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.     

Mass transfer in polycrystalline ytterbium monosilicate under oxygen potential gradients at high temperatures

Mass transfer in polycrystalline Yb₂SiO₅ wafers with precise composition control was evaluated and analyzed by oxygen permeation experiments at high temperatures using an oxygen tracer. Oxygen permeation proceeded due to mutual grain boundary diffusion of oxide ions and Yb ions without synergistic effects such as acceleration or suppression. The oxygen shielding properties of Yb₂SiO₅ were compared with those of the other line compounds such as Yb₂Si₂O₇ and Al₂O₃ based on the determined mass transfer parameters. It was found that the more preferentially an oxide ion diffuses in the grain boundary compared to the interior of the grain, the greater the effect of suppressing the movement of the oxide ion by applying an oxygen potential gradient becomes.     

水杨酸处理诱导采后甜瓜抗坏血酸-还原型谷胱甘肽循环代谢清除过氧化氢的作用及机制

目的：研究抗坏血酸（ascorbic acid，AsA）-还原型谷胱甘肽（reduced glutathione，GSH）循环代谢在水杨酸处理采后甜瓜诱导的过量H2O2清除过程中的作用。方法：用4 mmol/L水杨酸浸泡‘玉金香’厚皮甜瓜10 min，测定处理后果实常温贮藏过程中丙二醛（malondialdehyde，MDA）含量，分析活性氧的积累水平、超氧化物歧化酶（superoxide dismutase，SOD）和过氧化氢酶（catalase，CAT）活力，以及AsA-GSH循环过程相关酶活力及产物和底物含量。结果：水杨酸处理降低了果实MDA含量，第10天处理组MDA含量较对照组降低14.6%；显著提高了果实O2－·的产生速率和H2O2含量（P＜0.05），其中处理后第2天O2－·的产生速率高出同期对照组的1.9 倍，第6天H2O2含量高出对照组果实29.7%；提高了果实SOD活力，但抑制了CAT活力，说明H2O2的清除可能是依赖于除酶促系统外的其他系统。此外，水杨酸处理提高了果实抗坏血酸过氧化物酶、单脱氢抗坏血酸过氧化物酶、脱氢抗坏血酸还原酶和谷胱甘肽还原酶的活力，增加了AsA和氧化型谷胱甘肽的含量，降低了脱氢抗坏血酸和GSH的含量。结论：水杨酸处理诱导了厚皮甜瓜果实的氧爆，抑制了MDA产生，由水杨酸诱导产生的过量H2O2主要依靠AsA-GSH循环系统清除。     

基于改进SOA-VMD的磁声发射信号去噪算法

磁声发射（MAE）是铁磁性材料磁化过程中产生的声发射信号，在构件应力检测和微观损伤检测中有着广泛的应用。针对MAE信号非稳态、复杂性、衰减性等特点，提出海鸥算法结合变分模态分解（SOA-VMD）的去噪方法，为克服海鸥算法求解过程中易陷入局部最优解问题，利用柯西变异算子产生随机迭代过程，使改进算法即柯西变异海欧算法（CVSOA）跳出早熟收敛。采用以幅值谱熵为适应度函数，优化VMD算法中分解模态个数K和二次惩戒因子α两个参数，将含噪声的MAE信号进行VMD分解重构。经仿真信号和实际检测信号分析表明，改进后的CVSOA-VMD算法全局寻优能力和去噪性能优于传统的SOA-VMD算法，降噪后的MAE信号特征值对于不同应力下均方根、偏斜度特征值的重复性更好，可靠性更高。     

Metabolic Profiling of VOCs Emitted by Bacteria Isolated from Pressure Ulcers and Treated with Different Concentrations of Bio-AgNPs

Considering the advent of antibiotic resistance, the study of bacterial metabolic behavior stimulated by novel antimicrobial agents becomes a relevant tool to elucidate involved adaptive pathways. Profiling of volatile metabolites was performed to monitor alterations of bacterial metabolism induced by biosynthesized silver nanoparticles (bio-AgNPs). Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae and Proteus mirabilis were isolated from pressure ulcers, and their cultures were prepared in the presence/absence of bio-AgNPs at 12.5, 25 and 50 µg mL⁻¹. Headspace solid phase microextraction associated to gas chromatography–mass spectrometry was the employed analytical platform. At the lower concentration level, the agent promoted positive modulation of products of fermentation routes and bioactive volatiles, indicating an attempt of bacteria to adapt to an ongoing suppression of cellular respiration. Augmented response of aldehydes and other possible products of lipid oxidative cleavage was noticed for increasing levels of bio-AgNPs. The greatest concentration of agent caused a reduction of 44 to 80% in the variety of compounds found in the control samples. Pathway analysis indicated overall inhibition of amino acids and fatty acids routes. The present assessment may provide a deeper understanding of molecular mechanisms of bio-AgNPs and how the metabolic response of bacteria is untangled.     

Designing amorphous formulations of polyphenols with naringin by spray-drying for enhanced solubility and permeability

Naringin (NAR), a major flavanone (FVA) glycoside, is a component of food mainly obtained from grapefruit. We used NAR as a food additive to improve the solubility and permeability of hydrophobic polyphenols used as supplements in the food industry. The spray-dried particles (SDPs) of NAR alone show an amorphous state with a glass transition temperature (T_g) at 93.2 °C. SDPs of hydrophobic polyphenols, such as flavone (FVO), quercetin (QCT), naringenin (NRG), and resveratrol (RVT) were prepared by adding varying amounts of NAR. All SDPs of hydrophobic polyphenols with added NAR were in an amorphous state with a single T_g, but SDPs of hydrophobic polyphenols without added NAR showed diffraction peaks derived from each crystal. The SDPs with NAR could keep an amorphous state after storage at a high humidity condition for one month, except for SDPs of RVT/NAR. SDPs with NAR enhanced the solubility of hydrophobic polyphenols, especially NRG solubility, which was enhanced more than 9 times compared to NRG crystal. The enhanced solubility resulted in the increased membrane permeability of NRG. The antioxidant effect of the hydrophobic NRG was also enhanced by the synergetic effect of NAR. The findings demonstrated that NAR could be used as a food additive to enhance the solubility and membrane permeability of hydrophobic polyphenols.     

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.