On the meaning of the transmissivity values obtained from recovery tests

      Recovery tests are based on estimating transmissivity, T, from the heads that rebound after pumping has stopped. Recovery tests can be performed in wells where conventional constant-rate pumping tests would not be possible. Test interpretation is based on the simple Theis recovery method, related to late time drawdown in an infinite homogeneous aquifer. Yet, field data often cannot be explained by the homogeneous theory. Because T is heterogeneous over an evolving range of scales, it is important to evaluate the support scale of hydraulic tests. Numerical simulations are performed to show that heterogeneity in T can explain these field observations. It is also shown that the local T value around the well can be inferred from early time-recovery data, assuming ideal conditions, whereas late time data yield a large-scale (regional) representative value. Even when recovery is observed for a short time, indirect information about the regional value can also be obtained. A method for the interpretation of recovery tests is proposed based on the Theis recovery method that takes into account the heterogeneity of aquifers. Finally, some guidelines are provided for best test performance depending on the scale of the problem. &nbsp

The Interplay between NF-kappaB and E2F1 Coordinately Regulates Inflammation and Metabolism in Human Cardiac Cells

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, thus suggesting that additional transcription factors are regulating PDK4. Interestingly, a recent study has demonstrated that the transcription factor E2F1, which is crucial for cell cycle control, may regulate PDK4 expression. Given that NF-κB may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-κB can downregulate PDK4 expression in human cardiac AC16 cells through E2F1 inhibition. Protein coimmunoprecipitation indicated that PDK4 downregulation entailed enhanced physical interaction between the p65 subunit of NF-κB and E2F1. Chromatin immunoprecipitation analyses demonstrated that p65 translocation into the nucleus prevented the recruitment of E2F1 to the PDK4 promoter and its subsequent E2F1-dependent gene transcription. Interestingly, the NF-κB inhibitor parthenolide prevented the inhibition of E2F1, while E2F1 overexpression reduced interleukin expression in stimulated cardiac cells. Based on these findings, we propose that NF-κB acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription

Enhancing Anthocyanin Extraction fromWine Lees: A Comprehensive Ultrasound-Assisted Optimization Study

Wine lees, an important by-product of the wine industry, pose a major environmental problem due to the enormous quantities of solid–liquid waste that are discarded annually without defined applications. In this study, the optimization of a method based on a Box–Behnken design with surface response has been carried out to obtain extracts with high anthocyanin content and potent antioxidant activity. Six variables have been considered: %EtOH, temperature, amplitude, cycle, pH, and ratio. The developed method exhibited important repeatability properties and intermediate precision, with less than 5% CV being achieved. Furthermore, these novel methods were successfully applied to diverse wine lees samples sourced from Cabernet Sauvignon and Syrah varieties (Vitis vinifera), resulting in extracts enriched with significant anthocyanin content and noteworthy antioxidant activity. Additionally, this study evaluated the influence of grape variety, fermentation type (alcoholic or malolactic), and sample treatment on anthocyanin content and antioxidant activity, providing valuable insights for further research and application in various sectors. The potential applications of these high-quality extracts extend beyond the winemaking industry, holding promise for fields like medicine, pharmaceuticals, and nutraceuticals, thus promoting a circular economy and mitigating environmental contamination

Air-sea CO2 fluxes in the Atlantic as measured during the FICARAM cruises

A total of fourteen hydrographic cruises spanning from 2000 to 2008 were conducted during the spring and autumn seasons between Spain and the Southern Ocean, under the framework of the Spanish research project FICARAM. The performed underway measurements are processed and analysed to describe the meridional air-sea CO2 fluxes (F CO2) along the Atlantic Ocean. The data was organised into different biogeochemical oceanographic provinces, according mainly to the thermohaline characteristics. The obtained spatial and temporal distributions of F CO2 follow the generally expected patterns and annual trends. The Subtropical regions in both hemispheres alternated the CO2 source and sink nature from autumn to spring, respectively. On the other hand, Tropical waters and the Patagonian Sea clearly behaved as sinks of atmospheric CO2 like the waters of the Drake Passage during autumn. The obtained results during the cruises also revealed significant long-term trends, such as the warming of equatorial waters (0.11±0.03 Cyr−1) and the decrease of surface salinity (−0.16±0.01 yr−1) in tropical waters caused by the influence of the Amazon River plume. This reduction in surface salinity appears to have a direct influence over the CO2 storage rates, fostering the uptake capacity of atmospheric CO2 (−0.09±0.03 molm−2 yr−1). An analysis of the biogeochemical forcing on the CO2 fugacity (fCO2) variability performed from an empirical algorithm highlighted the major role of the Amazon River input in the tropical North Atlantic fluxes. In addition, it has provided a quantitative measure of the importance of the thermodynamic control of F CO2 at temperate latitudes

Deletion of Gadd45a Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer’s Disease Hallmarks.

Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy,cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, weanalyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders suchas Alzheimer’s Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a−/−)mice to evaluate AD progression. Behavioral tests showed that Gadd45a−/− mice presented lowerworking and spatial memory, pointing out an apparent cognitive impairment compared with WTanimals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involvedin its phosphorylation in the hippocampus. Moreover, Gadd45a−/− animals significantly increased thebrain’s pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins andthe dendritic spine length of the neurons were reduced in Gadd45a−/− mice, which could contributeto the cognitive alterations observed in these animals. Overall, these findings demonstrate that thelack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting thatpromoting this protein’s expression or function might be a promising therapeutic strategy to slowdown AD progression.</p

Hospitalization budget impact during the COVID-19 pandemic in Spain

To Mrs. Anne Murray for her support to translate the manuscript. This article is part of the doctoral thesis of Laura Álvarez as part of the Doctoral Program in Pharmacy, Granada University (Spain).Objectives: The aim was to determine the direct impact of the COVID-19 pandemic on Spain’s health budget. Methods: Budget impact analyses based on retrospective data from patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) admitted to a Spanish hospital between February 26 and May 21, 2020. Direct medical costs from the perspective of the hospital were calculated. We analyzed diagnostic tests, drugs, medical and nursing care, and isolation ward and ICU stays for three cohorts: patients seen in the emergency room only, hospitalized patients who tested positive for SARS-CoV-2, and patients who tested negative. Results: The impact on the hospital’s budget for the 3 months was calculated at €15,633,180, 97.4% of which was related to health care and hospitalization. ICU stays accounted for 5.3% of the total costs. The mean cost per patient was €10,744. The main costs were staffing costs (10,131 to 11,357 €/patient for physicians and 10,274 to 11,215 €/patient for nurses). Scenario analysis showed that the range of hospital expenditure was between €14,693,256 and €16,524,924. The median impact of the pandemic on the Spanish health budget in the sensitivity analysis using bootstrapped individual data was €9357 million (interquartile range [IQR], 9071 to 9689) for the conservative scenario (113,588 hospital admissions and 11,664 ICU admissions) and €10,385 million (IQR, 110,030 to 10,758) for the worst-case scenario (including suspected cases). Conclusion: The impact of COVID-19 on the Spanish public health budget (12.3% of total public health expenditure) is greater than multiple sclerosis, cancer and diabetes cost

Inhibition of Cardiac Hypertrophy by Triflusal (4-Trifluoromethyl Derivative of Salicylate) and Its Active Metabolite

ABSTRACT The nuclear factor (NF)-B signaling pathway is an important intracellular mediator of cardiac hypertrophy. The aim of the present study was to determine whether triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), a salicylate derivative used as antiplatelet agent, and its active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) inhibit cardiac hypertrophy in vitro and in vivo by blocking the NF-B signaling pathway. In cultured neonatal rat cardiomyocytes, HTB (300 M, a concentration reached in clinical use) inhibited phenylephrine (PE)-induced protein synthesis ([ 3 H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF), and sarcomeric disorganization. Assessment of the effects of triflusal in pressure overload-induced cardiac hypertrophy by aortic banding resulted in a significant reduction in the ratio of heart weight to body weight and in a reduction of the mRNA levels of the cardiac hypertrophy markers ANF and ␣-actinin compared with untreated banded rats. Electrophoretic mobility shift assay revealed an increase in the NF-B binding activity in cardiac nuclear extracts of banded rats that was prevented by triflusal treatment. It is noteworthy that banded rats treated with oral triflusal, compared with untreated rats, showed enhanced protein levels of IB␣, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Finally, HTB increased phospho-IB␣ levels in neonatal cardiomyocytes and inhibited proteosome activity, suggesting that this drug prevented proteosome-mediated degradation of IB␣. These results indicate that triflusal, a drug with a well characterized pharmacological and safety profile currently used as antiplatelet, inhibits cardiomyocyte growth by interfering with the NF-B signaling pathway through a post-transcriptional mechanism involving reduced-proteosome degradation of IB␣. Cardiac hypertrophy is a response of the heart to a wide range of extrinsic stimuli, such as arterial hypertension, valvular heart disease, myocardial infarction, and cardiomyopathy. Although this process is initially compensatory for an increase workload, its prolongation frequently results in congestive heart failure, arrhythmia, and sudden deat

Tissue Compatibility of SN-38-Loaded Anticancer Nanofiber Matrices

Delivery of chemotherapy in the surgical bed has shown preclinical activity to control cancer progression upon subtotal resection of pediatric solid tumors, but whether this new treatment is safe for tumor‐adjacent healthy tissues remains unknown. Here, Wistar rats are used to study the anatomic and functional impact of electrospun nanofiber matrices eluting SN‐38 a potent chemotherapeutic agent on several body sites where pediatric tumors such as neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma arise. Blank and SN‐38‐loaded matrices embracing the femoral neurovascular bundle or in direct contact with abdominal viscera (liver, kidney, urinary bladder, intestine, and uterus) are placed. Foreign body tissue reaction to the implants is observed though no histologic damage in any tissue/organ. Skin healing is normal. Tissue reaction is similar for SN‐38‐loaded and blank matrices, with the exception of the hepatic capsule that is thicker for the former although within the limits consistent with mild foreign body reaction. Tissue and organ function is completely conserved after local treatments, as assessed by the rotarod test (forelimb function), hematologic tests (liver and renal function), and control of clinical signs. Overall, these findings support the clinical translation of SN‐38‐loaded nanofiber matrices to improve local control strategies of surgically resected tumors

Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.This study was partly supported by the grants RTI2018-093999-B-I00 and PID2021-122116OB-I00 (M.V-C.), PID2021-122766OB-I00 (A.M.V.), and PID2019-105989RB-I00 (J.B.) from MCIN/AEI/10.13039/501100011033 and “ERDF, A Way of Making Europe”. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is a Carlos III Health Institute project. Support was also received from the CERCA Programme/Generalitat de Catalunya. Meijian Zhang was supported by a grant from the China Scholarship Council (CSC) (202007565030).Peer reviewe