In Silico Screening Identification of Fatty Acids and Fatty Acid Derivatives with Antiseizure Activity: In Vitro and In Vivo Validation.

High fat diets have been used as complementary treatments for seizure disorders for more than a century. Moreover, many fatty acids and derivatives, including the broad-spectrum antiseizure medication valproic acid, have been explored and used as pharmacological agents to treat epilepsy. In this work, we have explored the anticonvulsant potential of a large library of fatty acids and fatty acid derivatives, the LIPID MAPS Structure Database, using structure-based virtual screening to assess their ability to block the voltage-gated sodium channel 1.2 (NaV1.2), a validated target for antiseizure medications. Four of the resulting in silico hits were submitted for experimental confirmation using in vitro patch clamp experiments, and their protective role was evaluated in an acute mice seizure model, the Maximal Electroshock seizure model. These four compounds were found to protect mice against seizures. Two of them exhibited blocking effects on NaV1.2, CaV2.2, and CaV3.1.

LANDMARK comparison of early outcomes of newer-generation Myval transcatheter heart valve series with contemporary valves (Sapien and Evolut) in real-world individuals with severe symptomatic native aortic stenosis: a randomised non-inferiority trial

BACKGROUND Transcatheter aortic valve implantation is an established, guideline-endorsed treatment for severe aortic stenosis. Precise sizing of the balloon-expandable Myval transcatheter heart valve (THV) series with the aortic annulus is facilitated by increasing its diameter in 1•5 mm increments, compared with the usual 3 mm increments in valve size. The LANDMARK trial aimed to show non-inferiority of the Myval THV series compared with the contemporary THVs Sapien Series (Edwards Lifesciences, Irvine, CA, USA) or Evolut Series (Medtronic, Minneapolis, MN, USA). METHODS In this prospective, multinational, randomised, open-label, non-inferiority trial across 31 hospitals in 16 countries (Germany, France, Sweden, the Netherlands, Italy, Spain, New Zealand, Portugal, Greece, Hungary, Poland, Slovakia, Slovenia, Croatia, Estonia, and Brazil), 768 participants with severe symptomatic native aortic stenosis were randomly assigned (1:1) to the Myval THV or a contemporary THV. Eligibility was primarily decided by the heart team in accordance with 2021 European Society of Cardiology guidelines. As per the criteria of the third Valve Academic Research Consortium, the primary endpoint at 30 days was a composite of all-cause mortality, all stroke, bleeding (types 3 and 4), acute kidney injury (stages 2­4), major vascular complications, moderate or severe prosthetic valve regurgitation, and conduction system disturbances resulting in a permanent pacemaker implantation. Non-inferiority of the study device was tested in the intention-to-treat population using a non-inferiority margin of 10•44% and assuming an event rate of 26•10%. This trial is registered with ClinicalTrials.gov, NCT04275726, and EudraCT, 2020-000137-40, and is closed to new participants. FINDINGS Between Jan 6, 2021, and Dec 5, 2023, 768 participants with severe symptomatic native aortic stenosis were randomly assigned, 384 to the Myval THV and 384 to a contemporary THV. 369 (48%) participants had their sex recorded as female, and 399 (52%) as male. The mean age of participants was 80•0 years (SD 5•7) for those treated with the Myval THV and 80•4 years (5•4) for those treated with a contemporary THV. Median Society of Thoracic Surgeons scores were the same in both groups (Myval 2•6% [IQR 1•7­4•0] vs contemporary 2•6% [1•7­4•0]). The primary endpoint showed non-inferiority of the Myval (25%) compared with contemporary THV (27%), with a risk difference of ­2•3% (one-sided upper 95% CI 3•8, pnon-inferiority<0•0001). No significant difference was seen in individual components of the primary composite endpoint. INTERPRETATION In individuals with severe symptomatic native aortic stenosis, the Myval THV met its primary endpoint at 30 days.

Direct Inhibition of BK Channels by Cannabidiol, One of the Principal Therapeutic Cannabinoids Derived from Cannabis sativa.

