293 research outputs found
Parametric and numerical modeling tools to forecast hydrogeological impacts of a tunnel
The project of interest involving a hydroelectrical diversion tunnel through a crystalline rock massif in the Alps required a detailed hydrogeological study to forecast the magnitude of water inflows within the tunnel and possible effects on groundwater flow The tunnel exhibits a length of 9.5 km and is located on the right side of the Toce River in Crevoladossola (Verbania Province, Piedmont region, northern Italy). Under the geological framework of the Alps, the tunnel is located within the Lower Penninic Frappes in the footwall of the Simplon Normal Fault, and the geological succession is mostly represented by Antigorio gneiss (metagranites) and Baceno metasediments (metacarbonates). Due to the presence of important mineralized springs for commercial mineral water purposes, the above mentioned hydrogeological study focused on both quantity and quality aspects via rainfall data analysis, monitoring of major spring flow rates, monitoring of hydraulic heads and pumping rates of existing wells/boreholes, hydrochemical and isotopic analysis of springs and boreholes and hydraulic tests (Lefranc and Lugeon). The resulting conceptual model indicated dominant low-permeability (aquitard) behavior of the gneissic rock masses, except under conditions of intense fracturing due to tectonization, and aquifer behavior of the metasedimentary rocks, particularly when interested by dissolution. Groundwater flow systems are mainly controlled by gravity. The springs located near the Toce River were characterized by high mineralization and isotopic ratios, indicating long groundwater flow paths. Based on all the data collected and analyzed, two parametric methods were applied: 1) the Dematteis method, slightly adapted to the case study and the available data, which allows assessment of both potential inflows within the tunnel and potential impacts on springs (codified as the drawdown hazard index; DHI); 2) the Cesano method, which only allow assessment of potential inflows within the tunnel, thereby discriminating between major and minor inflows. Contemporarily, a groundwater flow model was implemented with the equivalent porous medium (EPM) approach in MODFLOW-2000. This model was calibrated under steady-state conditions against the available data (groundwater levels inside wells/piezometers and elevation and flow rate of springs). The Dematteis method was demonstrated to be more reliable and suitable for the site than was the Cesano method. This method was validated considering a tunnel through gneissic rock masses, and this approach considered intrinsic parameters of rock masses more notably than morphological and geomorphological factors were considered. The Cesano method relatively overestimated tunnel inflows, considering variations in the topography and overburden above the tunnel. Sensitivity analysis revealed a low sensitivity of these parametric methods to parameter values, except for the rock quality designation (RQD) employed to represent the fracturing degree. The numerical model was calibrated under ante-operam conditions, and sensitivity analysis evaluated the influence of uncertainties in the hydraulic conductivity (K) values of the different hydrogeological units.The hydraulic head distribution after tunnel excavation was forecasted considering three scenarios, namely, a draining tunnel, tunnel as a eater loss source, and tunnel sealed along its aquifer sectors, considering 3 levels of K reduction. Tunnel impermeabilization was very effective, thus lowering the drainage rate and impact on springs. The model quantitatively defined tunnel inflows and the effects on spring flow at the surface in terms of flow rate decrease. The Dematteis method and numerical model were combined to obtain a final risk of impact on the springs. This study likely overestimated the risk because all the values assigned to the parameters were chosen in a conservative way, and the steady-state numerical simulations were also very conservative (the transient state in this hydrogeological setting supposedly lasts 1-3 years). Monitoring of the tunnel and springs during tunnel boring could facilitate the feedback process
Long-term treatment of the developing retina with the metabotropic glutamate agonist APB induces long-term changes in the stratification of retinal ganglion cell dendrites
