Metabotropic glutamate receptor subtype 7 controls maternal care,maternal motivation and maternal aggression in mice

The group III metabotropic glutamate receptor subtype 7 (mGlu7) is an important regulator of glutamatergic and GABAergic neurotransmission and known to mediate emotionality and male social behavior. However, a possible regulatory role in maternal behavior remains unknown to date. Adequate expression of maternal behavior is essential for successful rearing and healthy development of the young. By understanding genetic and neural mechanisms underlying this important prosocial behavior, we gain valuable insights into possible dysregulations. Using genetic ablation as well as pharmacological modulation, we studied various parameters of maternal behavior in two different mouse strains under the influence of mGlu7. We can clearly show a regulatory role of mGlu7 in maternal behavior. Naïve virgin female C57BL/6 mGlu7 knockout mice showed more often nursing postures and less spontaneous maternal aggression compared to their heterozygous and wildtype littermates. In lactating C57BL/6 wildtype mice, acute central activation of mGlu7 by the selective agonist AMN082 reduced arched back nursing and accelerated pup retrieval without affecting maternal aggression. In addition, in lactating CD1 wildtype mice the selective mGlu7 antagonist XAP044 increased both pup retrieval and maternal aggression. With respect to receptor expression levels, mGlu7 mRNA expression was higher in lactating vs virgin C57BL/6 mice in the prefrontal cortex, but not hypothalamus or hippocampus. In conclusion, these findings highlight a significant role of the mGlu7 receptor subtype in mediating maternal behavior in mice. Region‐dependent studies are warranted to further extend our knowledge on the specific function of the brain glutamate system in maternal behavior.     

Design,Synthesis, and Biological Evaluation of 2‐(2‐Bromo‐3‐nitrophenyl)‐5‐phenyl‐1,3,4‐oxadiazole Derivatives as Possible Anti‐Breast Cancer Agents

Breast Cancer (BCa) is the most often diagnosed cancer among women who were in the late 1940’s. Breast cancer growth is largely dependent on the expression of estrogen and progesterone receptor. Breast cancer cells may have one, both, or none of these receptors. The treatment for breast cancer may involve surgery, hormonal therapy (Tamoxifen, an aromatase inhibitor, etc.) and oral chemotherapeutic drugs. The molecular docking technique reported the findings on the potential binding modes of the 2‐(2‐bromo‐3‐nitrophenyl)‐5‐phenyl‐1,3,4‐oxadiazole derivatives with the estrogen receptor (PDB ID: 3ERT). The 1,3,4‐oxadiazole derivatives 4a – 4j have been synthesized and described by spectroscopic method. 2‐(2‐Bromo‐6‐nitrophenyl)‐5‐(4‐bromophenyl)‐1,3,4‐oxadiazole ( 4c ) was reconfirmed by single‐crystal XRD. All the compounds have been tested in combination with generic Imatinib pharmaceutical drug against breast cancer cell lines isolated from Caucasian woman MCF‐7, MDA‐MB‐453 and MCF‐10A non‐cancer cell lines. The compounds with the methoxy (in 4c ) and methyl (in 4j ) substitution were shown to have significant cytotoxicity, with 4c showing dose‐dependent activation and decreased cell viability. The mechanism of action was reported by induced apoptosis and tested by a DNA enzyme inhibitor experiment (ELISA) for Methyl Transferase. Molecular dynamics simulations were made for hit molecule 4c to study the stability and interaction of the protein?ligand complex. The toxicity properties of ADME were calculated for all the compounds. All these results provide essential information for further clinical trials.     

Structural and immunogenomic insights into B-cell receptor activation

B cells express B-cell receptors(BCRs) which recognize antigen to trigger signaling cascades for B-cell activation and subsequent antibody production. BCR activation has a crucial influence on B-cell fate. How BCR is activated upon encountering antigen remains to be solved, although tremendous progresses have been achieved in the past few years. Here, we summarize the models that have been proposed to explain BCR activation, including the cross-linking model, the conformation-induced oligomerization model, the dissociation activation model, and the conformational change model. Especially, we elucidate the partially resolved structures of antibodies and/or BCRs by far and discusse how these current structural and further immunogenomic messages and more importantly the future studies may shed light on the explanation of BCR activation and the relevant diseases in the case of dysregulation.     

