Ca-Stimulated Type 8 Adenylyl Cyclase Is Required for Rapid Acquisition of Novel Spatial Information and for Working/Episodic-Like Memory

Ca-stimulated adenylyl cyclases (ACs) transduce neuronal stimulation-evoked increase in calcium to the production of cAMP, which impinges on the regulation of many aspects of neuronal function. Type 1 and type 8 AC (AC1 and AC8) are the only ACs that are directly stimulated by Ca. Although AC1 function was implicated in regulating reference spatial memory, the function of AC8 in memory formation is not known. Because of the different biochemical properties of AC1 and AC8, these two enzymes may have distinct functions. For example, AC1 activity is regulated by both Ca and G-proteins. In contrast, AC8 is a pure Ca sensor. It is neither stimulated by Gs nor inhibited by Gi. Recent studies also suggested that AC1 and AC8 were differentially concentrated at different subcellular domains, implicating that Ca-stimulated signaling might be compartmentalized. In this study, we used AC8 knock-out (KO) mice and found behavioral deficits in memory retention for temporal dissociative passive avoidance and object recognition memory. When examined by Morris water maze, AC8KOmice showed normal reference memory. However, the acquisition of newer spatial information was defective in AC8 KO mice. Furthermore, AC8 KO mice were severely impaired in hippocampus-dependent episodic-like memory when examined by the delayed matching-to-place task. Because AC8 is preferentially localized at the presynaptic active zone, our results suggest a novel role of presynaptic cAMP signaling in memory acquisition and retention, as well as distinct mechanisms underlying reference and working/episodic-like memory

Percutaneous radiofrequency ablation of HCC: reduced ablation duration and increased ablation size using single, internally cooled electrodes with an optimized pulsing algorithm

Purpose To assess the use of optimized radiofrequency (RF) to achieve larger, spherical ablation volumes with short application duration for hepatocellular carcinoma (HCC). Materials and methods Twenty-two patients (M:F = 17:5, median age 69.6 year, range 63–88) with 28 HCCs due to HCV + liver cirrhosis underwent RFA. 20/28 (71.4%) were tumors ≤3cm diameter, and 8/28 (28.6%) ranged from 3.2 to 4.2 cm. RF was applied using up to 2500mA via an optimized pulsing algorithm with real-time ultrasound monitoring to detect hyperechogenic changes. Single insertions of an internally cooled electrode were performed using exposed tips of 2 or 3 cm for 13 HCCs and 4 cm for 15 HCCs. All patients were followed-up for a minimum of 5 years with contrast-enhanced computed tomography (CECT). Results Technical success was achieved without adverse events in all cases. The mean ablation time was 8.5 ± 2.6 min. In 21/28 (75%), ablation duration ranged from 3 to 9 min, with 12 min duration applied in only 7/28 (25%). Mean coagulation diameters were 2.4 ± 0.14, 3.3 ± 0.62, and 4.4 ± 1.0, for 2, 3 and 4 cm electrodes, respectively (p 3 cm tumors developed local progression. One patient had multifocal disease with no local progression. Conclusion Efficient delivery of RF energy can considerably decrease the ablation time in many instances while achieving larger, relatively spherical, and reproducible areas of ablation with extremely low rates of local tumor progression and adverse events

Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections.

Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections

Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes

Glutathione is involved in environmental stress responses in Rhizobium tropici, including acid tolerance

The isolation of rhizobial strains which exhibit an intrinsic tolerance to acidic conditions has been reported and has facilitated studies on the basic mechanisms underlying acid tolerance. Rhizobium tropici strain CIAT899 displays a high intrinsic tolerance to acidity and therefore was used in this work to study the molecular basis of bacterial responses to acid conditions and other environmental stresses. We generated a collection of R. tropici CIAT899 mutants affected in acid tolerance using Tn5-luxAB mutagenesis, and one mutant strain (CIAT899-13T2), which fails to grow under acid conditions, was characterized in detail. Strain CIAT899-13T2 was found to contain a single Tn5-luxAB insertion in a gene showing a high degree of similarity with the Escherichia coli gshB gene, encoding the enzyme glutathione synthetase. Intracellular potassium pools and intracellular pH levels were found to be lower in the mutant than in the parent. The glutathione-deficient mutant was shown to be sensitive to weak organic acids, osmotic and oxidative stresses, and the presence of methylglyoxal. Glutathione restores responses to these stresses almost to wild-type levels. Our data show that in R. tropici the production of glutathione is essential for growth in extreme environmental conditions. The mutant strain CIAT899-13T2 induced effective nodules; however, it was found to be outcompeted by the wild-type strain in coinoculation experiments.Facultad de Ciencias ExactasInstituto de Biotecnologia y Biologia Molecula

Monitoring of cfrp-strengthened reinforced concrete bridge spans in low temperature conditions

The article discusses strengthening bridges using composite materials at extreme low temperatures. Provides the results some experimental studies FRP strengthened concrete samples at low temperatures

