Time Parallel Gravitational Collapse Simulation

This article demonstrates the applicability of the parallel-in-time method Parareal to the numerical solution of the Einstein gravity equations for the spherical collapse of a massless scalar eld. To account for the shrinking of the spatial domain in time, a tailored load balancing scheme is proposed and compared to load balancing based on number of time steps alone. The performance of Parareal is studied for both the sub-critical and black hole case; our experiments show that Parareal generates substantial speedup and, in the super-critical regime, can reproduce Choptuik's black hole mass scaling law

Enhanced Patch-Clamp Technique to Study Antimicrobial Peptides and Viroporins, Inserted in a Cell Plasma Membrane with Fully Inactivated Endogenous Conductances

Many short peptides selectively permeabilize the bacteria plasma membrane, leading to their lyses and death: they are therefore a source of antibacterial molecules, and inspiration for novel and more selective drugs. Another class of short (<100 residues) membrane proteins called viroporins, because they are coded by viral genes, permeabilizes the membrane of susceptible cells during infection of by most animal viruses. The permeabilization leads to host cell lyses and the release of the virus mass, replicated at host cell expense, to propagate the infection. Detailed knowledge of the permeabilization properties of these proteins would allow to design, for instance, selective blockers of these pores, that would contrast the spread of the viral infection. In this chapter, the patch-clamp technique is employed to study the mechanism of membrane permeabilization induced by the pore-forming peptides, under strict physiological conditions. This goal is achieved by recording the ion current through the channels formed by these peptides, once inserted in a cell plasma membrane. To avoid contamination by the cell membrane currents, all the endogenous current sources must be blocked. It has been found that the photoreceptor rod outer segment mechanically isolated from the retina of low vertebrates (OS) was the most suitable cell to carry on the above studies, because it was possible to fully block all its endogenous currents without using any drug (such as TTX, TEA, dihydropyridines, etc.), that could obstruct the peptide pores or interfere with the pore formation. The peptides were applied to (and removed from) the extracellular OS side in ~50 ms with a computer-controlled microperfusion system, in which every perfusion parameter (as the rate of solution flow, the temporal sequence of solution changes or the number of automatic, self-washing cycles) was controlled by a user-friendly interface. This system allowed rapid application and removal of ions, drugs and peptides on the cells with a controlled timing, so that the ion channel characteristics (as its selectivity, blockade and gating) and the dynamics of pore formation could be precisely assessed. On the basis of the electrophysiological recordings obtained with representative peptides and with selected analogs, as alamethicin F50/5, the cecoprine-mellitin hybrid peptide, and a 20-aminoacid long fragment of the viroporin poliovirus 2B, it will be shown that the membrane pore formation occurs according to the barrel and stave, toroidal, and carpet model, respectively, that are the most widely-accepted mechanisms of membrane permeabilization. When recording large currents (produced for instance by high concentrations of peptides and/or highly permeable peptides), it is necessary to minimize series resistance, to reduce time constant of charging the cell membrane capacitance and error in membrane potential control. A second problem arises from the asymmetry of the plasma membrane: it is possible that the permeabilization properties of a particular peptide could be different depending upon the side of the membrane to which it is applied. For example, it is conceivable that viroporins are optimized to insert in the intracellular face of the plasma membrane, because they are synthesized in host cell cytosol. These two problems could be circumvented by widening the patch pipette shank, through the calibrated combination of heat and air pressure. These pipettes dramatically reduce series resistance, and allow at the same time to insert pulled quartz or plastic tubes very close to the pipette tip, making it possible the delivery of large molecules to the cytosol with a controlled timing. Finally, it is presented here a simple procedure to consistently attain seals with conventional or pressure polished pipettes, made from just one glass type, on a wide variety of cell types, isolated from different amphibian, reptilian, fish, and mammalian tissues, and on artificial membranes made with many different lipid mixtures