Cannabidiol (CBD), one of the main Cannabis sativa bioactive compounds, is utilized in the treatment of major epileptic syndromes. Its efficacy can be attributed to a multimodal mechanism of action that includes, as potential targets, several types of ion channels. In the brain, CBD reduces the firing frequency in rat hippocampal neurons, partly prolonging the duration of action potentials, suggesting a potential blockade of voltage-operated K+ channels. We postulate that this effect might involve the inhibition of the large-conductance voltage- and Ca2+-operated K+ channel (BK channel), which plays a role in the neuronal action potential's repolarization. Thus, we assessed the impact of CBD on the BK channel activity, heterologously expressed in HEK293 cells. Our findings, using the patch-clamp technique, revealed that CBD inhibits BK channel currents in a concentration-dependent manner with an IC50 of 280 nM. The inhibition is through a direct interaction, reducing both the unitary conductance and voltage-dependent activation of the channel. Additionally, the cannabinoid significantly delays channel activation kinetics, indicating stabilization of the closed state. These effects could explain the changes induced by CBD in action potential shape and duration, and they may contribute to the observed anticonvulsant activity of this cannabinoid.

A Combined Ligand- and Structure-Based Virtual Screening To Identify Novel NaV1.2 Blockers: In Vitro Patch Clamp Validation and In Vivo Anticonvulsant Activity.

Epilepsy is a neurological disorder characterized by recurrent seizures that arise from abnormal electrical activity in the brain. Voltage-gated sodium channels (NaVs), responsible for the initiation and propagation of action potentials in neurons, play a critical role in the pathogenesis of epilepsy. This study sought to discover potential anticonvulsant compounds that interact with NaVs, specifically, the brain subtype hNaV1.2. A ligand-based QSAR model and a docking model were constructed, validated, and applied in a parallel virtual screening over the DrugBank database. Montelukast, Novobiocin, and Cinnarizine were selected for in vitro testing, using the patch-clamp technique, and all of them proved to inhibit hNaV1.2 channels heterologously expressed in HEK293 cells. Two hits were evaluated in the GASH/Sal model of audiogenic seizures and demonstrated promising activity, reducing the severity of sound-induced seizures at the doses tested. The combination of ligand- and structure-based models presents a valuable approach for identifying potential NaV inhibitors. These findings may provide a basis for further research into the development of new antiseizure drugs for the treatment of epilepsy.

A study of microbial diversity in a biofertilizer consortium.

Biofertilizers supply living microorganisms to help plants grow and keep their health. This study examines the microbiome composition of a commercial biofertilizer known for its plant growth-promoting activity. Using ITS and 16S rRNA gene sequence analyses, we describe the microbial communities of a biofertilizer, with 163 fungal species and 485 bacterial genera found. The biofertilizer contains a variety of microorganisms previously reported to enhance nutrient uptake, phytohormone production, stress tolerance, and pathogen resistance in plants. Plant roots created a microenvironment that boosted bacterial diversity but filtered fungal communities. Notably, preserving the fungal-inoculated substrate proves critical for keeping fungal diversity in the root fraction. We described that bacteria were more diverse in the rhizosphere than in the substrate. In contrast, root-associated fungi were less diverse than the substrate ones. We propose using plant roots as bioreactors to sustain dynamic environments that promote the proliferation of microorganisms with biofertilizer potential. The study suggests that bacteria grow close to plant roots, while root-associated fungi may be a subset of the substrate fungi. These findings show that the composition of the biofertilizer may be influenced by the selection of microorganisms associated with plant roots, which could have implications for the effectiveness of the biofertilizer in promoting plant growth. In conclusion, our study sheds light on the intricate interplay between plant roots and the biofertilizer's microbial communities. Understanding this relationship can aid in optimizing biofertilizer production and application, contributing to sustainable agricultural practices and improved crop yields.

Assessment of grape volatile composition using fluorescence indices of leaves in vineyards affected by iron chlorosis

Multiplex 330 (MX) is a portable, non-invasive fluorescence sensor that provides different multiparametric indices that are sensitive to the concentration of chlorophylls, flavonols, and anthocyanins on the leaf surface. This study investigated the use of these indices to assess the variability on free volatile composition of grapes (Vitis vinifera L.) in the field as well as other components of their quality potential in vineyards affected by iron deficiency chlorosis (IDC). Twenty non-irrigated Tempranillo/110 Richter vineyard subzones from non-affected to moderately affected by IDC were monitored in Ribera del Duero area (Spain) during two seasons. The results indicated that MX can characterize the spatial variation of leaf pigment concentrations, agronomic performance, and grape quality in vineyards affected by IDC. The MX indices measured at the leaf level close to harvest had better predictive values for the concentrations of free alcohols, volatile acids, C13-norisoprenoids, esters and acetates in the must than vine vigor, size or degree of technological maturity of the grapes. Our study demonstrates that the MX indices to estimate leaf pigment concentrations can be helpful to assess the technological maturity and free volatile composition of wine grapes in vineyards affected by IDC; nevertheless, the efficacy of the indexes may vary according to the year season.(AU)

Novel Dimeric hHv1 Model and Structural Bioinformatic Analysis Reveal an ATP-Binding Site Resulting in a Channel Activating Effect.

