Immune response against <i>Mycobacterium avium</i> subsp. <i>paratuberculosis</i>, Epstein-Barr virus, HERV-K and IRF5 in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory disease characterized by synovitis, systemic inflammation, autoantibodies that causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Its aetiology as well the exact etiopathogenetic mechanisms are not well clear so far. RA is triggered by an interplay between genes and environmental factors. Several studies showed that microorganisms play an important role in triggering autoimmunity through different mechanisms of action. Viral and bacterial infections, such as those caused by Epstein-Barr virus (EBV), Human Endogenous Retrovirus (HERVs) and mycobacteria, may play a pathogenetic role in RA through immunological cross-reactivity or molecular mimicry. Sardinians have a peculiar genetic background resulting from a long lasting geographical isolation with a strong incidence and prevalence of different autoimmune disease such as RA, multiple sclerosis (MS) and diabetes. During this PhD course, I have studied the role of EBV, HERV-K and Mycobacterium avium subsp. paratuberculosis (MAP) in RA pathogenesis and other rheumatic diseases for a better understanding of how these infectious agents can lead to a deregulation of transcription factors such as Interferon Regulatory Factor 5 (IRF5) that is important in the regulation of different cells type like macrophages and neutrophils. Finally, in order to better understand the etiopathogenesis of RA, an animal model has been used to study the molecular mechanisms involved in the above-mentioned diseases and to better understand the link between the environment and genes in RA with an objective to develop new therapeutic strategies

Multiple Residues in the Second Extracellular Loop Are Critical for M3 Muscarinic Acetylcholine Receptor Activation

Recent studies suggest that the second extracellular loop (o2 loop) of bovine rhodopsin and other class I G protein-coupled receptors (GPCRs) targeted by biogenic amine ligands folds deeply into the transmembrane receptor core where the binding of cis-retinal and biogenic amine ligands is known to occur. In the past, the potential role of the o2 loop in agonist-dependent activation of biogenic amine GPCRs has not been studied systematically. To address this issue, we used the M3 muscarinic acetylcholine receptor (M3R), a prototypic class I GPCR, as a model system. Specifically, we subjected the o2 loop of the M3R to random mutagenesis and subsequently applied a novel yeast genetic screen to identity single amino acid substitutions that interfered with M3R function. This screen led to the recovery of about 20 mutant M3Rs containing single amino acid changes in the o2 loop that were inactive in yeast. In contrast, application of the same strategy to the extracellular N-terminal domain of the M3R did not yield any single point mutations that disrupted M3R function. Pharmacological characterization of many of the recovered mutant M3Rs in mammalian cells, complemented by site-directed mutagenesis studies, indicated that the presence of several o2 loop residues is important for efficient agonist-induced M3R activation. Besides the highly conserved Cys220 residue, Gln207, Gly211, Arg213, Gly218, Ile222, Phe224, Leu225, and Pro228 were found to be of particular functional importance. In general, mutational modification of these residues had little effect on agonist binding affinities. Our findings are therefore consistent with a model in which multiple o2 loop residues are involved in stabilizing the active state of the M3R. Given the high degree of structural homology found among all biogenic amine GPCRs, our findings should be of considerable general relevance

Simultaneous quantization of bulk conduction and valence states through adsorption of nonmagnetic impurities on Bi2Se3

Exposing the (111) surface of the topological insulator Bi2Se3 to carbon monoxide results in strong shifts of the features observed in angle-resolved photoemission. The behavior is very similar to an often reported `aging' effect of the surface and it is concluded that this aging is most likely due to the adsorption of rest gas molecules. The spectral changes are also similar to those recently reported in connection with the adsorption of the magnetic adatom Fe. All spectral changes can be explained by a simultaneous confinement of the conduction band and valence band states. This is only possible because of the unusual bulk electronic structure of Bi2Se3. The valence band quantization leads to spectral features which resemble those of a band gap opening at the Dirac point.Comment: 5 pages, 4 figure

Homologous self-organising scale-invariant properties characterise long range species spread and cancer invasion

The invariance of some system properties over a range of temporal and/or spatial scales is an attribute of many processes in nature1, often characterised by power law functions and fractal geometry2. In particular, there is growing consensus in that fat-tailed functions like the power law adequately describe long-distance dispersal (LDD) spread of organisms 3,4. Here we show that the spatial spread of individuals governed by a power law dispersal function is represented by a clear and unique signature, characterised by two properties: A fractal geometry of the boundaries of patches generated by dispersal with a fractal dimension D displaying universal features, and a disrupted patch size distribution characterised by two different power laws. Analysing patterns obtained by simulations and real patterns from species dispersal and cell spread in cancer invasion we show that both pattern properties are a direct result of LDD and localised dispersal and recruitment, reflecting population self-organisation

Functional selectivity of GPCR-directed drug action through location bias.

