was positively correlated with Vascular endothelial growth factor (VEGF)(r=0.25, P<0.05) and Warrick score of chest CT in RA patients(r=0.27, P<0.05). The anti-cyclic citrullinated peptid(CCP) antibody, DAS28, VEGF and the incidence of RA-ILD were significantly higher than that in Sema4D negative group (P<0.05). Conclusions: Serum Sema4D level in RA patients is closely related to the disease activity, bone destruction and RA-ILD. Serum Sema4D can be used as an indicator of disease monitoring and prognosis evaluation in RA patients.
目的： 检测Semaphorin 4D（Sema4D）在类风湿关节炎（RA）患者血清中的表达水平，探讨Sema4D与RA临床表现、实验室指标、骨破坏及继发肺间质病变（ILD）的相关性，分析其对RA患者病情评价的意义。 方法： 收集2018年9月至2019年10月北京大学人民医院及北京市海淀医院风湿免疫科RA患者共108例，并根据疾病活动指数（DAS）28评分，将RA患者分为病情活动组（DAS28>2.6）与病情稳定组（DAS28≤2.6）。另纳入健康对照者50名。采用酶联免疫吸附试验（ELISA）检测血清中Sema4D的水平，分析其与RA临床表现、实验室指标、骨破坏程度及RA-ILD的相关性。 结果： 血清Sema4D水平：RA病情活动组显著高于病情稳定组和健康对照组（P<0.05）。RA患者血清Sema4D水平与C-反应蛋白（CRP）（r=0.28，P<0.05）、类风湿因子（RF）（r=0.25，P<0.05）、DAS28（r=0.45，P<0.01）呈正相关。RA患者血清Sema4D水平与β-胶原特殊序列（β-Crosslaps）（r=0.20，P<0.05）及双手X线片Sharp-van der Heijde评分（SHS）（r=0.13，P<0.05）呈正相关。RA患者血清Sema4D水平与血管内皮生长因子（VEGF）（r=0.25，P<0.05）及胸部CT的Warrick评分（r=0.27，P<0.05）呈正相关。RA患者Sema4D阳性组的抗CCP抗体、DAS28、VEGF及RA-ILD发生率显著高于Sema4D阴性组（P<0.05）。 结论： RA患者血清Sema4D水平与病情活动、骨破坏及RA-ILD均具有相关性，血清Sema4D可作为RA患者病情监测及预后评估的指标。.

The exotoxin TcsL is a major virulence factor in Paeniclostridium (Clostridium) sordellii and responsible for the high lethality rate associated with P. sordellii infection. Here, we present a genome-wide CRISPR-Cas9-mediated screen using a human lung carcinoma cell line and identify semaphorin (SEMA) 6A and 6B as receptors for TcsL. Disrupting SEMA6A/6B expression in several distinct human cell lines and primary human endothelial cells results in reduced TcsL sensitivity, while SEMA6A/6B over-expression increases their sensitivity. TcsL recognizes the extracellular domain (ECD) of SEMA6A/6B via a region homologous to the receptor-binding site in Clostridioides difficile toxin B (TcdB), which binds the human receptor Frizzled. Exchanging the receptor-binding interfaces between TcsL and TcdB switches their receptor-binding specificity. Finally, administration of SEMA6A-ECD proteins protects human cells from TcsL toxicity and reduces TcsL-induced damage to lung tissues and the lethality rate in mice. These findings establish SEMA6A and 6B as pathophysiologically relevant receptors for TcsL.

Plexin family proteins mediate semaphorin signalling during dendritic arbour development. However, the role of PlexinA3 in the growth of dendrites of cultured cerebellar granule neurons (CGNs) is not known. We found that PlexinA3 colocalizes with CRMP2 (collapsin response mediator protein 2) in dendritic shafts. Immunoprecipitation and glutathione transferase pulldown assays showed that the intracellular Ras-binding domain of PlexinA3 directly interacts with CRMP2. PlexinA3 was necessary and sufficient for the growth of CGN dendrites, as genetic knockdown of PlexinA3 reduced but its overexpression increased dendritic lengths and dendritic tip numbers. These increases were enhanced with CRMP2 overexpression and abolished with CRMP2 knockdown, indicating that CRMP2 is the downstream effector. Furthermore, PlexinA3/CRMP2 signalling contributed to Sema3A-controlled dendritic growth. Together, these data identify a novel PlexinA3/CRMP2 pathway in semaphorin-regulated growth of cultured CGN dendrites.

Obesity is a worldwide health problem. Semaphorins are involved in axonal guidance; however, the role of secretory semaphorin 3G (SEMA3G) in regulating adipocyte differentiation remains unclear. Microarray analysis showed that the SEMA3G gene was upregulated in an in vitro model of adipogenesis. In this study, SEMA3G was highly expressed in the white adipose tissue and liver. Analysis of 3T3-L1 cell and primary mouse preadipocyte differentiation showed that SEMA3G mRNA and protein levels were increased during the middle stage of cell development. In vitro experiments also showed that adipocyte differentiation was promoted by SEMA3G; however, SEMA3G inhibition using a recombinant lentiviral vector expressing a specific shRNA showed the opposite results. Mice were fed a chow or high-fat diet (HFD); knockdown of SEMA3G was found to inhibit weight gain, reduce fat mass in the tissues, prevent lipogenesis in the liver tissue, reduce insulin resistance and ameliorate glucose tolerance in HFD mice. Additionally, the effect of SEMA3G on HFD-induced obesity was activated through PI3K/Akt/GSK3β signaling in the adipose tissue and the AMPK/SREBP-1c pathway in the liver. Moreover, the plasma concentrations of SEMA3G and leptin were measured in 20 obese and 20 non-obese human subjects. Both proteins were increased in obese subjects, who also exhibited a lower level of adiponectin and presented with insulin resistance. In summary, we demonstrated that SEMA3G is an adipokine essential for adipogenesis, lipogenesis, and insulin resistance and is associated with obesity. SEMA3G inhibition may, therefore, be useful for treating diet-induced obesity and its complications.