Projeto servir : aprendizagem e qualificação através de uma entidade de classe

O presente estudo teve como objetivo geral analisar, através de um resgate histórico, a trajetória do Projeto Servir - espaço de qualificação dos Servidores Públicos Municipais de Bento Gonçalves, criado e administrado pelo Sindicato dos Servidores Públicos Municipais de Bento Gonçalves (SINDISERP-BG) há aproximadamente vinte anos. A pesquisa utilizada foi qualitativa/quantitativa, exploratória, bibliográfica e documental. Inicialmente, o Projeto Servir foi apresentado com dados gerais e atuais. Depois, os conceitos de sindicatos de trabalhadores, qualificação e educação de trabalhadores. Em seguida, foi feita uma breve descrição sobre políticas públicas, passando para um detalhamento do Projeto Servir. Após, a análise dos dados coletados, por fim a conclusão.The present study had as general objective to analyze, through a historical rescue, the Servir Project trajectory - a qualification space of the Municipal Public Servants of Bento Gonçalves, created and administrated by the Union of Municipal Public Servants of Bento Gonçalves (SINDISERP-BG), for approximately twenty years. The research used was qualitative/quantitative, exploratory, bibliographical and documentary. Initially, the Servir Project was presented with its general and current data. Then, the main concepts of Labor Unions, professional qualification and education from their workers. After that, a brief description of public policies, going on to a detailing about the Servir Project. After, the collected data, lastly the conclusion

THE ROLE OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS IN AMYOTROPHIC LATERAL SCLEROSIS: POTENTIAL MECHANISMS FOR NEUROPROTECTION

The vast majority of neurodegenerative disorders are adult-onset, incurable diseases. Understanding the pathogenetic mechanisms underlying these disorders and finding molecules apt to correct such processes are, therefore, among the hottest topics of biomedical research. Amyotrophic Lateral Sclerosis is one of the most common adult-onset neurodegenerative diseases characterized by progressive degeneration of upper and lower motor neurons leading to paralysis and death due to respiratory failure within 3-5 years from the onset. Only one drug, riluzole, has proved effective in extending the lifespan of patients with ALS, but only by 3-6 months. For this reason the development of effective therapies for this pathology is highly invocated, but to date all attempts to develop novel treatments have failed. In this context, two recent reports on the neuroprotective activity of the PPAR\uf067 agonist Pioglitazione in ALS mice result of considerable interest: in these studies, two independent groups demonstrated that Pioglitazone, an agent which is currently used in therapy for the treatment of type II diabetes, is neuroprotective in a mouse model of Amyotrophic Lateral Sclerosis, the hSOD1-G93A transgenic mice. Pioglitazone treatment started before the appearance of the symptoms, improved the motor performance and reduced the weight loss, attenuated motor neuron death and increased the survival. In addition, Pioglitazone reduced microglial activation and gliosis in the spinal cord, decreasing the production of pro-inflammatory mediators, such as iNOS, NF-kB and COX2. On this ground, we decided to investigate the transcriptional activity of PPARs in the central nervous system of the hSOD1-G93A mouse line, a well-characterized animal model of Amyotrophic Lateral Sclerosis, with the aim of identifying the stage of the disease at which the activity of PPARs becomes relevant to the pathology. To this end, we took advantage of the transgenic mouse PPRE-Luc, available in the laboratory, in which the reporter gene luciferase is expressed under the control of a promoter responsive to PPARs. Thus, we crossed the PPRE-Luc mice with the hSOD1-G93A animals to obtain mice that are heterozygous for the PPRE-Luc transgene and heterozygous or null for the hSOD1-G93A transgene. The analysis of the enzymatic activity of luciferase in the spinal cord and the brain areas of PPRE-Luc;hSOD1-G93A mice shows an abrupt increase of PPAR activity at the end stage of the disease in the spinal cord, which is the organ principally involved in the pathology, and in all the brain areas analysed. We demonstrated that this phenomenon clearly depends on the pathology because it is not shared by the peripheral organs (e.g. kidney and liver). Furthermore, it is not dependent on the metabolic modifications induced from the starvation that the animals experience during the last days of their life when they are almost completely paralysed and, thus, unable to reach for food and water. We subsequently decided to further investigate this mechanism by identifying the isoform(s) responsible for the increase of PPARs activity at the last stage of the disease and the cell type(s) involved. We first analysed the nuclear translocation of PPAR\u3b1, PPAR\u3b2/\u3b4 and PPAR\u3b3 in the spinal cord of hSOD1-G93A mice with an ELISA-based Transcription Factor Assay. The results obtained from these experiments showed that the overall nuclear presence of the different isoforms of PPARs does not change during the course of the disease. In order to obtain a cell specific information about the distribution of PPARs in the spinal cord, we next analysed the localization of PPAR\u3b1, PPAR\u3b2/\u3b4 and PPAR\u3b3 by immunohistochemistry on sections from the lumbar spinal cord of hSOD1-G93A at the different stages of the pathology using primary antibodies for the specific isoforms of PPARs and cell specific markers. Our stainings revealed that all the three isoforms of PPARs are expressed in spinal cord motor neurons; PPAR\u3b1 and PPAR\u3b2/\u3b4 are localized prevalently into the nucleus but show also a cytoplasmic staining, while PPAR\u3b3 is exclusively nuclear. All the three isoforms are present also in astrocytes where they are exclusively nuclear while only PPAR\u3b3 was detectable in microglia, and was localized into the nucleus. Immunohistochemical analysis confirms that the increase in PPAR activity at the end stage of the disease is not dependent on the increase in the nuclear presence of the receptors in the different cell types of the spinal cord, suggesting that it possibly derives from ligand-dependent effects and/or the differential recruitment of co-regulators. To identify the specific isoform whose activity is important during the pathology we analysed the expression of isoform-specific target genes, i.e. MCAD for PPAR\u3b1, Acsl6 for PPAR\u3b2/\u3b4 and LPL for PPAR\u3b3. Only the expression of LPL abruptly increases at the end stage of the disease strongly suggesting that the increase in luciferase activity detected at the later stage of ALS is due to the activation of PPAR\u3b3. To confirm this result we analysed other PPAR\u3b3 target genes, i.e. Catalase, Glutathione S-tranferase alpha-2 and Peroxisome Proliferator Activated Receptor gamma coactivator 1-alpha. The RT-PCR analysis of the expression of Cat, Gsta2 and PGC1\u3b1 showed that Cat and PGC1\u3b1 show a similar trend of reduction till the onset of the disease, 100 days, then the levels of PGC1\u3b1 slightly increase while the Cat expression increases in a significant manner. Gsta2 expression remains fairly constant till the end stage when it increases significantly. On these bases we decided to further investigate the mechanisms of PPAR\u3b3 activation at the end stage of the disease by identifying the cell type involved. The analysis of the fluorescence intensity into the cellular nuclei of lumbar spinal cord sections stained for PPAR\u3b3 demonstrated that the intensity of the receptor signal is greater in motor neurons than in non-neuronal cells. This data led us to hypothesize that motor neurons could be the most likely cell type involved in the activation of PPAR\u3b3 at the end stage of the disease in vivo. Thus, we decided to analyse the expression of the PPAR\u3b3 target genes previously analysed in the spinal cords of hSOD1-G93A mice in an immortalized motor neuronal cell line, the NSC-34 cells. The expression of LPL, Cat and PGC1\u3b1 in NSC-34 cells transiently transfected with the hSOD1-G93A- encoding expression vector is significantly increased as compared to the NSC-34 cells transfected with the empty vector. These data clearly confirm the involvement of motor neurons in PPAR\u3b3 activation at the last stage of the disease; on these bases future studies will be aimed to further elucidate the mechanisms of PPAR\u3b3 protective activity on motor neurons in ALS

