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

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

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

Processing of Retinal Signals in Normal and HCN Deficient Mice

This study investigates the role of two different HCN channel isoforms in the light response of the outer retina. Taking advantage of HCN-deficient mice models and of in vitro (patch-clamp) and in vivo (ERG) recordings of retinal activity we show that HCN1 and HCN2 channels are expressed at distinct retinal sites and serve different functions. Specifically, HCN1 operate mainly at the level of the photoreceptor inner segment from where, together with other voltage sensitive channels, they control the time course of the response to bright light. Conversely, HCN2 channels are mainly expressed on the dendrites of bipolar cells and affect the response to dim lights. Single cell recordings in HCN1−/− mice or during a pharmacological blockade of Ih show that, contrary to previous reports, Ikx alone is able to generate the fast initial transient in the rod bright flash response. Here we demonstrate that the relative contribution of Ih and Ikx to the rods' temporal tuning depends on the membrane potential. This is the first instance in which the light response of normal and HCN1- or HCN2-deficient mice is analyzed in single cells in retinal slice preparations and in integrated full field ERG responses from intact animals. This comparison reveals a high degree of correlation between single cell current clamp data and ERG measurements. A novel picture emerges showing that the temporal profile of the visual response to dim and bright luminance changes is separately determined by the coordinated gating of distinct voltage dependent conductances in photoreceptors and bipolar cells

High-Pass Filtering of Input Signals by the Ih Current in a Non-Spiking Neuron, the Retinal Rod Bipolar Cell

Hyperpolarization–activated cyclic nucleotide–sensitive (HCN) channels mediate the If current in heart and Ih throughout the nervous system. In spiking neurons Ih participates primarily in different forms of rhythmic activity. Little is known, however, about its role in neurons operating with graded potentials as in the retina, where all four channel isoforms are expressed. Intriguing evidence for an involvement of Ih in early visual processing are the side effects reported, in dim light or darkness, by cardiac patients treated with HCN inhibitors. Moreover, electroretinographic recordings indicate that these drugs affect temporal processing in the outer retina. Here we analyzed the functional role of HCN channels in rod bipolar cells (RBCs) of the mouse. Perforated–patch recordings in the dark–adapted slice found that RBCs exhibit Ih, and that this is sensitive to the specific blocker ZD7288. RBC input impedance, explored by sinusoidal frequency–modulated current stimuli (0.1–30 Hz), displays band–pass behavior in the range of Ih activation. Theoretical modeling and pharmacological blockade demonstrate that high–pass filtering of input signals by Ih, in combination with low–pass filtering by passive properties, fully accounts for this frequency–tuning. Correcting for the depolarization introduced by shunting through the pipette–membrane seal, leads to predict that in darkness Ih is tonically active in RBCs and quickens their responses to dim light stimuli. Immunohistochemistry targeting candidate subunit isoforms HCN1–2, in combination with markers of RBCs (PKC) and rod–RBC synaptic contacts (bassoon, mGluR6, Kv1.3), suggests that RBCs express HCN2 on the tip of their dendrites. The functional properties conferred by Ih onto RBCs may contribute to shape the retina's light response and explain the visual side effects of HCN inhibitors

Caspase Inhibition with XIAP as an Adjunct to AAV Vector Gene-Replacement Therapy: Improving Efficacy and Prolonging the Treatment Window

AAV-mediated gene therapy in the rd10 mouse, with retinal degeneration caused by mutation in the rod cyclic guanosine monophosphate phosphodiesterase β-subunit (PDEβ) gene, produces significant, but transient, rescue of photoreceptor structure and function. This study evaluates the ability of AAV-mediated delivery of X-linked inhibitor of apoptosis (XIAP) to enhance and prolong the efficacy of PDEβ gene-replacement therapy.Rd10 mice were bred and housed in darkness. Two groups of animals were generated: Group 1 received sub-retinal AAV5-XIAP or AAV5-GFP at postnatal age (P) 4 or 21 days; Group 2 received sub-retinal AAV5-XIAP plus AAV5- PDEβ, AAV5-GFP plus AAV5- PDEβ, or AAV- PDEβ alone at age P4 or P21. Animals were maintained for an additional 4 weeks in darkness before being moved to a cyclic-light environment. A subset of animals from Group 1 received a second sub-retinal injection of AAV8-733-PDEβ two weeks after being moved to the light. Histology, immunohistochemistry, Western blots, and electroretinograms were performed at different times after moving to the light.Injection of AAV5-XIAP alone at P4 and 21 resulted in significant slowing of light-induced retinal degeneration, as measured by outer nuclear thickness and cell counts, but did not result in improved outer segment structure and rhodopsin localization. In contrast, co-injection of AAV5-XIAP and AAV5-PDEβ resulted in increased levels of rescue and decreased rates of retinal degeneration compared to treatment with AAV5-PDEβ alone. Mice treated with AAV5-XIAP at P4, but not P21, remained responsive to subsequent rescue by AAV8-733-PDEβ when injected two weeks after moving to a light-cycling environment.Adjunctive treatment with the anti-apoptotic gene XIAP confers additive protective effect to gene-replacement therapy with AAV5-PDEβ in the rd10 mouse. In addition, AAV5-XIAP, when given early, can increase the age at which gene-replacement therapy remains effective, thus effectively prolonging the window of opportunity for therapeutic intervention