The gradual restriction of initially multistratified retinal ganglion cell (RGC) dendrites into ON and OFF sublaminae of the inner plexiform layer (IPL) can be effectively blocked by treating the developing retina with 2-amino-4-phosphonobutyrate (APB), the metabotropic glutamate agonist, or by light deprivation. Previous studies have focused on the short-term consequences of such manipulations, so the long-term effects of arresting dendritic stratification on the structural development of RGCs are as yet unknown. In the present study, we have addressed this issue by performing a morphological analysis of alpha RGCs labeled by retrograde transport of horseradish peroxidase injected into the dorsal lateral geniculate nucleus of adult cats that received monocular injections of APB from postnatal (P) day 2 until P30. A large proportion of the alpha cells in the APB-treated eye (44%) were found to have multistratified dendrites that terminated in both the ON and OFF sublaminae of the IPL. The dendritic arborization pattern in the sublaminae of the IPL of these cells was asymmetric, showing a variety of forms. Immunolabeling of retinal cross-sections showed that mGLUR6 receptors appeared normal in density and location, while qualitative observation suggested an increase in the axonal arborization of rod bipolar cells. These findings indicate that long-term treatment of the neonatal retina with APB induces a long- lasting structural reorganization in retinal circuitry that most likely accounts for some of the previously described changes in the functional properties of RGCs
Environmental enrichment extends photoreceptor survival and visual function in a mouse model of retinitis pigmentosa
Slow, progressive rod degeneration followed by cone death leading to blindness is the pathological signature of all forms of
human retinitis pigmentosa (RP). Therapeutic schemes based on intraocular delivery of neuroprotective agents prolong the
lifetime of photoreceptors and have reached the stage of clinical trial. The success of these approaches depends upon
optimization of chronic supply and appropriate combination of factors. Environmental enrichment (EE), a novel
neuroprotective strategy based on enhanced motor, sensory and social stimulation, has already been shown to exert
beneficial effects in animal models of various disorders of the CNS, including Alzheimer and Huntington disease. Here we
report the results of prolonged exposure of rd10 mice, a mutant strain undergoing progressive photoreceptor degeneration
mimicking human RP, to such an enriched environment from birth. By means of microscopy of retinal tissue,
electrophysiological recordings, visual behaviour assessment and molecular analysis, we show that EE considerably
preserves retinal morphology and physiology as well as visual perception over time in rd10 mutant mice. We find that
protective effects of EE are accompanied by increased expression of retinal mRNAs for CNTF and mTOR, both factors known
as instrumental to photoreceptor survival. Compared to other rescue approaches used in similar animal models, EE is highly
effective, minimally invasive and results into a long-lasting retinal protection. These results open novel perspectives of
research pointing to environmental strategies as useful tools to extend photoreceptor survival
Estimation of recharge in mountain hard-rock aquifers based on discrete spring discharge monitoring during base-flow recession
Estimation of aquifer recharge is key to effective groundwater management and protection. In mountain hard-rock aquifers, the average annual discharge of a spring generally reflects the vertical aquifer recharge over the spring catchment. However, the determination of average annual spring discharge requires expensive and challenging field monitoring. A power-law correlation was previously reported in the literature that would allow quantification of the average annual spring discharge starting from only a few discharge measurements in the low-flow season, in a dry summer climate. The correlation is based upon the Maillet model and was previously derived by a 10-year monitoring program of discharge from springs and streams in hard-rock aquifers composed of siliciclastic and calcareous turbidites that did not have well defined hydrogeologic boundaries. In this research, the same correlation was applied to two ophiolitic (peridotitic) hard-rock aquifers in the Northern Apennines (Northern Italy) with well-defined hydrogeologic boundaries and base-outflow springs. The correlation provided a reliable estimate of the average annual spring discharge thus confirming its effectiveness regardless of bedrock lithology. In the two aquifers studied, the measurable annual outputs (i.e. sum of average annual spring discharges) could be assumed equal to the annual inputs (i.e. vertical recharge) based on the clear-cut aquifer boundaries and a quick groundwater circulation inferable from spring water parameters. Thus, in such setting, the aforementioned correlation also provided an estimate of the annual aquifer recharge allowing the assessment of coefficients of infiltration (i.e. ratio between aquifer recharge and total precipitation) ranging between 10 and 20%
Chemical Quality and Hydrogeological Settings of the El-Farafra Oasis (Western Desert of Egypt) Groundwater Resources in Relation to Human Uses
