Mapa hidrogeológico de la cuenca del río Ica

Se evalúa hidrogeológicamente la Cuenca del Río Ica. Se realiza un diagnóstico integral de las fuentes principales, se evalúa en forma detallada la litología, se brindan las características petrofísicas y se elabora un mapa hidrogeológico a escala 1:100,000. A partir de este mapa y considerando los parámetros hidrológicos e hidrogeológicos, se proponen técnicas de captación y recarga de los acuíferos. Finalmente, se brinda información para la población y autoridades, acerca de una adecuada gestión integral de los recursos hídricos. El área correspondiente a la cuenca del río Ica abarca 7,187.50 km2, comprendida entre los paralelos 14º 57’ 00’’ y 13º 30’ 00’’ de Latitud Sur y entre los meridianos 75º 06’ 00’’ y 75º 00’ 00’’ de Longitud Oeste. El río Ica nace en el departamento de Huancavelica a 4,500 msnm en la Laguna de Parinacocha y recorre terrenos de geografía muy compleja. Estructuralmente, la zona de estudio se halla afectada por pliegues y fallas. Los materiales que constituyen los niveles acuíferos de mayor importancia son los depósitos aluviales y fluviales, denominados acuíferos porosos no consolidados. En la parte alta de la cuenca, las rocas sedimentarias, volcano-sedimentarias, volcánicas e intrusivas, afectadas por la tectónica (pliegues, fallas y fracturas), conforman los acuíferos fisurados. La caracterización hidrogeológica de la cuenca, según unidad estratigráfica, y aplicando la nomenclatura de la Asociación Internacional de Hidrogeólogos, muestra: acuíferos, acuitardos, acuicludos y acuifugos. Los acuíferos evaluados son: acuíferos fisurados sedimentarios (Chilcatay, Murco, Hualhuani, Choros y Labra; acuíferos fisurados volcánico-sedimentarios (rocas volcánicas hacia el techo y rocas sedimentarias en la base, con importante permeabilidad); acuíferos fisurados volcánicos (especialmente, Caudalosa y Nazca); acuíferos porosos no consolidados (alta permeabilidad y porosidad primaria, compuestos de arena, gravas y sedimentos limo arcillosos, que facilitan la libre circulación). En cuanto a los Acuitardos, se identifican los Intrusivos (especialmente, Batolito de la Costa y el Batolito de San Nicolás) y Sedimentarios (Yumaque, Cañete y otros). Entre los acuicludos, el estudio se refiere al de Pisco y Cachios. Los acuifugos comprenden esquistos biotíticos y cloríticos con niveles restringidos de mármoles dolomíticos, y por paragneis graníticos y metasedimentarios

The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains

Altres ajuts: ICREA (ICREA-Academia 2015 and 2020); Fundació la Marató de TV3 (20144330)Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of intraneuronal proteinaceous inclusions known as Lewy bodies and Lewy neurites. The major protein component of Lewy inclusions is the intrinsically disordered protein α-synuclein (α-Syn), which can adopt diverse amyloid structures. Different conformational strains of α-Syn have been proposed to be related to the onset of distinct synucleinopathies; however, how specific amyloid fibrils cause distinctive pathological traits is not clear. Here, we generated three different α-Syn amyloid conformations at different pH and salt concentrations and analyzed the activity of SynuClean-D (SC-D), a small aromatic molecule, on these strains. We show that incubation of α-Syn with SC-D reduced the formation of aggregates and the seeded polymerization of α-Syn in all cases. Moreover, we found that SC-D exhibited a general fibril disaggregation activity. Finally, we demonstrate that treatment with SC-D also reduced strain-specific intracellular accumulation of phosphorylated α-Syn inclusions. Taken together, we conclude that SC-D may be a promising hit compound to inhibit polymorphic α-Syn aggregation

Discovery of Neuroprotective Agents Based on a 5-(4-Pyridinyl)-1,2,4-triazole Scaffold