Numerical solutions to linear transfer problems of polarized radiation III. Parallel preconditioned Krylov solver tailored for modeling PRD effects

Context. The polarization signals produced by the scattering of anistropic radiation in strong resonance lines encode important information about the elusive magnetic fields in the outer layers of the solar atmosphere. An accurate modeling of these signals is a very challenging problem from the computational point of view, in particular when partial frequency redistribution (PRD) effects in scattering processes are accounted for with a general angle-dependent treatment. Aims. We aim at solving the radiative transfer problem for polarized radiation in nonlocal thermodynamic equilibrium conditions, taking angle-dependent PRD effects into account. The problem is formulated for a two-level atomic model in the presence of arbitrary magnetic and bulk velocity fields. The polarization produced by scattering processes and the Zeeman effect is considered. Methods. The proposed solution strategy is based on an algebraic formulation of the problem and relies on a convenient physical assumption, which allows its linearization. We applied a nested matrix-free GMRES iterative method. Effective preconditioning is obtained in a multifidelity framework by considering the light-weight description of scattering processes in the limit of complete frequency redistribution (CRD). Results. Numerical experiments for a one-dimensional (1D) atmospheric model show near optimal strong and weak scaling of the proposed CRD-preconditioned GMRES method, which converges in few iterations, independently of the discretization parameters. A suitable parallelization strategy and high-performance computing tools lead to competitive run times, providing accurate solutions in a few minutes. Conclusions. The proposed solution strategy allows the fast systematic modeling of the scattering polarization signals of strong resonance lines, taking angle-dependent PRD effects into account together with the impact of arbitrary magnetic and bulk velocity fields. Almost optimal strong and weak scaling results suggest that this strategy is applicable to realistic 3D models. Moreover, the proposed strategy is general, and applications to more complex atomic models are possible

