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The calcium pump (sarco/endoplasmic reticulum Ca2+-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca2+ during muscle relaxation. Active Ca2+ transport by SERCA involves the structural transition from a low-Ca2+ affinity E2 state toward a high-Ca2+ affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca2+ ions passing through the membrane. X-ray crystallography studies have suggested that a hydrated pore located at the C-terminal domain of SERCA serves as a conduit for proton countertransport, but the existence and function of this pathway have not yet been fully characterized. We used atomistic simulations to demonstrate that in the protonated E2 state and the absence of initially bound water molecules, the C-terminal pore becomes hydrated in the nanosecond timescale. Hydration of the C-terminal pore is accompanied by the formation of water wires that connect the transport sites with the cytosol. Water wires are known as ubiquitous proton-transport devices in biological systems, thus supporting the notion that the C-terminal domain serves as a conduit for proton release. Additional simulations showed that the release of a single proton from the transport sites induces bending of transmembrane helix M5 and the interaction between residues Arg762 and Ser915. These structural changes create a physical barrier against full hydration of the pore and prevent the formation of hydrogen-bonded water wires once proton transport has occurred through this pore. Together, these findings support the notion that the C-terminal proton release pathway is a functional element of SERCA and also provide a mechanistic model for its operation in the catalytic cycle of the pump. 相似文献
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Oxana Kazakova Irina Smirnova Elena Tretyakova Ren Csuk Sophie Hoenke Lucie Fischer 《International journal of molecular sciences》2021,22(4)
Semi-synthetic triterpenoids, holding an amino substituted seven-membered A-ring (azepano-ring), which could be synthesized from triterpenic oximes through a Beckmann type rearrangement followed by a reduction of lactame fragment, are considered to be novel promising agents exhibiting anti-microbial, alpha-glucosidase, and butyrylcholinesterase inhibitory activities. In this study, in an attempt to develop new antitumor candidates, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives of betulin, oleanolic, ursolic, and glycyrrhetinic acids were evaluated for their cytotoxic activity against five human cancer cell lines and non-malignant mouse fibroblasts by means of a colorimetric sulforhodamine assay. Azepanoallobetulinic acid amide derivative 11 was the most cytotoxic compound of this series but showed little selectivity between the different human tumor cell lines. Flow cytometry experiments showed compound 11 to act mainly by apoptosis (44.3%) and late apoptosis (21.4%). The compounds were further screened at the National Cancer Institute towards a panel of 60 cancer cell lines. It was found that compounds 3, 4, 7, 8, 9, 11, 15, 16, 19, and 20 showed growth inhibitory (GI50) against the most sensitive cell lines at submicromolar concentrations (0.20–0.94 μM), and their cytotoxic activity (LC50) was also high (1–6 μM). Derivatives 3, 8, 11, 15, and 16 demonstrated a certain selectivity profile at GI50 level from 5.16 to 9.56 towards K-562, CCRF-CEM, HL-60(TB), and RPMI-8226 (Leukemia), HT29 (Colon cancer), and OVCAR-4 (Ovarian cancer) cell lines. Selectivity indexes of azepanoerythrodiol 3 at TGI level ranged from 5.93 (CNS cancer cell lines SF-539, SNB-19 and SNB-75) to 14.89 for HCT-116 (colon cancer) with SI 9.56 at GI50 level for the leukemia cell line K-562. The present study highlighted the importance of A-azepano-ring in the triterpenic core for the development of novel antitumor agents, and a future aim to increase the selectivity profile will thus lie in the area of modifications of azepano-triterpenic acids at their carboxyl group. 相似文献
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Cell encapsulation within hydrogel droplets is transforming what is feasible in multiple fields of biomedical science such as tissue engineering and regenerative medicine, in vitro modeling, and cell-based therapies. Recent advances have allowed researchers to miniaturize material encapsulation complexes down to single-cell scales, where each complex, termed a single-cell microgel, contains only one cell surrounded by a hydrogel matrix while remaining <100 μm in size. With this achievement, studies requiring single-cell resolution are now possible, similar to those done using liquid droplet encapsulation. Of particular note, applications involving long-term in vitro cultures, modular bioinks, high-throughput screenings, and formation of 3D cellular microenvironments can be tuned independently to suit the needs of individual cells and experimental goals. In this progress report, an overview of established materials and techniques used to fabricate single-cell microgels, as well as insight into potential alternatives is provided. This focused review is concluded by discussing applications that have already benefited from single-cell microgel technologies, as well as prospective applications on the cusp of achieving important new capabilities. 相似文献
5.
Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (NEU1), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific NEU1G227R and NEU1V275A/R347Q mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of NEU1G227R- and NEU1V275A/R347Q- mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with NEU1G227R- and NEU1V275A/R347Q- mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy–lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs. 相似文献
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Mohammad Ali Mousavi Mahsa Baghban Salehi 《Polymer-Plastics Technology and Engineering》2021,60(1):47-59
ABSTRACT The hydrophobic polyether sulfone membranes were prepared by the sol-gel method to be applied in an air gap membrane distillation setup for desalination. The surface modifications were carried out using Trimethylsilyl chloride (TMSCl) and Methyltrimethoxysilane (MTMS) solutions. The membranes were characterized using Attenuated Total Reflection Infrared (ATR-IR) spectroscopy, Scanning Electron Microscopy (SEM), and Optical Contact Angle (OCA) methods. The effects of membrane preparation as well as operating conditions such as temperature difference, salt concentration, feed rotation speed, and cold-side temperature on membrane performance were investigated using central composite design method. It was found that feed temperature has the largest effect among the parameters on the permeation flux. The flow rate and salt rejection of the membrane in the optimum conditions were 4.47 Kg m?2 h?1 and 99.37%, respectively. 相似文献
10.
Optimization of room-temperature TCR of polycrystalline La0.9-xSrxK0.1MnO3 ceramics by Sr adjustment
Hongjiang Li Kaili Chu Xingrui Pu Xiaohan Yu Xiaoli Guan Shuaizhao Jin Xiang Liu 《Ceramics International》2021,47(1):94-101
High-density La0.9-xSrxK0.1MnO3 ceramics (LSKMO, A-site = La, Sr and K, 0 ≤ x ≤ 0.25) are successfully fabricated by using facile sol-gel method. Electrical properties are performed by using combination of phenomenological percolation (PP) model, double exchange (DE) mechanism, and Jahn-Teller (JT) effect. Moreover, X-ray diffraction and scanning electron microscopy are employed to analyze the structure and morphology of LSKMO ceramics. Valence states and ionic stoichiometry are assessed by using X-ray photoemission spectrometry. Results reveal that Sr2+ ions, substituting La3+ ions, significantly influenced DE mechanism and JT effect. In addition, Sr-doping plays essential role in improving electrical properties of LSKMO ceramics. At optimal doping content of x = 0.09, peak temperature coefficient of resistance (TCR) of the resistivity is found to be 11.56% K?1 at 297.15 K, which is optimal TCR for A-site K-occupied perovskite manganese oxides. These results confirm that polycrystalline LSKMO ceramics render high room-temperature TCR values due to Sr-doping. 相似文献