The human voltage-gated proton channel (hHv1) is a highly selective ion channel codified by the HVCN1 gene. It plays a fundamental role in several physiological processes such as innate and adaptive immunity, insulin secretion, and sperm capacitation. Moreover, in humans, a higher hHv1 expression/function has been reported in several types of cancer cells. Here we report a multitemplate homology model of the hHv1 channel, built and refined as a dimer in Rosetta. The model was then subjected to extensive Gaussian accelerated molecular dynamics (GaMD) for enhanced conformational sampling, and representative snapshots were extracted by clustering analysis. Combining different structure- and sequence-based methodologies, we predicted a putative ATP-binding site located on the intracellular portion of the channel. Furthermore, GaMD simulations of the ATP-bound dimeric hHv1 model showed that ATP interacts with a cluster of positively charged residues from the cytoplasmic N and C terminal segments. According to the in silico predictions, we found that 3 mM intracellular ATP significantly increases the H+ current mediated by the hHv1 channel expressed in HEK293 cells and measured by the patch-clamp technique in an inside-out configuration (2.86 ± 0.63 fold over control at +40 mV). When ATP was added on the extracellular side, it was not able to activate the channel supporting the idea that the ATP-binding site resides in the intracellular face of the hHV1 channel. In a physiological and pathophysiological context, this ATP-mediated modulation could integrate the cell metabolic state with the H+ efflux, especially in cells where hHv1 channels are relevant for pH regulation, such as pancreatic ß-cells, immune cells, and cancer cells.

Structure-Based Virtual Screening Identifies Novobiocin, Montelukast, and Cinnarizine as TRPV1 Modulators with Anticonvulsant Activity In Vivo.

The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel, known to be involved in the regulation of many important physiological and pathological processes. In the last few years, it has been proposed as a promising target to develop novel anticonvulsant compounds. However, thermoregulatory effects associated with the channel inhibition have hampered the path for TRPV1 antagonists to become marketed drugs. In this regard, we conducted a structure-based virtual screening campaign to find potential TRPV1 modulators among approved drugs, which are known to be safe and thermally neutral. To this end, different docking models were developed and validated by assessing their pose and score prediction powers. Novobiocin, montelukast, and cinnarizine were selected from the screening as promising candidates for experimental testing and all of them exhibited nanomolar inhibitory activity. Moreover, the in vivo profiles showed promising results in at least one of the three models of seizures tested.

Utilidad del modelo 5MPB-Toledo para predecir bacteriemia en el paciente anciano / Usefulness of the 5MPB-Toledo model to predict bacteremia in the elderly patient

Resumen Objetivo: Analizar la utilidad del modelo predictivo de bacteriemia (5MPB-Toledo) en los mayores de 65 años atendidos por infección en el servicio de urgencias (SU). Material y Método: Estudio observacional prospectivo y multicéntrico de los hemocultivos (HC) obtenidos en pacientes mayores de 65 años atendidos por infección en 66 SU españoles desde el 1 de diciembre de 2019 hasta el 30 de abril de 2020. Se analizó la capacidad predictiva del modelo con el área bajo la curva (ABC) de la característica operativa del receptor (COR) y se calculó el rendimiento diagnóstico de los puntos de corte (PC) del modelo elegido con los cálculos de la sensibilidad, la especificidad, el valor predictivo positivo y el valor predictivo negativo. Resultados: Se incluyeron 2.401 episodios de HC extraídos. De ellos, se consideró como bacteriemia verdadera a 579 (24,11%) y como HC negativo a 1.822 (75,89%). Entre los negativos, 138 (5,74%) se consideraron contaminados. Se categorizó a los pacientes en bajo (0-2 puntos), moderado (3-5 puntos) y alto (6-8 puntos) riesgo, con una probabilidad de bacteriemia de 1,2%, 18,1% y 80,7%, respectivamente. El ABC-COR del modelo tras remuestreo fue de 0,908 (IC 95%: 0,897-0,924). El rendimiento diagnóstico del modelo, considerando un PC ≥ 5 puntos, obtiene una sensibilidad de 94% (IC 95%:92-96), especificidad de 77% (IC 95%:76-79) y un valor predictivo negativo de 97% (IC 95%:96-98). Conclusión: El modelo 5MPB-Toledo es de utilidad para predecir bacteriemia en los mayores de 65 años atendidos en el SU por un episodio de infección.