Scalable approximation and solvers for ionic electrodiffusion in cellular geometries

The activity and dynamics of excitable cells are fundamentally regulated and moderated by extracellular and intracellular ion concentrations and their electric potentials. The increasing availability of dense reconstructions of excitable tissue at extreme geometric detail pose a new and clear scientific computing challenge for computational modelling of ion dynamics and transport. In this paper, we design, develop and evaluate a scalable numerical algorithm for solving the time-dependent and nonlinear KNP-EMI equations describing ionic electrodiffusion for excitable cells with an explicit geometric representation of intracellular and extracellular compartments and interior interfaces. We also introduce and specify a set of model scenarios of increasing complexity suitable for benchmarking. Our solution strategy is based on an implicit-explicit discretization and linearization in time, a mixed finite element discretization of ion concentrations and electric potentials in intracellular and extracellular domains, and an algebraic multigrid-based, inexact block-diagonal preconditioner for GMRES. Numerical experiments with up to $10^8$ unknowns per time step and up to 256 cores demonstrate that this solution strategy is robust and scalable with respect to the problem size, time discretization and number of cores.Comment: 26 page

Assessment of the CRD approximation for the observer's frame RIII redistribution matrix

Approximated forms of the RII and RIII redistribution matrices are frequently applied to simplify the numerical solution of the radiative transfer problem for polarized radiation, taking partial frequency redistribution (PRD) effects into account. A widely used approximation for RIII is to consider its expression under the assumption of complete frequency redistribution (CRD) in the observer frame (RIII CRD). The adequacy of this approximation for modeling the intensity profiles has been firmly established. By contrast, its suitability for modeling scattering polarization signals has only been analyzed in a few studies, considering simplified settings. In this work, we aim at quantitatively assessing the impact and the range of validity of the RIII CRD approximation in the modeling of scattering polarization. Methods. We first present an analytic comparison between RIII and RIII CRD. We then compare the results of radiative transfer calculations, out of local thermodynamic equilibrium, performed with RIII and RIII CRD in realistic 1D atmospheric models. We focus on the chromospheric Ca i line at 4227 A and on the photospheric Sr i line at 4607 A

Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases

Recent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia

PLCB2 (phospholipase C, beta 2)

Review on PLCB2 (phospholipase C, beta 2), with data on DNA, on the protein encoded, and where the gene is implicated

Ubiquitination as a key regulatory mechanism for O3-induced cutaneous redox inflammasome activation

NLRP1 is one of the major inflammasomes modulating the cutaneous inflammatory responses and therefore linked to a variety of cutaneous conditions. Although NLRP1 has been the first inflammasome to be discovered, only in the past years a significant progress was achieved in understanding the molecular mechanism and the stimuli behind its activation. In the past decades a crescent number of studies have highlighted the role of air pollutants as Particulate Matter (PM), Cigarette Smoke (CS) and Ozone (O3) as trigger stimuli for inflammasomes activation, especially via Reactive Oxygen Species (ROS) mediators. However, whether NLRP1 can be modulated by air pollutants via oxidative stress and the mechanism behind its activation is still poorly understood. Here we report for the first time that O3, one of the most toxic pollutants, activates the NLRP1 inflammasome in human keratinocytes via oxidative stress mediators as hydrogen peroxide (H2O2) and 4-hydroxy-nonenal (4HNE). Our data suggest that NLRP1 represents a target protein for 4HNE adduction that possibly leads to its proteasomal degradation and activation via the possible involvement of E3 ubiquitin ligase UBR2. Of note, Catalase (Cat) treatment prevented inflammasome assemble and inflammatory cytokines release as well as NLRP1 ubiquitination in human keratinocytes upon O3 exposure. The present work is a mechanistic study that follows our previous work where we have showed the ability of O3 to induce cutaneous inflammasome activation in humans exposed to this pollutant. In conclusion, our results suggest that O3 triggers the cutaneous NLRP1 inflammasome activation by ubiquitination and redox mechanism