Coupling hydro-geo-chemical and isotopic approaches to assess the main factors controlling karst development in a fissure-dominated carbonate aquifer system (s-Spain)

Sierra Tejeda, Almijara and Albuñuelas mountains comprise a large outcrop (750 km² ca) of Triassic marbles in between of Málaga and Granada provinces in S Spain. They constitute a large entity carbonate aquifer system providing strategic groundwater resources for drinking water supply in sparse urban settlements and crops irrigation. The present research aims to refine the current hydrogeological knowledge of large-scale fissure-dominated carbonate aquifers regarding flow mechanisms and geochemical processes defining observed groundwater quality. To this, a two-year monitoring program of aquifer dynamics have been conducted in three selected discharge points (Fájara, Cijancos and Maro springs) showing characteristic spring responses. A combined approach based on the analysis of spring discharge and time series of selected hydrochemical and isotopic tracers (Na+, Ca+2, Mg+2, TA, TOC, Cl-, SO4-2 and δ13CTDIC) and on the geochemical calculations from the chemical signature of spring waters have been followed. The results indicate that the more bicarbonate enriched waters and the lowest hydrochemical variability of Cijancos spring, practically in all analyzed solutes, denotes a fissure type dominant flow system, while the larger variations in meteoric/soil tracers (Cl- and TOC) observed in Fajara spring chemograph as consequence of rainfall inputs characterize a karst drainage from a better hierarchized fracture-enlarged flow system. Maro spring waters are rich in Na+, Ca+2, Cl- and SO4-2, have higher δ13CTDIC amplitude and the temporal variations of major ions display marked dilutions after rainfall events followed by rapid recoveries of pre-event concentrations, evidence a complex flow system and variable groundwater source contribution. The chemical reactions deduced from the molar ratios of spring water chemistry are commonly CO2 dissolution and calcite dissolution, but also salt evapoconcentration in soil layer and gypsum dissolution in the case of Maro spring.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Monitoring and preliminary analysis of the natural responses recorded in a poorly accessible streambed spring located at a fluviokarstic gorge in Southern Spain

The analysis of natural responses (hydrodynamic, hydrothermal and hydrochemical) of karst springs is a well-established approach to provide insights into the hydrogeological functioning of the aquifers that they drain. However, a suitable monitoring program of these responses are often difficult to launch in poorly accessible streambed springs, due to the mixing between surface water and groundwater, in addition to topographic impediments. This work describes the installation procedure of the measurement equipment and the preliminary hydrogeological dataset collected at the Charco del Moro spring (Southern Spain) during one year. This outlet emerges 5 m below water surface, at the bottom of a partially flooded 20 - 200 m deep and 2 km long gorge, eroded by the Guadiaro River streamflow. It is considered the largest discharge point in the region, draining groundwater from northern nearby carbonate outcrops, although its catchment area is not established yet. Continuous (hourly) monitoring of electrical conductivity, water temperature, turbidity and water level (discharge) reflects a high degree of heterogeneity in the duality of groundwater flow and storage dynamics, which is typical of karst conduit flow systemsUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents

Antagonists of the A(2B) adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A(2B)AR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (K-i < 100 nM) and outstanding selectivity for A(2B)AR. From these, five molecules corresponding to the new benzothiazole scaffold were below the K-i < 10 nM threshold, in addition to a novel dual A(2A)/A(2B) antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A(2B)AR. Two A(2B)AR selective antagonists and the dual A(2A)AR/A(2B)AR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A(2B)AR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A(2B)AR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A(2A)AR antagonism in the context of immune checkpoint inhibition

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Procesos de aplicación conceptual y práctico de la normatividad tributaria en contextos investigativos procedimentales tributarios para el fortalecimiento de las competencias disciplinares y profesionales