Abstract Objective: To analyse a risk score to predict bacteremia (MPB5-Toledo) in the patients aged older 65 years seen in the emergency departments (ED) due to infections. Patients and Methods: Prospective and multicenter observational cohort study of the blood cultures (BC) ordered in 66 Spanish ED for patients aged older 65 years seen from December 1, 2019, to April 30, 2020. The predictive ability of the model was analyzed with the area under the Receiver Operating Characteristic curve (AUC-ROC). The prognostic performance for true bacteremia was calculated with the cut-off values chosen for getting the sensitivity, specificity, positive predictive value and negative predictive value. Results: A total of 2.401 blood samples wered cultured. True cases of bacteremia were confirmed in 579 (24.11%). The remaining 1.822 cultures (75.89%) wered negative. And, 138 (5.74%) were judged to be contaminated. Low risk for bacteremia was indicated by a score of 0 to 2 points, intermediate risk by 3 to 5 points, and high risk by 6 to 8 points. Bacteremia in these 3 risk groups was predicted for 1.2%, 18.1%, and 80.7%, respectively. The model´s area under the receiver ope rating characteristic curve was 0.908 (95% CI, 0.897-0.924). The prognostic performance with a model´s cut-off value of ≥ 5 points achieved 94% (95% CI: 92-96) sensitivity, 77% (95% CI: 76-79) specificity, and negative predictive value of 97% (95% CI: 96-98). Conclusion: The 5MPB-Toledo score is useful for predicting bacteremia in the patients aged older 65 years seen in the emergency departments due to infections.

Aroma composition of Tempranillo grapes as affected by iron deficiency chlorosis and vine water status

Water deficit and iron nutritional deficiency (iron chlorosis) are frequent environmental stresses affecting grapevine production in the Mediterranean region. The objectives of this work were (i) to study the combined effects of both stresses on aromatic profile of Tempranillo grapes, occurring simultaneously in the vineyard, and (ii) to evaluate the viability of foliar chlorophyll content at veraison (Chl) to early assess aromatic quality potential of grapes in those conditions. Twenty non-irrigated vineyard subzones (10 m × 10 m each), affected and non-affected by iron chlorosis, were monitored in Ribera del Duero Appellation of Origin (North-Central Spain) during two consecutive seasons. Factorial ANOVA was performed to study the effects of predawn leaf water potential and Chl measured at veraison on the must composition parameters and, specifically, on the concentrations of free and bound aromatic compounds. Water deficit tended to increase color intensity and extractable anthocyanin content of the grapes, whereas the incidence of iron deficiency enhanced total phenolic compound content within subzones with better water status. More water or iron stressed subzones restricted C6-alcohols contents than less stressed subzones. Without significant effects on vine vigor, yield or berry size, the incidence of iron chlorosis increased the concentrations of some specific terpenes, C13-norisoprenoids, volatile acids and volatile phenols. These results showed that low to moderate iron stress can have positive effects on grape aromatic quality, and demonstrated that Chl can be a useful tool in precision viticulture to map the aromatic potential within rainfed vineyards affected by iron chlorosis.(AU)

Aroma composition of Tempranillo grapes as affected by iron deficiency chlorosis and vine water status

Water deficit and iron nutritional deficiency (iron chlorosis) are frequent environmental stresses affecting grapevine production in the Mediterranean region. The objectives of this work were (i) to study the combined effects of both stresses on aromatic profile of Tempranillo grapes, occurring simultaneously in the vineyard, and (ii) to evaluate the viability of foliar chlorophyll content at veraison (Chl) to early assess aromatic quality potential of grapes in those conditions. Twenty non-irrigated vineyard subzones (10 m × 10 m each), affected and non-affected by iron chlorosis, were monitored in Ribera del Duero Appellation of Origin (North-Central Spain) during two consecutive seasons. Factorial ANOVA was performed to study the effects of predawn leaf water potential and Chl measured at veraison on the must composition parameters and, specifically, on the concentrations of free and bound aromatic compounds. Water deficit tended to increase color intensity and extractable anthocyanin content of the grapes, whereas the incidence of iron deficiency enhanced total phenolic compound content within subzones with better water status. More water or iron stressed subzones restricted C6-alcohols contents than less stressed subzones. Without significant effects on vine vigor, yield or berry size, the incidence of iron chlorosis increased the concentrations of some specific terpenes, C13-norisoprenoids, volatile acids and volatile phenols. These results showed that low to moderate iron stress can have positive effects on grape aromatic quality, and demonstrated that Chl can be a useful tool in precision viticulture to map the aromatic potential within rainfed vineyards affected by iron chlorosis.

