Atomic-Level Mechanisms for Phospholamban Regulation of the Calcium Pump

AbstractWe performed protein pKa calculations and molecular dynamics (MD) simulations of the calcium pump (sarcoplasmic reticulum Ca2+-ATPase (SERCA)) in complex with phospholamban (PLB). X-ray crystallography studies have suggested that PLB locks SERCA in a low-Ca2+-affinity E2 state that is incompatible with metal-ion binding, thereby blocking the conversion toward a high-Ca2+-affinity E1 state. Estimation of pKa values of the acidic residues in the transport sites indicates that at normal intracellular pH (7.1–7.2), PLB-bound SERCA populates an E1 state that is deprotonated at residues E309 and D800 yet protonated at residue E771. We performed three independent microsecond-long MD simulations to evaluate the structural dynamics of SERCA-PLB in a solution containing 100 mM K+ and 3 mM Mg2+. Principal component analysis showed that PLB-bound SERCA lies exclusively along the structural ensemble of the E1 state. We found that the transport sites of PLB-bound SERCA are completely exposed to the cytosol and that K+ ions bind transiently (≤5 ns) and nonspecifically (nine different positions) to the two transport sites, with a total occupancy time of K+ in the transport sites of 80%. We propose that PLB binding to SERCA populates a novel (to our knowledge) E1 intermediate, E1⋅H+771. This intermediate serves as a kinetic trap that controls headpiece dynamics and depresses the structural transitions necessary for Ca2+-dependent activation of SERCA. We conclude that PLB-mediated regulation of SERCA activity in the heart results from biochemical and structural transitions that occur primarily in the E1 state of the pump

A model for the electromagnetic spectrum of the inner jets of Cen A

Centaurus A, the closest active galaxy, has been detected from radio to high-energy gamma-rays. The synchrotron radiation by extremely high energy protons may be a suitable mechanism to explain the MeV to GeV emission detected by the instruments of the Compton Gamma-Ray Observatory, as coming from the inner jets. This scenario requires a relatively large magnetic field of about 10^4 G that could be present only close to the central black hole. We investigate the spectral energy distribution (SED) resulting from a one-zone compact acceleration region, where both leptonic and hadronic relativistic populations arise. We present here results of such a model, where we have considered synchrotron radiation by primary electrons and protons, inverse Compton interactions, and gamma-ray emission originated by the inelastic hadronic interactions between relativistic protons and cold nuclei within the jets themselves. Photo-meson production by relativistic hadrons were also taken into account, as well as the effects of secondary particles injected by all interactions. The internal and external absorption of gamma rays is shown to be of great relevance to shape the observable SED, which was also recently constrained by the results of HESS.Comment: 13 pages (ref. style), submitted to MNRAS on December 04, 2008. Waiting for revie

1FGL J1417.7-4407: A likely gamma-ray bright binary with a massive neutron star and a giant secondary

We present multiwavelength observations of the persistent Fermi-LAT unidentified gamma-ray source 1FGL J1417.7-4407, showing it is likely to be associated with a newly discovered X-ray binary containing a massive neutron star (nearly 2 M_sun) and a ~ 0.35 M_sun giant secondary with a 5.4 day period. SOAR optical spectroscopy at a range of orbital phases reveals variable double-peaked H-alpha emission, consistent with the presence of an accretion disk. The lack of radio emission and evidence for a disk suggests the gamma-ray emission is unlikely to originate in a pulsar magnetosphere, but could instead be associated with a pulsar wind, relativistic jet, or could be due to synchrotron self-Compton at the disk--magnetosphere boundary. Assuming a wind or jet, the high ratio of gamma-ray to X-ray luminosity (~ 20) suggests efficient production of gamma-rays, perhaps due to the giant companion. The system appears to be a low-mass X-ray binary that has not yet completed the pulsar recycling process. This system is a good candidate to monitor for a future transition between accretion-powered and rotational-powered states, but in the context of a giant secondary.Comment: ApJL in pres

Analysis of energy consumption in Colombia using the holt method

Energy production is constantly facing major challenges today, because despite initiatives to promote the insertion of renewable energy, electricity consumption has shown considerable growth in recent years. In order to use an instrument that facilitates forecasts and predictive processes for the design of strategic plans associated with energy management, the application of the Holt Method is proposed using data on electricity demand in Colombia, GDP per capita and industrial value added, making an analysis of the last 10 years, based on figures from the World Bank. The final results predict that energy consumption for the period 2018-2020 will be between 66,231 GWk and 66,885 GWk

Distinct sub-second dopamine signaling in dorsolateral striatum measured by a genetically-encoded fluorescent sensor