La presente investigación planteó como objetivo realizar las memorias con las temáticas investigativas que se desarrollaron en el Seminario de Investigación Aplicada, con el fin de actualizar en los participantes y fortalecer sus conocimientos específicos en materia tributaria con base en los temas investigativos dispuestos y orientados por cada docente desde su inicio, elaboración, construcción y presentación ante los docentes evaluadores. Los trabajos cumplen su fin primordial con es fortalecer con los desarrollos temático de cada módulo visto en el SIA sus capacidades y competencias profesionales especialmente en el contexto tributario, en cumplimiento al requerimiento para otorgar al título de Especialistas en Gerencia Tributaria. Luego las memorias compiladas son el resultado de los trabajos presentados y evaluados oportunamente por cada docente comprometido con la calidad en cuanto a las temáticas investigativas, calidad de los contenidos, talleres teóricos prácticos, elementos metodológicos y de más lineamentos institucionales y del programa. La importancia de las memorias radica en su contenido el cual desglosa definiciones, conceptos, desarrollos teóricos prácticos, constituyéndose en un ejemplar de consulta investigativa en áreas de conocimiento fiscal y tributario en el marco de la Ley 1819 de 2016 y sus decretos reglamentarios, en síntesis al interior encontraremos fundamentos teóricos prácticos, procedimentales y resolutivos de casos especiales de Gravamen a los Movimientos Financieros, Monotributo, Renta Personas Naturales, Renta Personas Jurídicas, Procedimiento Tributario, Impuestos Distritales, Normas internacionales de Información Financiera Pymes, entre otros temas

Considerations on the hydrogeological functioning of the carbonate aquifer of Sierra de Jarastepar (province of Málaga) deduced from a multitracer test

La realización de un ensayo de trazadores en el acuífero carbonático de la sierra de Jarastepar (Málaga) ha permitido avanzar en el conocimiento de su funcionamiento hidrogeológico. Las velocidades de flujo registradas, del orden de 100-110 m/h, demuestran la existencia un drenaje kárstico preferenciaI (de dirección NE-SO), entre los puntos de inyección (áreas de recarga situadas en la parte meridional y central de la sierra) y los manantiales de tipo trop plein (Pozancón y Alfaguara) situados en el borde SO de los afloramientos carbonáticos. Sin embargo, el hecho de que no se haya detectado trazador en los manantiales permanentes localizados en el borde SE (a menor cota) no es prueba suficiente para descartar la conexión hidrogeológica entre éstos y las calizas jurásicasResults from a tracer test carried out in the carbonate aquifer of Sierra de Jarastepar (Malaga) have permitted to characterize its hydrogeological behaviour. The calculated groundwater flow velocities, around 100-110 m /h , high light the existence of a NE-SW preferential flow path from the injection points (recharge areas located at the southern and central part sof the massif) toward the over flow springs (Pozancon and Alfaguara) placed at the SW edge of carbonate outcrops. However, the factt hat dyes have not been detecte in the permanent springs located in the SE border (at lower altitude) it is not a clear evidence for rejecting the hydrogeological connection between these and the Jurassic limestone

Karst development of an evaporitic system and its hydrogeological implications inferred from GIS-based analysis and tracing techniques

The geomorphological characteristics and hydrogeological functioning of a geologically heterogeneous evaporitic karst plateau in Southern Spain were studied. Land surface information (LiDAR data) was used to analyze the shape and distribution of closed depressions. An artificial tracer test and monitoring of the natural responses of the main spring have allowed to infer the karstic development of the studied system. Three dyes were injected in selected swallow holes to trace the main groundwater flowpaths and to estimate the dimension of the conduit network. Discharge, electrical conductivity and temperature were monitored in the groundwater that drains the evaporitic plateau during an individual and intense recharge pulse. Tracing techniques were adapted to high salinity environments by using specific calibration standards (NaCl + dye). The hydrological connection detected between two of the swallow holes and the outlet, and the deduced orientation pattern for closed areas, would suggest that the karst evolution (internal and external) is related to fault orientation. The rapid tracer detection (16-20 h) and high estimated maximum flow velocities (125-192 m/h), together with the fast impulsional response of the controlled physical-chemical parameters in spring waters (~15-16 h) demonstrate the existence of quick flows under recharge conditions with well-defined system drainage, indicating a high degree of internal karstification (estimated master conduit diameter ~1.5 m). However, flooding of the depressions feeding swallow holes and analysis of the spring response times from natural and artificial tracers point to a restriction of the system´s drainage, most likely due to the constrained morphology of the karst conduits. This results in sustained recharge periods and delayed spring responses of some parameters, highlighting the relevant role of concentrated recharge in the hydrogeological behavior of the studied evaporitic karst

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies

Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies

Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern