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1.
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
2.
Bouaziz Youssef Royer Eric Bresson Guillaume Dhome Michel 《Multimedia Tools and Applications》2022,81(16):22449-22480
Multimedia Tools and Applications - Changes in appearance present a tremendous problem for the visual localization of an autonomous vehicle in outdoor environments. Data association between the... 相似文献
3.
Alfonso Martín-Bernab Josep Tarrag-Celada Valrie Cunin Sylvie Michelland Roldn Corts Johann Poignant Cyril Boyault Walid Rachidi Sandrine Bourgoin-Voillard Marta Cascante Michel Seve 《International journal of molecular sciences》2021,22(7)
Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies. 相似文献
4.
Solenn Percelay Jean-Marie Billard Thomas Freret Annie Andrieux Michel Boulouard Valentine Bouet 《International journal of molecular sciences》2021,22(5)
For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of the MAP6 gene, early-life stress—maternal separation, and pharmacological treatment—chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis. 相似文献
5.
Superconducting qubits are solid state electrical circuits fabricated using techniques borrowed from conventional integrated circuits. They are based on the Josephson tunnel junction, the only non-dissipative, strongly non-linear circuit element available at low temperature. In contrast to microscopic entities such as spins or atoms, they tend to be well coupled to other circuits, which make them appealling from the point of view of readout and gate implementation. Very recently, new designs of superconducting qubits based on multi-junction circuits have solved the problem of isolation from unwanted extrinsic electromagnetic perturbations. We discuss in this review how qubit decoherence is affected by the intrinsic noise of the junction and what can be done to improve it.
PACS: 03.67.-a, 03.65.Yz, 85.25.-j, 85.35.Gv 相似文献
6.
PA Grace 《Canadian Metallurgical Quarterly》1997,166(3):152-156
PURPOSE: To examine the management and possible causes of primary valve malfunction of the Krupin eye valve with disk. METHODS: The authors reviewed the results of 113 patients undergoing implantation of the Krupin eye valve with disk and identified eight patients with primary valve malfunction requiring surgical revision. RESULTS: Valve revision involved manipulation (n = 1 case), explantation of the malfunctioning valve and implantation of a new valve (n = 2), and amputation of the valve (n = 5). Six of eight patients had final intraocular pressures of < 21 mmHg on one or no medications at a mean interval of 15.9 months (range 5-36) after surgical revision. Transient postoperative hypotony was noted in three patients and chronic hypotony with loss of light perception in one patient. One explanted valve was examined and found to have partially fused leaflets. CONCLUSIONS: Surgical revision in cases of primary valve malfunction of the Krupin eye valve with disk may be accomplished relatively safely with an acceptable level of postoperative complications. The etiology of primary valve malfunction may be related to the sterilization process and prolonged storage before implantation. 相似文献
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9.
Christian Ligoure Michel Cloitre Christille Le Chatelier Fabrice Monti 《Polymer》2005,46(17):6402-6410
A remarkable correlation exists between the degree of expansion of polyurethane foams and the structure of the reacting premixes. Polyurethane foams obtained from reacting premixes containing microemulsions are highly expanded. The expansion rate is proportional to the volume fraction of microemulsion in the premix. The stability of premixes with and without microemulsion is completely different suggesting distinct creaming mechanisms. We apply this idea to synthesize polyurethane foams from microemulsions successfully. This approach can be used to rationalize the design of polyurethane formulations leading to highly expanded foams. 相似文献
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