Parámetros diagnósticos en los lactantes con sospecha de infección del tracto urinario / Diagnostic parameters in infants with suspected urinary tract infection

Introducción: La sintomatología de la infección del tracto urinario es variable en la edad pediátrica, por ende, se presentan cuadros clínicos típicos y atípicos diversos debido a múltiples factores estudiados y definidos, que ofrecen dificultad para la confirmación diagnóstica. Objetivo: Identificar la utilidad de los parámetros diagnósticos de la infección urinaria. Métodos: Estudio observacional, analítico, de caso y controles, en lactantes ingresados con sospecha de infección urinaria en el Hospital Pediátrico Universitario Octavio de la Concepción y de la Pedraja admitidos en el servicio de clínicas pediátricas. El universo fueron los lactantes con sospecha de infección del tracto urinario y la muestra fue de 191 pacientes que cumplieron con los criterios de inclusión. Las variables utilizadas fueron la edad, el sexo, signos y síntomas, factores clínicos, formas clínicas, parámetros microbiológicos, parámetros clínicos según presencia de criterios de Rochester y escalas de evaluación para infección bacteriana y los parámetros de laboratorio. Resultados: Las variables clínicas más importantes asociadas a una infección urinaria fueron la edad menor de tres meses, la fiebre y el no disfrute de la lactancia materna, mientras que las de laboratorio fueron anemia, leucocitosis, neutrofilia y eritrosedimentación elevada. Conclusiones: Se identifica un conjunto de parámetros clínicos y estudios de laboratorio útiles en la atención médica del niño con infección urinaria. La forma de presentación febril es la característica especial de la enfermedad y las investigaciones hematológicas y del sedimento urinario son fuentes de apoyo diagnóstico(AU)

Introduction: The symptomatology of urinary tract infection is variable in pediatric ages, therefore, there are typical and atypical clinical pictures due to multiple factors studied and defined but that offer difficulty for diagnostic confirmation. Objective: Identify the usefulness of the diagnostic parameters of urinary tract infection. Methods: Observational, analytical, case-control study in infants admitted with suspected urinary tract infection at Octavio de la Concepción y de la Pedraja University Pediatric Hospital and admitted to the pediatric clinic service. The total sample were infants with suspected urinary tract infection and the sample was 191 patients who met the inclusion criteria. The variables used were age, sex, signs and symptoms, clinical factors, clinical forms, microbiological parameters, clinical parameters according to the presence of Rochester criteria and evaluation scales for bacterial infection and laboratory parameters. Results: The most important clinical variables associated with a urinary tract infection were: age less than three months, fever and non-enjoyment of breastfeeding; while laboratory variables were: anemia, leukocytosis, neutrophilia and elevated erythrosedimentation. Conclusions: A set of clinical parameters and laboratory studies useful in the medical care of children with urinary tract infection are identified. The form of febrile presentation is the specific characteristic of the disease and hematological and urinary sediment investigations are sources of diagnostic support(AU)

Efectividad del tratamiento quimioprofiláctico sobre las recurrencias en la infección del tracto urinario / Effectiveness of chemoprophylactic treatment in recurrences of urinary tract infection

