PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity

Due to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1α in vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1α expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1α expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies.España Ministerio de Economía y Competitividad SAF2012-3902

Interplay between pulsations and mass loss in the blue supergiant 55 Cygnus = HD 198478

Blue supergiant stars are known to display photometric and spectroscopic variability that is suggested to be linked to stellar pulsations. Pulsational activity in massive stars strongly depends on the star's evolutionary stage and is assumed to be connected with mass-loss episodes, the appearance of macroturbulent line broadening, and the formation of clumps in the wind. To investigate a possible interplay between pulsations and mass-loss, we carried out an observational campaign of the supergiant 55 Cyg over a period of five years to search for photospheric activity and cyclic mass-loss variability in the stellar wind. We modeled the H, He I, Si II and Si III lines using the nonlocal thermal equilibrium atmosphere code FASTWIND and derived the photospheric and wind parameters. In addition, we searched for variability in the intensity and radial velocity of photospheric lines and performed a moment analysis of the line profiles to derive frequencies and amplitudes of the variations. The Halpha line varies with time in both intensity and shape, displaying various types of profiles: P Cygni, pure emission, almost complete absence, and double or multiple peaked. The star undergoes episodes of variable mass-loss rates that change by a factor of 1.7-2 on different timescales. We also observe changes in the ionization rate of Si II and determine a multiperiodic oscillation in the He I absorption lines, with periods ranging from a few hours to 22.5 days. We interpret the photospheric line variations in terms of oscillations in p-, g-, and strange modes. We suggest that these pulsations can lead to phases of enhanced mass loss. Furthermore, they can mislead the determination of the stellar rotation. We classify the star as a post-red supergiant, belonging to the group of alpha Cyg variables.Comment: 20 pages, 18 figures, 3 tables, accepted to Astronomy & Astrophysic

Atmospheric NLTE-models for the spectroscopic analysis of blue stars with winds : II. Line-blanketed models

We present new or improved methods for calculating NLTE, line-blanketed model atmospheres for hot stars with winds (spectral types A to O), with particular emphasis on fast performance. These methods have been implemented into a previous, more simple version of the model atmosphere code FASTWIND (Santolaya-Rey et al. 1997) and allow us to spectroscopically analyze large samples of massive stars in a reasonable time-scale, using state-of-the-art physics. Although this updated version of the code has already been used in a number of recent investigations, the corresponding methods have not been explained in detail so far, and no rigorous comparison with results from alternative codes has been performed. This paper intends to address both topics. In particular, we describe our (partly approximate) approach to solve the equations of statistical equilibrium for those elements that are primarily responsible for line-blocking and blanketing, as well as an approximate treatment of the line-blocking itself, which is based on a simple statistical approach using suitable means of line opacities and emissivities. Both methods are validated by specific tests. Furthermore, we comment on our implementation of a consistent temperature structure. In the second part, we concentrate on a detailed comparison with results from two codes used in alternative spectroscopical investigations, namely CMFGEN (Hillier & Miller 1998) and WM-Basic (Pauldrach et al. 2001). All three codes predict almost identical temperature structures and fluxes for λ > 400 Å, whereas at lower wavelengths a number of discrepancies are found. Particularly in the HeII continua, where fluxes and corresponding numbers of ionizing photons react extremely sensitively to subtle differences in the models, we consider any uncritical use of these quantities (e.g., in the context of nebula diagnostics) as unreliable. Optical H/He lines as synthesized by FASTWIND are compared with results from CMFGEN, obtaining a remarkable coincidence, except for the HeI singlets in the temperature range between 36 000 to 41 000 K for dwarfs and between 31 000 to 35 000 K for supergiants, where CMFGEN predicts much weaker lines. Consequences of these discrepancies are discussed. Finally, suggestions are presented as to adequately parameterize model-grids for hot stars with winds, with only one additional parameter compared to standard grids from plane-parallel, hydrostatic models.Facultad de Ciencias Astronómicas y Geofísica

Investigating nano-precipitation in a V-containing HSLA steel using small angle neutron scattering

Interphase precipitation (IPP) of nanoscale carbides in a vanadium-containing high-strength low-alloy steel has been investigated. Small angle neutron scattering (SANS) and transmission electron microscopy (TEM) were employed to characterize the precipitates and their size distributions in Fe-0.047C-0.2V-1.6Mn (in wt.%) alloy samples which had been austenitized, isothermally transformed at 700 °C for between 3 and 600 min and water quenched. TEM confirms that, following heat treatment, rows of vanadium-containing nanoscale interphase precipitates were present. Model-independent analysis of the nuclear SANS signal and model fitting calculations, using oblate spheroid and disc-shapes, were performed. The major axis diameter increased from 18 nm after 3 min to 35 nm after 600 min. Precipitate volume percent increased from 0.09 to 0.22 vol% over the same period and number density fell from 2 × 1021 to 5 × 1020 m−3. A limited number of measurements of precipitate maximum diameters from TEM images showed the mean value increased from 8 nm after 5 min to 28 nm after 600 min which is in reasonable agreement with the SANS data

Systemic administration of a fibroblast growth factor receptor 1 agonist rescues the cognitive deficit in aged socially isolated rats.

Social isolation predominantly occurs in elderly people and it is strongly associated with cognitive decline. However, the mechanisms that produce isolation-related cognitive dysfunction during aging remain unclear. Here, we evaluated the cognitive, electrophysiological, and morphological effects of short- (4 weeks) and long-term (12 weeks) social isolation in aged male Wistar rats. Long-term but not short-term social isolation increased the plasma corticosterone levels and impaired spatial memory in the Morris water maze. Moreover, isolated animals displayed dampened hippocampal long-term potentiation in vivo, both in the dentate gyrus (DG) and CA1, as well as a specific reduction in the volume of the stratum oriens and spine density in CA1. Interestingly, social isolation induced a transient increase in hippocampal basic fibroblast growth factor (FGF2), whereas fibroblast growth factor receptor 1 (FGFR1) levels only increased after long-term isolation. Importantly, subchronic systemic administration of FGL, a synthetic peptide that activates FGFR1, rescued spatial memory in long-term isolated rats. These findings provide new insights into the neurobiological mechanisms underlying the detrimental effects on memory of chronic social isolation in the aged.pre-print507 K

Inflammatory Animal Model for Parkinson's Disease: The Intranigral Injection of LPS Induced the Inflammatory Process along with the Selective Degeneration of Nigrostriatal Dopaminergic Neurons

We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinson's disease (PD). The implication of neuroinflammation on this disease was originally established in 1988, when the presence of activated microglia in the substantia nigra (SN) of parkinsonians was reported by McGeer et al. Neuroinflammation could be involved in the progression of the disease or even has more direct implications. We injected 2 μg of the potent proinflammatory compound lipopolysaccharide (LPS) in different areas of the CNS, finding that SN displayed the highest inflammatory response and that dopaminergic (body) neurons showed a special and specific sensitivity to this process with the induction of selective dopaminergic degeneration. Neurodegeneration is induced by inflammation since it is prevented by anti-inflammatory compounds. The special sensitivity of dopaminergic neurons seems to be related to the endogenous dopaminergic content, since it is overcome by dopamine depletion. Compounds that activate microglia or induce inflammation have similar effects to LPS. This model suggest that inflammation is an important component of the degeneration of the nigrostriatal dopaminergic system, probably also in PD. Anti-inflammatory treatments could be useful to prevent or slow down the rate of dopaminergic degeneration in this disease

Atmospheric NLTE-Models for the Spectroscopic Analysis of Blue Stars with Winds. II. Line-Blanketed Models