受体酪氨酸激酶Axl对胶质母细胞瘤细胞增殖、凋亡和侵袭的影响

摘要 目的：研究受体酪氨酸激酶Axl在胶质母细胞瘤组织和细胞系U-118MG细胞中的表达情况及其对U-118MG细胞增殖、凋亡、侵袭的影响。方法：收集2015年3月至2018年5月在本院进行手术切除并经病理分型证实的胶质母细胞瘤组织标本（n=30）,另取脑外伤手术中因作内减压而切除的正常脑组织作为对照（n=28）。采用荧光实时定量 (qRT-PCR)检测正常脑组织和胶质母细胞瘤肿瘤组织中Axl mRNA表达水平;采用Western blot检测人小神经胶质HM细胞、U-118MG细胞以及Axl-shRNA转染后U-118MG细胞中Axl蛋白表达水平;采用CCK-8检测Axl-shRNA转染后U-118MG细胞增殖能力;采用流式细胞术检测Axl-shRNA转染后U-118MG细胞凋亡水平;采用Transwell小室实验检测Axl-shRNA转染后U-118MG细胞的侵袭能力。结果：在胶质母细胞瘤组织中Axl mRNA表达水平显著高于正常脑组织（P<0.05）;U-118MG细胞Axl蛋白表达水平显著高于人小神经胶质细胞系HM细胞,差异有统计学意义（P<0.05）;转染Axl-shRNA后,U-118MG细胞中Axl蛋白表达水平显著降低（P<0.05）。与U-118MG细胞和转染control-shRNA细胞相比, 转染Axl-shRNA的U-118MG细胞增殖能力降低（P<0.05）,凋亡水平升高（P<0.05）,侵袭能力降低（P<0.05）。结论：在胶质母细胞瘤组织和U-118MG细胞中,Axl表达水平显著增高,并且Axl表达水平与U-118MG细胞增殖、凋亡及侵袭密切关联。     

Effect of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Alpha Variants on Spontaneous Clearance and Fibrosis Progression during Hepatitis C Virus Infection in Moroccan Patients

Virologica Sinica - Hepatitis C virus (HCV) is still one of the main causes of liver disease worldwide. Metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), induced by HCV have...     

The potential interaction between body condition score at calving and dietary starch content on productive and reproductive performance of early-lactating dairy cows

Improving reproductive performance is one of the most important factors affecting the profitability of dairy herds. This study investigated the effect of feeding a high starch (HS) diet and body condition score (BCS) at calving on blood metabolites, fertility and ovarian function and milk production in Holstein dairy cows. One hundred seventy-four multiparous cows were fed common close-up and early lactation diets during the first 15 days in milk (DIM). Cows were randomly assigned to 1 of 2 experimental diets from 16 until 50 DIM (n = 87 per group); normal starch (228 g/kg diet DM; NS) or HS (270 g/kg diet DM; HS) diets. Each treatment group was further subdivided based on BCS at calving as normal BCS (BCS ⩽ 3.5; normal BCS (NBCS); n = 45) or high BCS (HBCS) (BCS ⩾ 3.75; HBCS; n = 42). A significant difference was detected for increased milk production (47.24 v. 44.55 kg/day) and decreased milk fat (33.93 v. 36.33 g/kg) in cows fed HS or NS, respectively. Plasma glucose and insulin concentrations were significantly higher in cows fed the HS compared to the NS diet. Diets significantly affected DIM at first artificial insemination (AI, 79.51 ± 3.83 v. 90.40 ± 3.83 days for cows fed HS and NS diets, respectively). High BCS groups had greater milk fat content and elevated plasma nonesterified fatty acids (NEFA), β hydroxybutyrate (BHB) and bilirubin concentrations. In general, feeding higher starch diets to normal BCS cows during the first 50 DIM improved productive and reproductive performance of early-lactating dairy cows.     

最大等速离心运动诱发肌肉损伤程度与肌酸激酶水平的关系

为探讨人体进行最大等速离心运动(ECC)诱发血液肌酸激酶(CK)水平变化、血清肌酸激酶水平与肌肉损伤(EIMD)的关系,本研究筛选出150名"缺乏运动"的健康大学生为受试者,进行血样采集,进行前测包括血清肌酸激酶(CK)、最大等长肌力(MVC)、肘关节活动角度(ROM)、上臂围(CIR)、肌肉感受(VAS)。受试者进行5组×12次最大等速离心运动,运动后恢复期,将全部受试者血清肌酸激酶值进行排序:血清肌酸激酶值最高和最低20%样本,高肌酸激酶水平组(HCK组)和低肌酸激酶水平组(low LCK组),利用SPSS18.0统计学软件,以方差分析和多元回归分析进行统计分析。本研究发现全部受试者、高肌酸激酶水平组、低肌酸激酶水平组在最大等速离心运动后各评估指标均显著高于比前测结果,p<0.05。全部受试者、高肌酸激酶水平组受试者在最大等速离心运动后各指标变化皆明显大于低肌酸激酶水平组受试者,p<0.05。受试者血清肌酸激酶峰值与最大等长肌力、肘关节活动角度、上臂围、肌肉感受最大变化值有相关,p<0.05。本研究认为肌肉损伤程度与肌酸激酶水平具有显著相关,尤其高血清肌酸激酶水平者肌酸激酶水平较大程度反映肌肉损伤程度趋势。本研究表明,肘关节活动角度、上臂围具有预测肌酸激酶峰值的效果。     