Introducción: Los síntomas urinarios constituyen el motivo de consulta pediátrica más frecuente en relación con el aparato urinario durante cualquier época del año y a cualquier edad. Los argumentos para el uso o no de la quimioprofilaxis para evitar las recurrencias, son variables. Objetivo: Verificar la efectividad de la quimioprofilaxis para prevenir las recurrencias en la infección del tracto urinario en niños de 1 a 24 meses. Métodos: Se realizó un cuasi-experimento conformado por 58 pacientes que ingresaron en el Hospital Pediátrico de Holguín que cumplieron con los criterios de inclusión. Las variables de estudio fueron: número de recurrencias, momento de aparición durante la observación, presencia de recurrencia, quimioprofilaxis, tipo de quimioprofilaxis, edad, sexo, microorganismo aislado, factor predisponente, clasificación de riesgo. Se trabajó con 95 por ciento de confiabilidad lo que significó que valores de p por debajo de 0,05 fueron considerados como significativos. Se realizó el procesamiento en el programa SPSS versión 22.0. Resultados: De 58 pacientes estudiados solo tuvieron recurrencia 6,9 por ciento; de los que no recibieron quimioprofilaxis ninguno tuvo recurrencia y los que recibieron tratamiento quimioprofiláctico, 4 tuvieron recurrencia, por lo que haber recibido o no quimioprofilaxis no influyó en la aparición de recurrencia y menos después de 18 meses de una primera infección urinaria. Conclusiones: La presencia de recurrencias después de 18 meses de una primera infección urinaria en niños menores de 2 años no es un evento frecuente y parece que la quimioprofilaxis no es efectiva(AU)

Introduction: Urinary symptoms are the most frequent reason for pediatric consultation related to the urinary system during any time of the year and at any age. The arguments for the use or not of chemoprophylaxis to avoid recurrences are variable. Objective: Confirm the effectiveness of chemoprophylaxis to prevent recurrences of urinary tract infections in children aged 1 to 24 months. Methods: A quasi-experiment consisting of 58 patients admitted to the Children's Hospital of Holguín who met the inclusion criteria was conducted. The study variables were: number of recurrences, time of onset during observation, presence of recurrence, chemoprophylaxis, type of chemoprophylaxis, age, sex, isolated microorganism, predisposing factor, risk classification. We worked with 95 percent of reliability which meant that p values below 0.05 were considered significant. Processing was performed in the SPSS version 22.0 program. Results: From the 58 patients studied, only 6.9% had recurrence; of those who did not receive chemoprophylaxis none had recurrence and of those who received chemoprophylactic treatment, 4 had recurrence; so, having received or not chemoprophylaxis did not influence the appearance of recurrence and less after 18 months of a first urinary infection. Conclusions: The presence of recurrences after 18 months of a first urinary tract infection in children under 2 years of age is not a frequent event and it seems that chemoprophylaxis is not effective(AU)

Differential expression of the long and truncated Hv1 isoforms in breast-cancer cells.

Metabolic reprogramming of cancer cells results in a high production of acidic substances that must be extruded to maintain tumor-cell viability. The voltage-gated proton channel (Hv1) mediates highly selective effluxes of hydronium-ion (H+ ) that prevent deleterious cytoplasmic acidification. In the work described here, we demonstrated for the first time that the amino-terminal-truncated isoform of Hv1 is more highly expressed in tumorigenic breast-cancer-cell lines than in nontumorigenic breast cells. With respect to Hv1 function, we observed that pharmacologic inhibition of that channel, mediated by the specific blocker 5-chloro-2-guanidinobenzimidazole, produced a drop in intracellular pH and a decrease in cell viability, both in monolayer and in three-dimensional cultures, and adversely affected the cell-cycle in tumorigenic breast cells without altering the cycling of nontumorigenic cells. In conclusion, our results demonstrated that the Hv1 channel could be a potential tool both as a biomarker and as a therapeutic target in breast-cancer disease.

Combined effects of water status and iron deficiency chlorosis on grape composition in non-irrigated vineyards

Although water deficit and iron deficiency chlorosis are common environmental stresses in the Mediterranean area, few data are reported in the literature on their effects on vineyards, when acting simultaneously. The main objective of this research was to study the combined effects of iron deficiency and water status on vigor, yield and fruit composition in rainfed vineyards. Moreover, the investigation aimed to evaluate the feasibility of using foliar chlorophyll content (Chl) and predawn leaf water potential (LWP), measured at veraison, to assess potential quality of grapes in the framework of precision viticulture. For this, 24 non-irrigated ‘Tempranillo vineyard subzones were monitored in Ribera del Duero (North-Central Spain) during three consecutive seasons (2011-2013). The analysis of variance and principal component analysis showed that malic acid concentrations of the must were impacted only by Chl, whereas total soluble solids and total acidity were mainly modified by LWP. Both water and iron status reduced yield and berry weight and had additive effects on extractable anthocyanin content in grapes, total polyphenol index and color density of the must. In all seasons, the ratio Chl/LWP had a better predicting value for quality parameters of these grapes than leaf area index, Chl or LWP individually. The present work demonstrates the potential interest of physiological indexes combining water status and foliar chlorosis as indicators of grape phenolic potential in rainfed vineyards affected by iron deficiency.(AU)