In the Egyptian deserts, new land reclamation projects have been recently established to meet the increasing-population growth rate and food demand. These projects mainly depend on the different groundwater aquifers. El-Farafra Oasis is one of the "1.5-million-feddan reclamation project" areas recently established in the Western Desert of Egypt where the only available water source is the world's largest fossil freshwater reservoir "the Nubian Sandstone Aquifer System (NSAS)". Groundwater-dependent springs, and their artificial counterpart "drilled wells", are reliable water systems throughout the world. In the present study, hydrochemical parameters were collected in 2015 from 16 different springs and wells of the El-Farafra Oasis, and analyzed using the different water quality indices. The calculated water quality index (WQI), its correlations with the water quality parameters Gibbs, Piper, US Salinity-Lab Staff and Wilcox diagrams, and Principal Component Analysis (PCA) were used to evaluate the groundwater suitability for human drinking and irrigation purposes. WQI values revealed good-to-excellent groundwater quality for human drinking. In addition, the spring and well water samples investigated showed good indices for irrigation activities. Gibbs and Piper's diagrams were presented, with most samples falling into the rock-dominance category, and belonging to hydrogeochemical facies determining the following water types: Mg(HCO3)(2) type water (37.5% of the samples), no dominant ions (mixed water-type category; Ca/MgCl2) (50% of the samples), and, finally, NaCl water type (the remaining 12.5%). The groundwater chemistry in the study area is mainly controlled by rock-water interactions, particularly the dissolution of carbonate rocks and silicate weathering. The elevated nutrient concentrations, in particular nitrates, are most likely due to agricultural activities, indicating substantial anthropogenic activities in the area studied
Ecohydrogeology: The interdisciplinary convergence needed to improve the study and stewardship of springs and other groundwater-dependent habitats, biota, and ecosystems
This essay discusses the need for, advantages and challenges of integrating the scientific disciplines of ecology and hydrogeology in the study of groundwater-dependent ecosystems (GDEs). We provide a definition for ecohydrogeology as \u201ca unifying, synthetic field of study integrating the approaches from the ecological and hydrogeological sciences in the study of groundwater (GW)-related ecosystems, habitats, and organisms to advance science, stewardship, and policy\u201d. We selected specific case studies to illustrate first how hydrogeological approaches can favour in-depth understanding and modelling of springs and crenobiontic (spring-dependent) species distribution, assemblage composition and organization. Second, this essay also examines how taxa and assemblages serve as bioassays and ecosystem indicators to infer hydrogeological aspects of GW flow and discharge, as well as quantitative and qualitative human impacts. We consider both types of features and parameters as ecohydrogeological indicators. The examples presented include topics related to springs and other GDE geomorphological types and classification, GW quality influences on crenobiont distribution, phreatophyte (= plant species the roots of which reach to and into the water table) ecophysiology in relation to water table depth, and flow variability in karstic systems, to nutrient dynamics in relation to dinoflagellate blooms in GDE montane lakes. Conceptual approaches that integrate ecology with hydrogeology include the investigation of GDE distribution and ecology, groundwater-surface water (GW-SW) interactions, and the development of the discipline of ecohydrology. Despite widespread applications, the scientific community still lacks a complete or effective integration of the principles described in the fields of groundwater hydrogeology with ecology, ecophysiology, and environmental biology. Springs are aquatic-wetland-riparian habitats that link shallow subsurface-surface processes and assemblages, often functioning as biodiversity hotspots, ecotones, keystone, and refugial ecosystems, for which coordination between studies of hydrogeology and ecology are both obvious and essential. Over the past century, springs ecosystem ecology has been largely ignored by hydrologists, and, conversely, hydrogeology has been under-emphasized by ecologists. Recent global recognition of the extraordinary biodiversity and socio-cultural significance of springs, coupled with their globally highly threatened conservation status, stimulated this inquiry into how to better integrate hydrogeology with springs ecosystem ecology. Acknowledging the highly threatened status of springs ecosystems around the world, there is an urgent need to integrate and invigorate the union of these disciplines into ecohydrogeology, the study of groundwater-dependent organisms, habitats, ecosystems, and management policy
The bacterial toxin CNF1 as a tool to induce retinal degeneration reminiscent of retinitis pigmentosa.