The development of genetically encoded dopamine sensors such as dLight has provided a new approach to measuring slow and fast dopamine dynamics both in brain slices and in vivo, possibly enabling dopamine measurements in areas like the dorsolateral striatum (DLS) where previously such recordings with fast-scan cyclic voltammetry (FSCV) were difficult. To test this, we first evaluated dLight photometry in mouse brain slices with simultaneous FSCV and found that both techniques yielded comparable results, but notable differences in responses to dopamine transporter inhibitors, including cocaine. We then used in vivo fiber photometry with dLight in mice to examine responses to cocaine in DLS. We also compared dopamine responses during Pavlovian conditioning across the striatum. We show that dopamine increases were readily detectable in DLS and describe transient dopamine kinetics, as well as slowly developing signals during conditioning. Overall, our findings indicate that dLight photometry is well suited to measuring dopamine dynamics in DLS

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

Aging in Male Wistar Rats Associates with Changes in Intestinal Microbiota, Gut Structure, and Cholecystokinin-Mediated Gut-Brain Axis Function

Aging in mammals is characterized by failure of the homeostatic mechanisms that regulate energy balance. Several mechanisms have been proposed such as the presence of a low-grade chronic inflammation in different tissues, as well as leptin and insulin resistance, but the primary alteration is not fully elucidated. The gut microbiota has recently emerged as a key player in a variety of metabolic and neurological disorders. A main concept in this context is the gut–brain axis that refers to alterations in the gut that mediate effects in the central nervous system, including those related with the control of energy balance. Using 16S rRNA analysis, we demonstrate that aged male Wistar rats have increased presence of mucin-degrading and lipopolysaccharide (LPS)-producing bacteria. In addition, old animals exhibit a lower number of neutral mucin secreting goblet cells, and a decrease of tight junctions and adherens junctions marker proteins, zonula occludens protein-1 (ZO-1) and β-catenin, respectively. These data are compatible with a thinner mucus layer and a weaker gut barrier in older animals that likely facilitate LPS leakage. Our data also show that cholecystokinin (CCK) satiating effect is impaired in aged rats, one of the expected effects of increased LPS leakage. In contrast, no overt signs of gut or systemic inflammation are observed. Changes in microbiota in old male Wistar rats present features of situations of increased adiposity, but different from those of obese animals. These could partly explain the increased adiposity and fat deposition in liver and heart as observed here.Spanish Government (grants BFU2008-04901-C03-01/BFI to J.M.C., BIO2016-76601-C3-2-R to M.F.-L., and RTI2018-094052-B-100 [MCI/AEI/FEDER, UE to A.M.V.] and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (Instituto de Salud Carlos III) and Comunidad de Madrid, Spain (grants S2010/BMD-2423 to J.M.C., F.E., L.G.G., and A.M.V. and S2017/BMD-3684 to F.E. and A.M.V.). C.R. was supported by a predoctoral aid from Spanish Government. The Centro de Biología Molecular is recipient of institutional aids from Banco de Santander and Ramón Areces Foundation

Similarly Efficacious Anti-Malarial Drugs SJ733 and Pyronaridine Differ in Their Ability to Remove Circulating Parasites in Mice

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the parasite clearance curve , has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation. METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine were compared against sodium artesunate in mice infected with Plasmodium berghei (strain ANKA). To measure each compound\u27s capacity for pRBC removal in vivo, flow cytometric monitoring of a single cohort of fluorescently-labelled pRBC was employed, and combined with ex vivo parasite culture to assess parasite maturation and replication. RESULTS: These three compounds were found to be similarly efficacious in controlling established infection by reducing overall parasitaemia. While sodium artesunate acted relatively consistently across the life-stages, single-dose SJ733 elicited a biphasic effect, triggering rapid, partly phagocyte-dependent removal of trophozoites and schizonts, followed by arrest of residual ring-stages. In contrast, pyronaridine abrogated maturation of younger parasites, with less pronounced effects on mature parasites, while modestly increasing pRBC removal. CONCLUSIONS: Anti-malarials SJ733 and pyronaridine, though similarly efficacious in reducing overall parasitaemia in mice, differed markedly in their capacity to arrest replication and remove pRBC from circulation. Thus, similar parasite clearance curves can result for anti-malarials with distinct capacities to inhibit, kill and clear parasites

Nonlinear Measures for Characterizing Rough Surface Morphologies

We develop a new approach to characterizing the morphology of rough surfaces based on the analysis of the scaling properties of contour loops, i.e. loops of constant height. Given a height profile of the surface we perform independent measurements of the fractal dimension of contour loops, and the exponent that characterizes their size distribution. Scaling formulas are derived and used to relate these two geometrical exponents to the roughness exponent of a self-affine surface, thus providing independent measurements of this important quantity. Furthermore, we define the scale dependent curvature and demonstrate that by measuring its third moment departures of the height fluctuations from Gaussian behavior can be ascertained. These nonlinear measures are used to characterize the morphology of computer generated Gaussian rough surfaces, surfaces obtained in numerical simulations of a simple growth model, and surfaces observed by scanning-tunneling-microscopes. For experimentally realized surfaces the self-affine scaling is cut off by a correlation length, and we generalize our theory of contour loops to take this into account.Comment: 39 pages and 18 figures included; comments to [email protected]