Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.     

Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.     

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene,a Major Active Metabolite of Bisphenol A,Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway

4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.     

唐钢ER70S-6焊丝钢的生产工艺研究及质量分析

介绍了唐钢ER70S-6焊丝钢的特点，对盘条质量进行了分析。对该钢化学成分、冶炼和轧制工艺进行了优化研究，使其综合性能明显改善。     

我国第一套Φ170mm三辊轧管机组

介绍了我国第一套Φ１７０ｍｍ三辊轧管机组热轧设备和产品规格及技术特点。     

ER流体特性及其研究现状

本文简要介绍了ER流体现象及其力学和电学性能,给出了描述ER流体行为的一般理论,提出了ER流体应用中目前存在的主要问题。     

舞钢管线钢的开发与生产

系统介绍了舞钢开发的针状铁素体型X70宽厚板的设计思路、工艺特点和实物水平；采用电炉 炉外精炼 连铸 TMCP工艺生产的X70宽厚板满足西气东输专用技术条件的要求，并批量应用在西气东输主干线工程中。     

首钢“川气出川”工程用17.5mmX70管线钢的试制

介绍了首钢试制17.5mm规格高强度、高韧性X70管线钢的生产工艺（成分设计、炼钢和轧钢工艺）及产品的力学性能。在华油钢管厂完成制管（管径为1016mm）以及相应的检验后，所有性能指标全部达到“川气出川”管道工程的技术规范要求。     

Optimal estimation of parameters of dynamical systems by neural network collocation method

In this paper we propose a new method to estimate parameters of a dynamical system from observation data on the basis of a neural network collocation method. We construct an object function consisting of squared residuals of dynamical model equations at collocation points and squared deviations of the observations from their corresponding computed values. The neural network is then trained by optimizing the object function.The proposed method is demonstrated by performing several numerical experiments for the optimal estimates of parameters for two different nonlinear systems. Firstly, we consider the weakly and highly nonlinear cases of the Lorenz model and apply the method to estimate the optimum values of parameters for the two cases under various conditions. Then we apply it to estimate the parameters of one-dimensional oscillator with nonlinear damping and restoring terms representing the nonlinear ship roll motion under various conditions. Satisfactory results have been obtained for both the problems.     

西气东输工程用X70热轧板卷屈服强度检测值波动大的探讨

对西气东输工程用X70热轧板卷检验过程中出的屈服强度σ0.5波动大的情况进行了分析，认为拉伸试样弯曲是主要原因。这一问题可通过反复压平试样，确保试样的平直度以及适当提高钢的强度的方法加以解决。