Retinitis pigmentosa (RP) comprises a group of inherited pathologies characterized by progressive photoreceptor degeneration. In rodent models of RP, expression of defective genes and retinal degeneration usually manifest during the first weeks of postnatal life, making it difficult to distinguish consequences of primary genetic defects from abnormalities in retinal development. Moreover, mouse eyes are small and not always adequate to test pharmacological and surgical treatments. An inducible paradigm of retinal degeneration potentially extensible to large animals is therefore desirable. Starting from the serendipitous observation that intraocular injections of a Rho GTPase activator, the bacterial toxin Cytotoxic Necrotizing Factor 1 (CNF1), lead to retinal degeneration, we implemented an inducible model recapitulating most of the key features of Retinitis Pigmentosa. The model also unmasks an intrinsic vulnerability of photoreceptors to the mechanism of CNF1 action, indicating still unexplored molecular pathways potentially leading to the death of these cells in inherited forms of retinal degeneratio
Myriocin Effect on Tvrm4 Retina, an Autosomal Dominant Pattern of Retinitis Pigmentosa
Tvrm4 mice, a model of autosomal dominant retinitis pigmentosa (RP), carry a mutation of Rhodopsin gene that can be activated by brief exposure to very intense light. Here, we test the possibility of an anatomical, metabolic, and functional recovery by delivering to degenerating Tvrm4 animals, Myriocin, an inhibitor of ceramide de novo synthesis previously shown to effectively slow down retinal degeneration in rd10 mutants (Strettoi et al., 2010; Piano et al., 2013). Different routes and durations of Myriocin administration were attempted by using either single intravitreal (i.v.) or long-term, repeated intraperitoneal (i.p.) injections. The retinal function of treated and control animals was tested by ERG recordings. Retinas from ERG-recorded animals were studied histologically to reveal the extent of photoreceptor death. A correlation was observed between Myriocin administration, lowering of retinal ceramides, and preservation of ERG responses in i.v. injected cases. Noticeably, the i.p. treatment with Myriocin decreased the extension of the retinal-degenerating area, preserved the ERG response, and correlated with decreased levels of biochemical indicators of retinal oxidative damage. The results obtained in this study confirm the efficacy of Myriocin in slowing down retinal degeneration in genetic models of RP independently of the underlying mutation responsible for the disease, likely targeting ceramide-dependent, downstream pathways. Alleviation of retinal oxidative stress upon Myriocin treatment suggests that this molecule, or yet unidentified metabolites, act on cellular detoxification systems supporting cell survival. Altogether, the pharmacological approach chosen here meets the necessary pre-requisites for translation into human therapy to slow down RP
Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators
Correction to: Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators. Acta Neuropathol Commun. 2023 Jul 12;11(1):116. doi: 10.1186/s40478-023-01600-2. PMID: 37438824.Glial-origin brain tumors, including glioblastomas (GBM), have one of the worst prognoses due to their rapid and fatal progression. From an oncological point of view, advances in complete surgical resection fail to eliminate the entire tumor and the remaining cells allow a rapid recurrence, which does not respond to traditional therapeutic treatments. Here, we have reviewed new immunotherapy strategies in association with the knowledge of the immune micro-environment. To understand the best lines for the future, we address the advances in the design of neoantigen vaccines and possible new immune modulators. Recently, the efficacy and availability of vaccine development with different formulations, especially liposome plus mRNA vaccines, has been observed. We believe that the application of new strategies used with mRNA vaccines in combination with personalized medicine (guided by different omic's strategies) could give good results in glioma therapy. In addition, a large part of the possible advances in new immunotherapy strategies focused on GBM may be key improving current therapies of immune checkpoint inhibitors (ICI), given the fact that this type of tumor has been highly refractory to ICI.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project “CP21/00116 and PI22/0117” and co-funded by the European Union to RG, by “Asociación Española contra el Cancer (AECC) grant: INVES192GARG to RG and by Ministerio de Ciencia e Innovación and FEDER funds: PI21/01406 to JMSS.S
On optimal temozolomide scheduling for slowly growing glioblastomas
Background: Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma (GBM), and is commonly used in low-grade gliomas (LGG). In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes. Methods: Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR-wt/EGFR-vIII in primary progenitors from p16/p19 ko mice and grown in-vitro and in-vivo in orthotopic allografts, and human GBM U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study. Results: Slow-growth "virtual" murine GBMs benefited from increasing TMZ dose separation in-silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors, and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically driven changes in tumor phenotype, which could explain the reduction in GBM growth speed. In-silico trials provided support for implementation methods in human patients. Conclusions: In-silico simulations, in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in slowly-growing GBMs.This research was funded by the James S. Mc. Donnell Foundation (USA) 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (Collaborative award 220020560, doi:10.37717/220020560); Ministry of Education, Science and Technological Development, Republic of Serbia (ref. number 451-03-9/2021-14/200007); Ministerio de Ciencia e Innovación and FEDER funds, Spain (grant number PID2019-110895RB-I00, doi: 10.13039/501100011033 to VMP-G, and RTI2018-093596 and PI21CIII/00002 to PS-G); and Universidad de Castilla-La Mancha (grant number 2020-PREDUCLM-15634 to JJ-S).S
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