Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump

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.     

Map management for robust long-term visual localization of an autonomous shuttle in changing conditions

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...     

Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

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.     

Functional Dysregulations in CA1 Hippocampal Networks of a 3-Hit Mouse Model of Schizophrenia

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 GABA_A 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.     

B Cells with a Senescent-Associated Secretory Phenotype Accumulate in the Adipose Tissue of Individuals with Obesity

Senescent cells accumulate in the adipose tissue (AT) of individuals with obesity and secrete multiple factors that constitute the senescence-associated secretory phenotype (SASP). This paper aimed at the identification of B cells with a SASP phenotype in the AT, as compared to the peripheral blood, of individuals with obesity. Our results show increased expression of SASP markers in AT versus blood B cells, a phenotype associated with a hyper-metabolic profile necessary to support the increased immune activation of AT-derived B cells as compared to blood-derived B cells. This hyper-metabolic profile is needed for the secretion of the pro-inflammatory mediators (cytokines, chemokines, micro-RNAs) that fuel local and systemic inflammation.     

A self‐scalable load injection service

Load testing of applications is an important and costly activity for software provider companies. Classical solutions are very difficult to set up statically, and their cost is prohibitive in terms of both human and hardware resources. Virtualized cloud computing platforms provide new opportunities for stressing an application's scalability, by providing a large range of flexible and less expensive (pay‐per‐use model) computation units. On the basis of these advantages, load testing solutions could be provided on demand in the cloud. This paper describes a Benchmark‐as‐a‐Service solution that automatically scales the load injection platform and facilitates its setup according to load profiles. Our approach is based on: (i) virtualization of the benchmarking platform to create self‐scaling injectors; (ii) online calibration to characterize the injector's capacity and impact on the benched application; and (iii) a provisioning solution to appropriately scale the load injection platform ahead of time. We also report experiments on a benchmark illustrating the benefits of this system in terms of cost and resource reductions. Copyright © 2013 John Wiley & Sons, Ltd.     

Understanding trust in ms-commerce: The roles of reported experience,linguistic style,profile photo,emotional, and cognitive trust

This paper examines what influences trust in mobile social commerce environment. Drawing on trust-based acceptance model (i.e. cognitive and emotional trust) and online review features (i.e. profile photo, linguistic style, and reported experience), we examine how these factors affect trust in mobile social commerce. Hypotheses were tested using survey data. The results of our model showed that there are significant influences of profile photo, reported experience, cognitive, and emotional trust towards trust in ms-commerce. This work contributes to existing literature by examining the roles of previous trust in mobile payments and online reviews on trust in mobile social commerce.     

PLC-RF diversity: channel outage analysis

Telecommunication Systems - Signals from indoor access points in a wireless fidelity suffer from high attenuation as a result of the thick walls and metal structures in the multilevel-storey...     

Implementing Qubits with Superconducting Integrated Circuits

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     

On the Way to Assess Emotions in Animals: Do Lambs (Ovis aries) Evaluate an Event Through Its Suddenness, Novelty, or Unpredictability?

Appraisal theories provide a framework that gives insight into emotions and could allow comparisons across species. According to these theories, events are first evaluated on their suddenness, novelty, and unpredictability. The authors examined the ability of lambs (Ovis aries) to evaluate an event according to these 3 criteria through 3 tests. The lambs responded to suddenness with a startle response coupled with an increase in heart rate and to novelty with an orientation response coupled with an increase of vagal activity. There was no clear evidence that lambs can detect the predictability of an event. Those results support the usefulness of appraisal theories to assess emotion in animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)