抑瘤素M受体对慢性自身免疫性荨麻疹发病机制的影响

本研究旨在探讨抑瘤素M受体(OSMR)在慢性自身免疫性荨麻疹(CAU)发病机制中的作用。本研究分别检测30例CAU患者及30名健康受试者的皮肤组织中OSMR、JAK和STAT3的表达,研究显示OSMR、JAK和STAT3在CAU患者皮肤组织中高表达(p<0.05)。转染OSMR-siRNA可显著降低CAU模型小鼠血清炎症因子IL-1、IL-6和IFN-γ水平,而转染JAK/STAT3信号通路激动剂Tyr705则可显著升高炎症因子水平(p<0.05)。转染OSMR-siRNA可显著降低CAU小鼠瘙痒次数、瘙痒时间和嗜酸性粒细胞计数,而转染Tyr705则可显著升高CAU小鼠瘙痒次数、瘙痒时间和嗜酸性粒细胞计数(p<0.05)。转染OSMR-siRNA促进了CAU小鼠上皮细胞的增殖能力,并抑制了细胞凋亡(p<0.05)。而转染Tyr705则抑制了CAU小鼠上皮细胞的增殖能力,并促进了细胞凋亡(p<0.05)。转染OSMR-siRNA下调了上皮细胞中OSMR、JAK和STAT3的表达,而转染Tyr705则上调了OSMR、JAK和STAT3的表达(p<0.05)。总之,本研究表明OSMR基因在CAU患者皮肤组织中高表达。OSMR基因沉默可通过抑制JAK/STAT3信号通路来抑制炎症因子表达及嗜酸性粒细胞数量,促进上皮细胞增殖并抑制细胞凋亡。     

Transient reductions in milk fat synthesis and their association with the ruminal and metabolic profile in dairy cows fed high-starch,low-fat diets

Sub-acute ruminal acidosis (SARA) is sometimes observed along with reduced milk fat synthesis. Inconsistent responses may be explained by dietary fat levels. Twelve ruminally cannulated cows were used in a Latin square design investigating the timing of metabolic and milk fat changes during Induction and Recovery from SARA by altering starch levels in low-fat diets. Treatments were (1) SARA Induction, (2) Recovery and (3) Control. Sub-acute ruminal acidosis was induced by feeding a diet containing 29.4% starch, 24.0% NDF and 2.8% fatty acids (FAs), whereas the Recovery and Control diets contained 19.9% starch, 31.0% NDF and 2.6% FA. Relative to Control, DM intake (DMI) and milk yield were higher in SARA from days 14 to 21 and from days 10 to 21, respectively (P < 0.05). Milk fat content was reduced from days 3 to 14 in SARA (P < 0.05) compared with Control, while greater protein and lactose contents were observed from days 14 to 21 and 3 to 21, respectively (P < 0.05). Milk fat yield was reduced by SARA on day 3 (P < 0.05), whereas both protein and lactose yields were higher on days 14 and 21 (P < 0.05). The ruminal acetate-to-propionate ratio was lower, and the concentrations of propionate and lactate were higher in the SARA treatment compared with Control on day 21 (P < 0.05). Plasma insulin increased during SARA, whereas plasma non-esterified fatty acids and milk β-hydroxybutyrate decreased (P < 0.05). Similarly to fat yield, the yield of milk preformed FA (>16C) was lower on day 3 (P < 0.05) and tended to be lower on day 7 in SARA cows (P < 0.10), whereas yield of de novo FA (<16C) was higher on day 21 (P < 0.01) in the SARA group relative to Control. The t10- to t11-18:1 ratio increased during the SARA Induction period (P < 0.05), but the concentration of t10-18:1 remained below 0.5% of milk fat, and t10,c12 conjugated linoleic acid remained below detection levels. Odd-chain FA increased, whereas branched-chain FA was reduced during SARA Induction from days 3 to 21 (P < 0.05). Sub-acute ruminal acidosis reduced milk fat synthesis transiently. Such reduction was not associated with ruminal biohydrogenation intermediates but rather with a transient reduction in supply of preformed FA. Subsequent rescue of milk fat synthesis may be associated with higher availability of substrates due to increased DMI during SARA.