Parkinson's disease (PD) is characterized by the death of dopaminergic neurons. The common histopathological hallmark in PD patients is the formation of intracellular proteinaceous accumulations. The main constituent of these inclusions is alpha-synuclein (α-syn), an intrinsically disordered protein that in pathological conditions creates amyloid aggregates that lead to neurotoxicity and neurodegeneration. The main goal of our study was to optimize our previously identified α-syn aggregation inhibitors of 5-(4-pyridinyl)-1,2,4-triazole chemotype in terms of in vivo efficacy. Our efforts resulted in the identification of ethyl 2-((4-amino-5-(pyridin-4-yl)-4 H -1,2,4-triazol-3-yl)thio)acetate (15), which displayed the ability to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine-induced bradykinesia as well as to affect the levels of PD markers after the administration of the same neurotoxin. In addition to the in vivo evaluation, for the 5-(4-pyridinyl)-1,2,4-triazole-based compounds, we measured the prevention of the fibrillization process using light scattering and a ThT binding assay; these compounds have been shown to slightly reduce the α-syn aggregation

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson's disease

Parkinson's disease is one of the most common neurodegenerative disorders in elderly age. One of the mechanisms involved in the neurodegeneration appears related to the aggregation of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To date, no highly effective treatment is currently available; therefore, there is an increasing interest in the search of new therapeutic tools. The modulation of α-syn aggregation represents an emergent and promising disease-modifying strategy for reducing or blocking the neurodegenerative process. Herein, by combining in silico and in vitro screenings we initially identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine (3) as α-syn aggregation inhibitor that was then considered a promising hit for the further design of a new series of small molecules. Therefore, we rationally designed new hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the binding mode of the newer inhibitors was predicted by docking studies

ZPD-2, a small compound that inhibits α-synuclein amyloid aggregation and its seeded polymerization

Altres ajuts: SV was supported by the ICREA (ICREA-Academia 2015) and the Fundación La Marató de TV3 (Ref. 20144330). JavS was supported by the Gobierno de Aragón (E45_17R). ED was supported by the Instituto de Salud Carlos III (PH613883/ERDF/ESF).α-Synuclein (α-Syn) forms toxic intracellular protein inclusions and transmissible amyloid structures in Parkinson's disease (PD). Preventing α-Syn self-assembly has become one of the most promising approaches in the search for disease-modifying treatments for this neurodegenerative disorder. Here, we describe the capacity of a small molecule (ZPD-2), identified after a high-throughput screening, to inhibit α-Syn aggregation. ZPD-2 inhibits the aggregation of wild-type α-Syn and the A30P and H50Q familial variants in vitro at substoichiometric compound:protein ratios. In addition, the molecule prevents the spreading of α-Syn seeds in protein misfolding cyclic amplification assays. ZPD-2 is active against different α-Syn strains and blocks their seeded polymerization. Treating with ZPD-2 two different PD Caenorhabditis elegans models that express α-Syn either in muscle or in dopaminergic (DA) neurons substantially reduces the number of α-Syn inclusions and decreases synuclein-induced DA neurons degeneration. Overall, ZPD-2 is a hit compound worth to be explored in order to develop lead molecules for therapeutic intervention in PD

Energy Drink Administration in Combination with Alcohol Causes an Inflammatory Response and Oxidative Stress in the Hippocampus and Temporal Cortex of Rats

Energy drinks (EDs) are often consumed in combination with alcohol because they reduce the depressant effects of alcohol. However, different researches suggest that chronic use of these psychoactive substances in combination with alcohol can trigger an oxidative and inflammatory response. These processes are regulated by both a reactive astrogliosis and an increase of proinflammatory cytokines such as IL-1β, TNF-α, and iNOS, causing cell death (apoptosis) at the central and peripheral nervous systems. Currently, mechanisms of toxicity caused by mixing alcohol and ED in the brain are not well known. In this study, we evaluated the effect of chronic alcohol consumption in combination with ED on inflammatory response and oxidative stress in the temporal cortex (TCx) and hippocampus (Hp) of adult rats (90 days old). Our results demonstrated that consuming a mixture of alcohol and ED for 60 days induced an increase in reactive gliosis, IL-1β, TNF-α, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide, in the TCx and Hp. We also found immunoreactivity to caspase-3 and a decrease of synaptophysin in the same brain regions. The results suggested that chronic consumption of alcohol in combination with ED causes an inflammatory response and oxidative stress, which induced cell death via apoptosis in the TCx and Hp of the adult rats

