Microtubules induce self-organization of polarized PAR domains in Caenorhabditis elegans zygotes

A hallmark of polarized cells is the segregation of the PAR polarity regulators into asymmetric domains at the cell cortex. Antagonistic interactions involving two conserved kinases, atypical protein kinase C (aPKC) and PAR-1, have been implicated in polarity maintenance, but the mechanisms that initiate the formation of asymmetric PAR domains are not understood. Here, we describe one pathway used by the sperm-donated centrosome to polarize the PAR proteins in Caenorhabditis elegans zygotes. Before polarization, cortical aPKC excludes PAR-1 kinase and its binding partner PAR-2 by phosphorylation. During symmetry breaking, microtubules nucleated by the centrosome locally protect PAR-2 from phosphorylation by aPKC, allowing PAR-2 and PAR-1 to access the cortex nearest the centrosome. Cortical PAR-1 phosphorylates PAR-3, causing the PAR-3-aPKC complex to leave the cortex. Our findings illustrate how microtubules, independently of actin dynamics, stimulate the self-organization of PAR proteins by providing local protection against a global barrier imposed by aPKC.     

RIC-7 promotes neuropeptide secretion

Secretion of neurotransmitters and neuropeptides is mediated by exocytosis of distinct secretory organelles, synaptic vesicles (SVs) and dense core vesicles (DCVs) respectively. Relatively little is known about factors that differentially regulate SV and DCV secretion. Here we identify a novel protein RIC-7 that is required for neuropeptide secretion in Caenorhabditis elegans. The RIC-7 protein is expressed in all neurons and is localized to presynaptic terminals. Imaging, electrophysiology, and behavioral analysis of ric-7 mutants indicates that acetylcholine release occurs normally, while neuropeptide release is significantly decreased. These results suggest that RIC-7 promotes DCV-mediated secretion.     

Cigarette smoking and serum soluble Fas levels: Findings from the JACC study

Cigarette smoking enhances low-grade systemic inflammation in the lung and other organs. Activated immune cells play an important role at early and late stages of inflammation, and in recent years, soluble Fas (sFas), an isoform of death molecule Fas, was found to interfere with the apoptotic pathways of these activated immune cells. The aim of this study was to confirm the association between cigarette smoking and sFas levels in healthy male subjects. We measured serum sFas levels of 4415 male subjects selected as controls for a nested case-control study within the large-scale cohort study conducted in Japan, called the JACC Study. Smoking status at baseline was evaluated by a self-administered questionnaire. Least square means of sFas according to smoking status and numbers of cigarettes smoked per day among smokers were calculated and adjusted for possible confounding factors. Mean sFas levels showed an increasing trend across never smokers, past smokers and current smokers, as 2.21 (95% CI: 2.14–2.27) ng/ml, 2.29 (2.22–2.36) ng/ml, and 2.36 (2.30–2.43) ng/ml, respectively. However, no dose-response relationship was observed between the number of cigarettes smoked per day and sFas levels among smokers.     

抗体药物的发展与应用

早期抗体药物是鼠源单克隆抗体,存在免疫原性强、半衰期短等问题。历经数十年的发展,抗体药物从最初的鼠源单抗,逐步发展为人鼠嵌合抗体、人源化抗体及全人源化抗体。通过片段重组、位点修饰、药物偶联等方法,科研人员研发了包括抗体融合蛋白、抗体偶联药物、双特异性抗体、小分子抗体片段等形式多样的抗体药物。抗体药物在恶性肿瘤、自身免疫病、感染性疾病的治疗上发挥重要作用。通过对抗体药物人源化历程,不同类型的抗体结构和特点,以及抗体药物在新型冠状病毒肺炎治疗中的应用进行综述,并对抗体药物的发展前景进行展望,以期为我国抗体药物的研发提供参考。     

Unique Protein Profiles of Extracellular Vesicles as Diagnostic Biomarkers for Early and Advanced Non‐Small Cell Lung Cancer

Extracellular vesicles (EVs) mediate intercellular communication via transferring proteins and other biological molecules and have been recently investigated as biomarkers of disease. Sensitive and specific biomarkers are required for lung cancer diagnosis and prognosis. The present study screens for abnormal EV proteins in non‐small cell lung cancer (NSCLC) using a quantitative proteomics strategy involving LC‐MS/MS to identify ideal biomarkers for NSCLC diagnosis. EVs are enriched from the sera of early and advanced NSCLC patients and healthy controls and from cell culture supernatants of lung adenocarcinoma and bronchial epithelial cell lines. In the sera and supernatants, 279 and 632 differentially expressed proteins, respectively, are associated with signaling pathways including extracellular membrane–receptor interaction, focal adhesion, and regulation of the actin cytoskeleton. Thirty‐two EV proteins are identified at the intersection of differentially expressed proteins between the NSCLC groups and cell lines. Based on bioinformatics analysis, in silico immunohistochemical, and PRM verification, fibronectin is selected for following in vitro studies and validation with an independent cohort. Fibronectin on EVs is estimated to perform well in the diagnosis of NSCLC patients based on AUC, showing great potential for clinical use and demonstrating the efficacy of this method for EV‐associated biomarker screening.     

Effects of anesthesia-induced modest hypothermia on cellular radiation sensitivity

To assess the mechanisms of modest hypothermia (MH) and its effects on cellular radiation response, a model of anesthesia-induced modest hypothermia (AIMH) in the adult mice and a model of pure MH in the newborn mice were established. The survival rate of lethally irradiated mice was increased to 72% through AIMH before irradiation. Both apoptosis and necrosis of human fetal bone marrow CD34+ hematopoietic stem cells cultured under MH were significantly decreased as detected by MTT and flow cytometry, with three-color labeled by PE-CD34+/ FITC-AnnexinV /7AAD. The survival and proliferation of mouse bone marrow MNC treated with MH after irradiation were also increased. The MH exerted similar protective effects on the leukemia cell lines A20, HL60, K562 to the normal bone marrow cells, but it enhanced the radiation sensitivity of leukemia cell line FBL3 and mouse melanoma B16F10. No effects have been found on the radiation sensitivity of those cells treated with MH before irradiation. The results also show     

BMI and All‐cause Mortality Among Japanese Older Adults: Findings From the Japan Collaborative Cohort Study

The association between BMI and all‐cause mortality may vary with gender, age, and ethnic groups. However, few prospective cohort studies have reported the relationship in older Asian populations. We evaluated the association between BMI and all‐cause mortality in a cohort comprised 26,747 Japanese subjects aged 65–79 years at baseline (1988–1990). The study participants were followed for an average of 11.2 years. Proportional‐hazards regression models were used to estimate mortality hazard ratios (HRs) and 95% confidence intervals. Until 2003, 9,256 deaths occurred. The underweight group was associated with a statistically higher risk of all‐cause mortality compared with the mid‐normal‐range group (BMI: 20.0–22.9); resulting in a 1.78‐fold (95% confidence interval: 1.45–2.20) and 2.55‐fold (2.13–3.05) increase in mortality risk among severest thin men and women (BMI: <16.0), respectively. Even within the normal‐range group, the lower normal‐range group (BMI: 18.5–19.9) showed a statistically elevated risk. In contrast, being neither overweight (BMI: 25.0–29.9) nor obese (BMI: ≥30.0) elevated the risk among men; however among women, HR was slightly elevated in the obese group but not in the overweight group compared with the mid‐normal‐range group. Among Japanese older adults, a low BMI was associated with increased risk of all‐cause mortality, even among those with a lower normal BMI range. The wide range of BMI between 20.0 and 29.9 in both older men and women showed the lowest all‐cause mortality risk.