We present new or improved methods for calculating NLTE, line-blanketed model atmospheres for hot stars with winds (spectral types A to O), with particular emphasis on a fast performance. These methods have been implemented into a previous, more simple version of the model atmosphere code FASTWIND (Santolaya-Rey et al.1997) and allow to spectroscopically analyze rather large samples of massive stars in a reasonable time-scale, using state-of-the-art physics. We describe our (partly approximate) approach to solve the equations of statistical equilibrium for those elements which are primarily responsible for line-blocking and blanketing, as well as an approximate treatment of the line-blocking itself, which is based on a simple statistical approach using suitable means for line opacities and emissivities. Furthermore, we comment on our implementation of a consistent temperature structure. In the second part, we concentrate on a detailed comparison with results from those two codes which have been used in alternative spectroscopical investigations, namely CMFGEN (Hillier & Miller 1998) and WM-Basic (Pauldrach et al. 2001). All three codes predict almost identical temperature structures and fluxes for lambda > 400 A, whereas at lower wavelengths a number of discrepancies are found. Optical H/He lines as synthesized by FASTWIND are compared with results from CMFGEN, obtaining a remarkable coincidence, except for the HeI singlets in the temperature range between 36,000 to 41,000 K for dwarfs and between 31,000 to 35,000 K for supergiants, where CMFGEN predicts much weaker lines. Consequences due to these discrepancies are discussed.Comment: 30 pages incl. 20 figures, accepted by A&

Mortality rates immediately after severe hurricanes in Cuba have decreased over the past three decades

ObjectivesThe objective of this study is to understand how Cuba responds to extreme weather events, which can help identify and disseminate good public health practice.Study designThe study design of this study is an observational study using routinely collected mortality data.MethodsNational daily mortality counts after severe hurricanes arrived on the Cuba landmass since 1990 were compared with baseline values. Incidence rate ratios of mortality during the hurricane and for the four weeks afterwards were calculated for four eligible hurricanes: Georges (1998), Dennis (2005), Ike (2008) and Irma (2017).ResultsMortality rates decreased over time (P < 0.001 for interaction), and no excess mortality counts were observed after Hurricane Irma in 2017.ConclusionsMortality rates for severe hurricanes that have made landfall in Cuba have decreased over three decades, despite the most recent hurricane (Irma) being one of the strongest observed in recent decades. This suggests that the Cuban public health preparations and responses to recent severe hurricanes are probably contributing to this mitigation in national mortality rates during these periods

Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease.

Parkinson's Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD

Atmospheric NLTE-models for the spectroscopic analysis of blue stars with winds : II. Line-blanketed models

We present new or improved methods for calculating NLTE, line-blanketed model atmospheres for hot stars with winds (spectral types A to O), with particular emphasis on fast performance. These methods have been implemented into a previous, more simple version of the model atmosphere code FASTWIND (Santolaya-Rey et al. 1997) and allow us to spectroscopically analyze large samples of massive stars in a reasonable time-scale, using state-of-the-art physics. Although this updated version of the code has already been used in a number of recent investigations, the corresponding methods have not been explained in detail so far, and no rigorous comparison with results from alternative codes has been performed. This paper intends to address both topics. In particular, we describe our (partly approximate) approach to solve the equations of statistical equilibrium for those elements that are primarily responsible for line-blocking and blanketing, as well as an approximate treatment of the line-blocking itself, which is based on a simple statistical approach using suitable means of line opacities and emissivities. Both methods are validated by specific tests. Furthermore, we comment on our implementation of a consistent temperature structure. In the second part, we concentrate on a detailed comparison with results from two codes used in alternative spectroscopical investigations, namely CMFGEN (Hillier & Miller 1998) and WM-Basic (Pauldrach et al. 2001). All three codes predict almost identical temperature structures and fluxes for λ > 400 Å, whereas at lower wavelengths a number of discrepancies are found. Particularly in the HeII continua, where fluxes and corresponding numbers of ionizing photons react extremely sensitively to subtle differences in the models, we consider any uncritical use of these quantities (e.g., in the context of nebula diagnostics) as unreliable. Optical H/He lines as synthesized by FASTWIND are compared with results from CMFGEN, obtaining a remarkable coincidence, except for the HeI singlets in the temperature range between 36 000 to 41 000 K for dwarfs and between 31 000 to 35 000 K for supergiants, where CMFGEN predicts much weaker lines. Consequences of these discrepancies are discussed. Finally, suggestions are presented as to adequately parameterize model-grids for hot stars with winds, with only one additional parameter compared to standard grids from plane-parallel, hydrostatic models.Facultad de Ciencias Astronómicas y Geofísica