Inhibition of α-synuclein aggregation and mature fibril disassembling with a minimalistic compound, ZPDm

Altres ajuts: ICREA-Academia. The Fundación La Marató de TV3 (Ref. 20144330). The Gobierno de Aragón (E45_17R).Synucleinopathies are a group of disorders characterized by the accumulation of α-Synuclein amyloid inclusions in the brain. Preventing α-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q α-Synuclein variants in vitro and interferes with α-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed α-Synuclein amyloid fibrils. Studies in a Caenorhabditis elegans model of Parkinson's Disease, prove that these in vitro properties are translated into a significant reduction in the accumulation of α-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities

DisProt in 2022: improved quality and accessibility of protein intrinsic disorder annotation

The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure.Fil: Quaglia, Federica. Università di Padova; Italia. Consiglio Nazionale delle Ricerche; ItaliaFil: Mészáros, Bálint. European Molecular Biology Laboratory; AlemaniaFil: Salladini, Edoardo. Università di Padova; ItaliaFil: Hatos, András. Università di Padova; ItaliaFil: Pancsa, Rita. Research Centre for Natural Sciences; HungríaFil: Chemes, Lucia Beatriz. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Pajkos, Mátyás. Eötvös Loránd University; HungríaFil: Lazar, Tamas. Vlaams Instituut voor Biotechnology; Hungría. Vrije Unviversiteit Brussel; BélgicaFil: Peña Díaz, Samuel. Universitat Autònoma de Barcelona; EspañaFil: Santos, Jaime. Universitat Autònoma de Barcelona; EspañaFil: Ács, Veronika. Research Centre for Natural Sciences; HungríaFil: Farahi, Nazanin. Vlaams Instituut voor Biotechnology; Bélgica. Vrije Unviversiteit Brussel; BélgicaFil: Fichó, Erzsébet. Research Centre for Natural Sciences; HungríaFil: Aspromonte, Maria Cristina. Università di Padova; Italia. Città della Speranza Pediatric Research Institute; ItaliaFil: Bassot, Claudio. Stockholms Universitet; SueciaFil: Chasapi, Anastasia. Centre for Research & Technology Hellas; GreciaFil: Davey, Norman E.. Chester Beatty Laboratories; Reino UnidoFil: Davidović, Radoslav. University of Belgrade; SerbiaFil: Laszlo Holland, Alicia Verónica. European Molecular Biology Laboratory; Alemania. Research Centre for Natural Sciences; HungríaFil: Elofsson, Arne. Stockholms Universitet; SueciaFil: Erdős, Gábor. Eötvös Loránd University; HungríaFil: Gaudet, Pascale. Swiss Institute of Bioinformatics; SuizaFil: Giglio, Michelle. University of Maryland School of Medicine; Estados UnidosFil: Glavina, Juliana. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Iserte, Javier Alonso. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Iglesias, Valentín. Universitat Autònoma de Barcelona; EspañaFil: Kálmán, Zsófia. Pázmány Péter Catholic University; HungríaFil: Lambrughi, Matteo. Danish Cancer Society Research Center; DinamarcaFil: Leonardi, Emanuela. Università di Padova; Italia. Pediatric Research Institute Città della Speranza; ItaliaFil: Rodriguez Sawicki, Luciana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Holographic dark energy in the DGP model

The braneworld model proposed by Dvali, Gabadadze and Porrati leads to an accelerated universe without cosmological constant or other form of dark energy. Nevertheless, we have investigated the consequences of this model when an holo- graphic dark energy is included, taken the Hubble scale as IR cutoff. We have found that the holographic dark energy leads to an accelerated universe flat (de Sitter like expansion) for the two branch: {\ko} = \pm1 of the DGP model. Nevertheless, in universes with no null curvature the dark energy presents an EoS corresponding to a phantom fluid during the present era and evolving to a de Sitter like phase for future cosmic time. In the special case in which the holographic parameter c is equal to one we have found a sudden singularity in closed universes. In this case the expansion is decelerating. ManuscriptComment: Latex, 12 pages, 4 figures; Submitted to Phys. Lett.