Combined effects of water status and iron deficiency chlorosis on grape composition in non-irrigated vineyards

Although water deficit and iron deficiency chlorosis are common environmental stresses in the Mediterranean area, few data are reported in the literature on their effects on vineyards, when acting simultaneously. The main objective of this research was to study the combined effects of iron deficiency and water status on vigor, yield and fruit composition in rainfed vineyards. Moreover, the investigation aimed to evaluate the feasibility of using foliar chlorophyll content (Chl) and predawn leaf water potential (LWP), measured at veraison, to assess potential quality of grapes in the framework of precision viticulture. For this, 24 non-irrigated ‘Tempranillo’ vineyard subzones were monitored in Ribera del Duero (North-Central Spain) during three consecutive seasons (2011-2013). The analysis of variance and principal component analysis showed that malic acid concentrations of the must were impacted only by Chl, whereas total soluble solids and total acidity were mainly modified by LWP. Both water and iron status reduced yield and berry weight and had additive effects on extractable anthocyanin content in grapes, total polyphenol index and color density of the must. In all seasons, the ratio Chl/LWP had a better predicting value for quality parameters of these grapes than leaf area index, Chl or LWP individually. The present work demonstrates the potential interest of physiological indexes combining water status and foliar chlorosis as indicators of grape phenolic potential in rainfed vineyards affected by iron deficiency.

Design, synthesis and biological evaluation of N-substituted α-hydroxyimides and 1,2,3-oxathiazolidine-4-one-2,2-dioxides with anticonvulsant activity.

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED50 = 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).

Abscisic acid and ethephon treatments applied to ‘Verdejo white grapes affect the quality of wine in different ways

Exogenous ethephon and abscisic acid (ABA) treatments are used worldwide to improve the coloring of red table grapes, but there is little information about their impact on the quality of white grapes and wines. The aim of this work was to evaluate the effects of exogenous ethephon and ABA applications at veraison on the composition of ‘Verdejo white grapes, and on the quality of their wines. To attain this objective, a field trial was carried out in a ‘Verdejo/110 Richter vineyard located in north-central Spain. Two levels of ethephon (0 and 1500 mg L−1) and ABA (0 and 800 mg L−1) were sprayed on clusters at veraison, in a factorial design for three consecutive seasons. Ethephon and ABA had additive effects, decreasing titratable acidity and increasing pH of the must, which could be exploited by accelerating the grape ripening process in cold-climate zones. Nevertheless, each growth regulator affected the composition and sensory analysis of the wines differently. Ethephon treatments produced wines with lower concentration of acids and better flavor quality than those made from untreated plants, while wines with ABA applications tended to have a higher ethanol concentration and poorer aroma quality than controls. The wines submitted to treatments with ethephon obtained the best overall evaluation in the sensory analysis throughout the trial.(AU)

Abscisic acid and ethephon treatments applied to ‘Verdejo’ white grapes affect the quality of wine in different ways

Exogenous ethephon and abscisic acid (ABA) treatments are used worldwide to improve the coloring of red table grapes, but there is little information about their impact on the quality of white grapes and wines. The aim of this work was to evaluate the effects of exogenous ethephon and ABA applications at veraison on the composition of ‘Verdejo’ white grapes, and on the quality of their wines. To attain this objective, a field trial was carried out in a ‘Verdejo’/110 Richter vineyard located in north-central Spain. Two levels of ethephon (0 and 1500 mg L−1) and ABA (0 and 800 mg L−1) were sprayed on clusters at veraison, in a factorial design for three consecutive seasons. Ethephon and ABA had additive effects, decreasing titratable acidity and increasing pH of the must, which could be exploited by accelerating the grape ripening process in cold-climate zones. Nevertheless, each growth regulator affected the composition and sensory analysis of the wines differently. Ethephon treatments produced wines with lower concentration of acids and better flavor quality than those made from untreated plants, while wines with ABA applications tended to have a higher ethanol concentration and poorer aroma quality than controls. The wines submitted to treatments with ethephon obtained the best overall evaluation in the sensory analysis throughout the trial.

Searching for New Leads To Treat Epilepsy: Target-Based Virtual Screening for the Discovery of Anticonvulsant Agents.

The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N, N'-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N, N'-diphenethylsulfamide.