Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer

Cell membrane translocation of heat shock protein gp96 from the endoplasmic reticulum has been observed in multiple tumors and is associated with tumor malignancy. However, the cancer-intrinsic function and the related mechanism of cell membrane gp96 as a pro-oncogenic chaperone remain further elucidated. In this study, we found that inhibition of gp96 intramolecular conformational changes by a single α-helix peptide p37 dramatically increased its binding to HER2, whereas decreased HER2 dimerization, phosphorylation and downstream signaling. Targeting cell membrane gp96 promoted HER2 ubiquitination and subsequent lysosomal degradation, which led to decreased cell growth and increased apoptosis, and inhibited tumor growth in vivo. We also demonstrate that gp96 inhibitory peptide p37 synergized with trastuzumab to suppress cell growth and induce apoptosis. Our work demonstrates that blocking gp96 conformational changes directs HER2 for cellular degradation, and represents a new therapeutic strategy for inhibiting HER2 signaling in cancer.     

Regional Homogeneity of Resting-State Brain Activity Suppresses the Effect of Dopamine-Related Genes on Sensory Processing Sensitivity

Sensory processing sensitivity (SPS) is an intrinsic personality trait whose genetic and neural bases have recently been studied. The current study used a neural mediation model to explore whether resting-state brain functions mediated the effects of dopamine-related genes on SPS. 298 healthy Chinese college students (96 males, mean age = 20.42 years, SD = 0.89) were scanned with magnetic resonance imaging during resting state, genotyped for 98 loci within the dopamine system, and administered the Highly Sensitive Person Scale. We extracted a “gene score” that summarized the genetic variations representing the 10 loci that were significantly linked to SPS, and then used path analysis to search for brain regions whose resting-state data would help explain the gene-behavior association. Mediation analysis revealed that temporal homogeneity of regional spontaneous activity (ReHo) in the precuneus actually suppressed the effect of dopamine-related genes on SPS. The path model explained 16% of the variance of SPS. This study represents the first attempt at using a multi-gene voxel-based neural mediation model to explore the complex relations among genes, brain, and personality.     

A Clinical Study of Acquired Immunodeficiency Syndrome Associated Penicillium Marneffei Infection from a Non-Endemic Area in China

Objective

To investigate the clinical characteristics, diagnosis, treatment and prognosis of penicilliosis among the patients with acquired immunodeficiency syndrome (AIDS) in non-endemic areas of China, and then to discuss its incubation period and the diagnostic performance of serum galactomannan test for penicilliosis.

Methods

Medical records and travel histories of penicilliosis patients in Zhongnan hospital from January 2006 to December 2013, and the interval from when the patients left the endemic area to the onset of the disease was analyzed. Serum galactomannan levels of penicilliosis patients and AIDS patients with fever were measured by the Platelia Aspergillus Enzyme Immunoassay Kit.

Results

A total of 47 AIDS-associated penicilliosis were confirmed by fungal culture, which accounted for 4.8% of 981 AIDS-related admissions. The sensitivity and specificity of serum galactomannan test for penicilliosis were 95.8% (23/24) and 90.9% (30/33), respectively, (cutoff index = 1.0). Two independent predictors for early mortality (death within 12 weeks) of the patients (21.3%, 10/47) were a delayed diagnosis and no treatment with antifungal therapy. Among 14 patients who became ill after leaving endemic areas, ten patients presented with the onset symptoms within 12 months (from 11 days to 360 days). We found a patient living with asymptomatic P. marneffei fungemia who had not received any antifungal therapy until 18 months’ follow up.

Conclusions

The co-infection of P. marneffei and HIV was not uncommon in the non-endemic areas of penicilliosis in China. There exists a latent form of infection for P. marneffei. The incubation period of penicilliosis may be quite different from one patient to another. In AIDS patients, the serum galactomannan test has utility for the diagnosis of penicilliosis. When patients with penicilliosis/AIDS were diagnosed early and treated with standardized antifungal therapy and combined antiretroviral therapy, their prognosis improved.     

Predisposition to tetraploidy in pulmonary vascular smooth muscle cells derived from the Eker rats

Somatic mutations in the tuberous sclerosis complex-2 (TSC2) gene are associated with pulmonary lymphangioleiomyomatosis (LAM), a disorder characterized by benign lesions of smooth muscle and/or smooth muscle-like cells in the lung. However, the cellular mechanisms underlying LAM disease are largely unknown. Given that the TSC2 gene product tuberin is involved in the regulation of cell growth and proliferation, the present study was designed to investigate the potential roles of TSC2 in regulation of the cell cycle. We studied cell cycle profiles of pulmonary vascular smooth muscle cells (SMCs) derived from Eker rats (Tsc2(+/EK)), a genetic model carrying a germline insertional deletion in one copy of the Tsc2 gene, and the wild-type rats (Tsc2(+/+)), a noncarrier counterpart. We found that Tsc2(+/EK), but not Tsc2(+/+), SMCs displayed increases in cells with > or =4N DNA content (> or =4N cells) and in the bromodeoxyuridine (BrdU) incorporation of > or =4N cells. Centrosome number was also increased in Tsc2(+/EK) SMCs, but the mitotic index was comparable between Tsc2(+/+) and Tsc2(+/EK) SMCs. Furthermore, Tsc2(+/EK) SMCs showed elevated phosphorylation of p70S6K and increased expression of cell cycle regulatory proteins Cdk1, cyclin B, Cdk2, and cyclin E. Inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin not only inhibited the phosphorylation of p70(S6K) and the expression of cell cycle regulatory proteins but also reduced accumulation of > or =4N cells and BrdU incorporation of >4N cells. Therefore, our results demonstrate that Tsc2(+/EK) SMCs are predisposed to undergo tetraploidization, involving activation of the mTOR pathway. These findings suggest an important role of Tsc2 in regulation of the cell cycle.     

