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.     

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。     

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.     

Efficient Visible-to-UV Photon Upconversion Systems Based on CdS Nanocrystals Modified with Triplet Energy Mediators

Developing high-performance visible-to-UV photon upconversion systems based on triplet–triplet annihilation photon upconversion (TTA-UC) is highly desired, as it provides a potential approach for UV light-induced photosynthesis and photocatalysis. However, the quantum yield and spectral range of visible-to-UV TTA-UC based on nanocrystals (NCs) are still far from satisfactory. Here, three different sized CdS NCs are systematically investigated with triplet energy transfer to four mediators and four annihilators, thus substantially expanding the available materials for visible-to-UV TTA-UC. By improving the quality of CdS NCs, introducing the mediator via a direct mixing fashion, and matching the energy levels, a high TTA-UC quantum yield of 10.4% (out of a 50% maximum) is achieved in one case, which represents a record performance in TTA-UC based on NCs without doping. In another case, TTA-UC photons approaching 4 eV are observed, which is on par with the highest energies observed in optimized organic systems. Importantly, the in-depth investigation reveals that the direct mixing approach to introduce the mediator is a key factor that leads to close to unity efficiencies of triplet energy transfer, which ultimately governs the performance of NC-based TTA-UC systems. These findings provide guidelines for the design of high-performance TTA-UC systems toward solar energy harvesting.     

Investigation of thermal residual stresses during laser ablation of tantalum carbide coated graphite substrates using micro-Raman spectroscopy and COMSOL multiphysics

Laser ablation of high-temperature ceramic coatings results in thermal residual stresses due to which the coatings fail by cracking and debonding. Hence, the measurement of such residual stresses during laser ablation process holds utmost importance from the view of performance of coatings in extreme conditions. The present research aims at investigating the effect of laser parameters such as laser pulse energy, scanning speed and line spacing on thermal residual stresses induced in tantalum carbide-coated graphite substrates. Residual stresses were measured using micro-Raman spectroscopy and correlated with Raman peak shifts. Transient thermal analysis was performed using COMSOL Multiphysics to model the single ablated track and residual stresses were reported at low, moderate and high pulse energy regimes. The results showed that the initial laser conditions caused higher tensile residual stresses. Moderate pulse energy regime comprised higher compressive residual stresses due to off centre overlapping of the laser pulses. Higher pulse energy (250 μJ), higher scanning speed (1000 mm/s) and moderate line spacing (20 μm) caused accumulation of tensile residual stresses during the final stage of laser ablation. The deviation of experimental residual stresses from COMSOL numerical model was attributed to unaccounted additional stresses induced during thermal spraying process and deformation potentials in the numerical model.     

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.     

Influence of Al3+ doping for V5+ on the structural,optical, thermal and electrical properties of V2-xAlxO5-δ (x=0–0.20) ceramics

This paper reports an investigation on the structure-properties correlation of trivalent metal oxide (Al₂O₃)-doped V₂O₅ ceramics synthesized by the melt-quench technique. XRD patterns confirmed a single orthorhombic V₂O₅ phase formation with increasing strain on the doping of Al₂O₃ in place of V₂O₅ in the samples estimated by Williamson-Hall analysis. FTIR and Raman investigations revealed a structural change as [VO₅] polyhedra converts into [VO₄] polyhedra on the doping of Al₂O₃ into V₂O₅. The optical band gap was found in a wide semiconductor range as confirmed by UV–visible spectroscopy analysis. The thermal and conductivity behavior of the prepared samples were studied using thermal gravimetric analysis (TGA) and impedance analyzer, respectively. All the prepared ceramics exhibit good DC conductivity (0.22–0.36 Sm^-1) at 400 ?C. These materials can be considered for intermediate temperature solid oxide fuel cell (IT-SOFC)/battery applications due to their good conductivity and good thermal stability.