Interferencia del Herpesvirus equino 1 (EHV-1) en la apoptosis inducida

La apoptosis es un tipo de muerte celular programada que puede ser desencadenada por múltiples factores, tanto internos como externos; dentro de estos últimos se encuentran las infecciones virales. Algunos alphaherpesvirus han desarrollado diversas estrategias para retardar o inhibir la muerte celular obteniendo, de esta manera, su propio beneficio al poder permanecer durante más tiempo en la célula. Hasta el momento no se ha identificado ningún mecanismo relacionado con la modulación de la muerte celular durante la infección con Herpesvirus equino tipo 1 (EHV-1). El objetivo del presente trabajo fue describir el efecto producido por la infección con EHV-1 sobre cultivos celulares inducidos a la muerte por apoptosis. La evaluación de la apoptosis se realizó mediante el reconocimiento de la fragmentación en escalera del ADN, la evaluación de la relación Anexina V/ioduro de propidio (IP) y la determinación del clivaje de la citoqueratina 18, utilizando técnicas de inmunofluorescencia. Los resultados indican una posible interferencia del EHV-1 con la muerte por apoptosis hacia la mitad de su ciclo de replicación, que se incrementa hacia el final del mismo.Apoptosis is a programmed cell death that can be triggered by many factors, both internal and external. Viral infections are included among the latter. Some alphaherpesvirus have developed several strategies to retard or inhibit cell death and thus the virus benefits itself by staying longer in the cell. So far, no mechanisms have been identified related to modulation of cell death during infection with equine herpesvirus type 1 (EHV-1). The aim of the present study was to describe the effect produced by the infection with EHV-1 on apoptosis-induced cell cultures. Assessment of apoptosis was performed by DNA laddering, the Annexin V/propidium iodide (PI) determination and the cytokeratin 18 cleavage analysis using immunofluorescence techniques. Results indicate a possible interference of EHV-1 with apoptotic cell death in the middle of its replication cycle, being increased by its end

Marine Hydrokinetic Energy from Western Boundary Currents

The kinetic energy in ocean currents, or marine hydrokinetic (MHK) energy, is a renewable energy resource that can help meet global energy requirements. An ocean circulation model-based census shows that subtropical surface western boundary currents (WBCs) are the only nearshore, large-scale currents swift enough to drive large electricity-generating ocean turbines envisioned for future use. We review several WBCs in the context of kinetic energy extraction. The power density in the Gulf Stream off North Carolina at times reaches several thousand watts per square meter at 75 m below the surface, and the annual average power is approximately 500-1,000 W m-2. Significant fluctuations occur with periods of 3-20 days (Gulf Stream meanders) and weeks to months (Gulf Stream path shifts). Interannual variations in annual average power occur because of year-to-year changes in these WBC motions. No large-scale turbines presently exist, and the road to establishing MHK facilities in WBCs will encounter challenges that are similar in many aspects to those associated with the development of offshore wind power

Embolization in Pediatric Patients: A Comprehensive Review of Indications, Procedures, and Clinical Outcomes

Embolization in pediatric patients encompasses a large spectrum of indications, ranging from the elective treatment of congenital diseases of the cardiovascular system to the urgent management of acute hemorrhagic conditions. In particular, the endovascular treatment of central and peripheral vascular malformations and hypervascular tumors represents a wide chapter for both congenital and acquired situations. Thanks to the progressive availability of low-profile endovascular devices and new embolic materials, the mini-invasive approach has gradually overtaken surgery. In this review, the main embolization procedures will be illustrated and discussed, with a focus on clinical indications and expected outcomes. The most recent mini-invasive techniques will be described, with hints on the cutting-edge devices and embolic materials

GEneSTATION 1.0: A Synthetic Resource of Diverse Evolutionary and Functional Genomic Data for Studying The Evolution of Pregnancy-Associated Tissues and Phenotypes

Mammalian gestation and pregnancy are fast evolving processes that involve the interaction of the fetal, maternal and paternal genomes. Version 1.0 of the GEneSTATION database (http://genestation.org) integrates diverse types of omics data across mammals to advance understanding of the genetic basis of gestation and pregnancy-associated phenotypes and to accelerate the translation of discoveries from model organisms to humans. GEneSTATION is built using tools from the Generic Model Organism Database project, including the biology-aware database CHADO, new tools for rapid data integration, and algorithms that streamline synthesis and user access. GEneSTATION contains curated life history information on pregnancy and reproduction from 23 high-quality mammalian genomes. For every human gene, GEneSTATION contains diverse evolutionary (e.g. gene age, population genetic and molecular evolutionary statistics), organismal (e.g. tissue-specific gene and protein expression, differential gene expression, disease phenotype), and molecular data types (e.g. Gene Ontology Annotation, protein interactions), as well as links to many general (e.g. Entrez, PubMed) and pregnancy disease-specific (e.g. PTBgene, dbPTB) databases. By facilitating the synthesis of diverse functional and evolutionary data in pregnancy-associated tissues and phenotypes and enabling their quick, intuitive, accurate and customized meta-analysis, GEneSTATION provides a novel platform for comprehensive investigation of the function and evolution of mammalian pregnancy