G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The β 2 -adrenergic GPCR can activate G s -linked cyclic AMP (G s -cAMP) signaling from endosomes. We show here that the homologous human β 1 -adrenergic receptor initiates an internal G s -cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that β-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose \u27location bias\u27 as a new principle for achieving functional selectivity of GPCR-directed drug action

Thermoelectric energy recovery at ionic-liquid/electrode interface

A Thermally Chargeable Capacitor containing a binary solution of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)-imide (EMIMTFSI) in acetonitrile is electrically charged by applying a tempera- ture gradient to two ideally polarisable electrodes. The corresponding thermoelectric coefficient is -1.7 mV/K for platinum foil electrodes and -0.3 mV/K for nanoporous carbon electrodes. Stored electrical energy is extracted by discharging the capacitor through a resistor. The measured capacitance of the electrode/ionic- liquid interface is 5 micro $\mu$F for each platinum electrode while it becomes four orders of magnitude larger $\approx 36$ mF for a single nanoporous carbon electrode. Reproducibility of the effect through repeated charging-discharging cycles under a steady-state temperature gradient demonstrates the robustness of the electrical charging pro- cess at the liquid/electrode interface. The acceleration of the charging by convective flows is also observed. This offers the possibility to convert waste-heat into electric energy without exchanging electrons between ions and electrodes, in contrast to what occurs in most thermogalvanic cells.Comment: 8 pages, 11 figure

Ecología de forrajeo del macá grande Podicephorus major en la laguna Mar Chiquita (Buenos Aires, Argentina)

We studied the foraging ecology of the great grebe Podicephorus major through diet, prey energy return and foraging behaviour across three increasingly marine sites in the coastal lagoon of Mar Chiquita, Argentina. Grebes were followed by focal observations; we recorded dive duration, number of apparent successful and unsuccessful dives, size and type of captured prey and handling time above water.We analysed foraging effort as capture rate (i.e. number of prey eaten per minute) and capture success (i.e. number of successful dives per total dives made); and foraging efficiency as the number of captured prey per foraging time, the total biomass consumed and the energy intake obtained per time. We expected a piscivorous diet, but the most frequent prey were crabs, represented by Cyrtograpsus angulatus and Neohelice granulate, followed by diverse fish species. Diving time for different prey types and foraging sites did not differ. Handling time was higher for crabs. Foraging effort and foraging efficiency were higher for grebes that preyed on crabs, but in terms of biomass and energy return no differences were found, not even between sites. This suggests an opportunistic foraging behaviour for the great grebe in response to the possible higher availability of crabs in this and possibly other estuaries.Se estudió la ecología de forrajeo del macá grande Podicephorus major a través de la dieta, el rendimiento calórico de las presas y el esfuerzo y eficiencia de forrajeo en una laguna costera del sudeste de Argentina. El comportamiento de forrajeo fue cuantificado utilizando observaciones focales, donde se registró la duración del buceo, número de buceos aparentemente exitosos y no exitosos, tamaño y tipo de presa capturada, y tiempo de manipulación sobre el agua. Se analizó el esfuerzo de forrajeo medido como tasa de captura (número de presas ingeridas por minuto); éxito de captura (número de buceos exitosos sobre el número de buceos totales); eficiencia de forrajeo como el número de presas capturadas por tiempo de forrajeo, la biomasa total consumida y por el retorno energético (tiempo de forrajeo por unidad temporal). Se esperaba una dieta piscívora, pero las presas más frecuentes fueron los cangrejos, representados por Cyrtograpsus angulatus y Neohelice granulata, seguido por diversas especies de peces. El tiempo de buceo para diferentes tipos de presa y los diferentes lugares de forrajeo no varió. El tiempo de manipulación fue mayor para los cangrejos. El esfuerzo y la eficiencia de forrajeo fue mayor para los individuos que se alimentaron de cangrejos, pero en términos de biomasa consumida y retorno energético no hubo diferencias, tampoco para las áreas de forrajeo. Esto sugiere un comportamiento trófico oportunista para el macá grande en respuesta a la posible alta disponibilidad de cangrejos en el área de estudio y posiblemente en otros estuarios.Fil: Josens, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Favero, Marco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Bo, Maria Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentin

Contribution of beta diversity in shaping stream macroinvertebrate communities among hydro-ecoregions

AbstractRivers are heterogeneous and patchy-structured systems in which regional biodiversity of aquatic communities typically varies as a function of local habitat conditions and spatial gradients. Understanding which environmental and spatial constraints shape the diversity and composition of benthic communities is therefore a pivotal challenge for basic and applied research in river ecology. In this study, benthic invertebrates were collected from 27 sites across three hydro-ecoregions with the aim of investigating patterns inα- andβdiversity. We first assessed the contribution to regional biodiversity of different and nested spatial scales, ranging from micro-habitat to hydro-ecoregion. Then, we tested differences inαdiversity, taxonomic composition and ecological uniqueness among hydro-ecoregions. Variance partitioning analysis was used to evaluate the mechanistic effects of environmental and spatial variables on the composition of macroinvertebrate communities. Macroinvertebrate diversity was significantly affected by all the spatial scales, with a differential contribution according to the type of metric. Sampling site was the spatial scale that mostly contributed to the total richness, while the micro-habitat level explained the largest proportion of variance in Shannon–Wiener index. We found significant differences in the taxonomic composition, with 39 invertebrate families significantly associated with one or two hydro-ecoregions. However, effects of environmental and spatial controls were context dependent, indicating that the mechanisms that promote beta diversity probably differ among hydro-ecoregions. Evidence for species sorting, due to natural areas and stream order, was observed for macroinvertebrate communities in alpine streams, while spatial and land-use variables played a weak role in other geographical contexts

Vertical Distrubution in the Water Column of Drifting Stream Macroinvertebrates

ABSTRACT We examined the macroinvertebrate composition and drift density in a Mediterranean lotic system, the Erro River (northwestern Italy). Drift density and composition were sampled for one year at three levels of the water column; temperature and flow velocity were also measured. We found that drift density was generally highest near the bottom. We also noticed that various taxa tended to drift at preferential levels of the water column, with 41.4 % of taxa mainly at the bottom level and 31.0 % mainly at the top. Drift density decreased with increasing water temperature. Both taxa richness and macroinvertebrate abundance in the drift were positively associated with natural riverbed richness and abundance