食物中的反式脂肪酸

反式脂肪酸是指含一个或多个独立反式双键的脂肪酸．主要产生于油脂的氢化及反刍动物的生物氢化过程。煎炸烘烤的食品、反刍动物制品、人造奶油是食物中反式脂肪酸的主要来源。研究表明,反式脂肪酸对机体可能有一定负面作用。大量摄入可能会导致冠心病的发生及婴幼儿的发育不良。     

天坑森林植物叶-凋落物-土壤C、N、P生态化学计量特征

为探究广西乐业大石围天坑森林群落的C、N、P养分循环特征,比较了天坑内外森林群落的植物叶片-凋落物-土壤C、N、P含量及其化学计量比,采用相关性分析和冗余分析等统计方法研究其内在联系和相互影响。结果表明,与天坑外部森林相比,天坑内部森林植物叶片和凋落物呈现出C低N、P高,土壤为C、N低P高的格局。植物叶片C:N、C:P与凋落物C、N:P显著正相关,植物叶片C与土壤P显著负相关;天坑外部森林的植物叶片N、N:P与土壤N:P显著负相关,植物叶片C:N与土壤C、C:N显著正相关,说明天坑森林内部凋落物的C、P养分可能主要来源于植物叶片,而天坑外部森林的植物叶片C、N主要来自土壤。土壤C:N:P对植物叶、凋落物的C:N:P变化的解释率分别为90.7%和50.6%,其中土壤P对植物叶和凋落物的C:N:P计量特征变化的解释度最高,坑内生境植物对P含量变化更为敏感、坑外植物对于N含量变化更为敏感,表明天坑内部森林可能是P素受限位点、天坑外部森林是N素受限位点。喀斯特天坑内部森林和外部森林植物叶-凋落物-土壤的C:N:P的差异和联系,体现了天坑内外森林群落的养分循环特征和植物群落的适应性。     

Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/β-catenin pathway

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colon, and it has become one of the world-recognized medical problems as it is recurrent and refractory. Berberine (BBR) is an effective drug for UC treatment. However, the underlying mechanism and targets remain obscure. In this study, we systematically investigated the therapeutic effect and its mechanism of BBR in ameliorating DSS-induced mouse colitis. Expectedly, the colon inflammation was significantly relieved by BBR, and microbiota depletion by antibiotic cocktail significantly reversed the therapeutic effect. Further studies showed that BBR can regulate the abundance and component of bacteria, reestablish the broken chemical and epithelial barriers. Meanwhile, BBR administration dramatically decreased ILC1 and Th17 cells, and increased Tregs as well as ILC3 in colonic tissue of DSS-induced mice, and it was able to regulate the expression of various immune factors at the mRNA level. Moreover, a proteomic study revealed that Wnt/β-catenin pathway was remarkably enhanced in colonic tissue of BBR-treated mice, and the therapeutic effect of BBR was disappeared after the intervention of Wnt pathway inhibitor FH535. These results substantially revealed that BBR restores DSS-induced colon inflammation in a microbiota-dependent manner, and BBR performs its protective roles in colon by maintaining the structure and function of the intestinal mucosal barrier, regulating the intestinal mucosal immune homeostasis and it works through the Wnt/β-catenin pathway. Importantly, these findings also provided the proof that BBR serves as a potential gut microbiota modulator and mucosal barrier protector for UC prevention and therapy.     

磷酸盐对V族大肠杆菌素形成的影响

含ColV质粒的大肠杆菌在含有磷酸盐的牛肉膏蛋白胨培养基上形成的菌落,当覆盖敏感菌后可以形成较大的抑菌圈。说明磷酸盐对ColV质粒所编码的V族大肠杆菌素的形成有促进作用。在培养基中加入二价离子螯合剂——EDTA对大肠杆菌素形成同样有促进作用,而增加二价阳离子Ca++或Mg++却起到相反的作用。磷酸盐的这种促进作用是由于它降低了牛肉膏蛋白胨培养基中二价阳离子的浓度而引起的。因此,在培养基中添加磷酸盐有助于分离ColV质粒含有菌和对V族大肠杆菌素的研究。