Molecular recognition of the HPLC Whelk-O1 selector towards the conformational enantiomers of nevirapine and oxcarbazepine

The presence of stereogenic elements is a common feature in pharmaceutical compounds, and affording optically pure stereoisomers is a frequent issue in drug design. In this context, the study of the chiral molecular recognition mechanism fundamentally supports the understanding and optimization of chromatographic separations with chiral stationary phases. We investigated, with molecular docking, the interactions between the chiral HPLC selector Whelk-O1 and the stereoisomers of two bioactive compounds, the antiviral Nevirapine and the anticonvulsant Oxcarbazepine, both characterized by two stereolabile conformational enantiomers. The presence of fast-exchange enantiomers and the rate of the interconversion process were studied using low temperature enantioselective HPLC and VT-NMR with Whelk-O1 applied as chiral solvating agent. The values of the energetic barriers of interconversion indicate, for the single enantiomers of both compounds, half-lives sufficiently long enough to allow their separation only at critically sub-ambient temperatures. The chiral selector Whelk-O1 performed as a strongly selective discriminating agent both when applied as a chiral stationary phase (CSP) in HPLC and as CSA in NMR spectroscopy

Whole-exome analysis in osteosarcoma to identify a personalized therapy

Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy. We identified 18,275 somatic variations in 8,247 genes and we found three mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the highest number of variations; it is an important component of a histone H3 lysine 4 methyltransferase complex and it is one of the histone modifiers previously implicated in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15 genes that showed variations only in patients that did not respond to therapy and developed metastasis and some of these genes are involved in carcinogenesis and tumor progression in other tumors. These data could offer the opportunity to get a key molecular target to identify possible new strategies for early diagnosis and new therapeutic approaches for osteosarcoma and to provide a tailored treatment for each patient based on their genetic profile

Clasificación de información en BigData mediante la utilización de técnicas de inteligencia artificial y análisis de redes sociales

El presente proyecto se enfoca a evaluar técnicas existentes e implementar desarrollos experimentales que permitan clasificar, ordenar, jerarquizar y analizar información sobre grandes volúmenes de datos heterogéneos (Big Data Analytics), mejorando y/o reformulando dichas técnicas. Dichas técnicas permitirán establecer las capacidades necesarias con las que debería contar una base de datos de información masiva, tanto desde la perspectiva de almacenamiento y técnicas de indexación, como de distribución de las consultas, escalabilidad y rendimiento en ambientes heterogéneos. Para ello se utilizarán Corpus científicos existentes de investigadores colaboradores del Centro Nacional Patagónico - CONICET, con la finalidad de contar con expertos que nos permitan realizar y estructurar los mecanismos de clasificación y evalúen los resultados de los desarrollos experimentales en estos Corpus. Adicionalmente a estos se analizará información pública digital en repositorios de portales y plataformas de información, tanto científica como de acceso general.Eje: Base de Datos y Minería de DatosRed de Universidades con Carreras en Informática (RedUNCI

Bluebot: una propuesta accesible de robótica móvil para propósitos didácticos

La robótica es un tema de importancia central para el desarrollo científico y tecnológico, y sus aplicaciones industriales son innumerables. Por otra parte, el uso de robots como medio didáctico es una alternativa significativa como motivación para materias introductorias y avanzadas en carreras de Informática e Ingeniería Electrónica, y sirve como eje de integración horizontal y vertical de contenidos curriculares. La robótica móvil es uno de los campos de investigación que mayor auge está teniendo como investigación aplicada. Dentro de este campo consideramos específicamente a los robots móviles teleoperados, que son aquellos cuyos movimientos son comandados a distancia. Estos robots, de uso industrial y militar son usados para ejecutar tareas peligrosas o para acceder a lugares de difícil acceso para los seres humanos (desactivación de bombas, exploraciones submarinas, el interior de centrales nucleares, etc.) Son plataformas de alto costo, imposibles de ser consideradas para una aplicación didáctica. Este proyecto consiste en el desarrollo de un robot didáctico bluebot, con tecnología sencilla y al alcance de las capacidades de una escuela, centro educativo o universidad de recursos limitados. El proyecto incluye la construcción de un robot (hardware) y del soporte informático (software) que permita su manejo por usuarios sin experiencia o formación específica. Mediante técnicas de enseñanza experimental el alumno inicial aprende nociones formales de algoritmo, secuencia y ejecución de autómatas. Para el alumno avanzado de ingeniería y de las carreras de informática el robot proporciona la posibilidad de experimentar en forma práctica con conceptos avanzados como las vistas en las materias de informática teórica y de control automático. El robot se telecomanda desde una computadora personal y en un futuro se incorporará un sistema de sensado de posición y de velocidad basado en la captura de imágenes provenientes de una cámara digital de bajo costo (tipo webcam). El alumno proporciona instrucciones en un lenguaje que inicialmente se ha diseñado de bajo nivel aunque se contempla el desarrollo de una gramática libre de contexto de alto nivel en desarrollos futuros. Uno de los principales objetivos de este proyecto es formar desarrolladores con la capacidad y experiencia para poder definir nuevos sistemas, productos y mercados que utilicen esta tecnología. Existe en el país un gran potencial para desarrollos en rob´otica, tanto en el contexto industrial como en aplicaciones para la gestión del medio ambiente, por lo que se espera un alto grado de transferencia tecnológica como producto colateral de la formación que puede darse a través de estas experiencias teóricas y prácticas. Un proyecto de estas características, dado el atractivo social que genera el uso de la tecnología y el muy bajo costo de la misma, es ideal para ser promocionado en colegios y otras instituciones educativas, para fomentar el interés en los estudios universitarios. Ello conseguirá atraer más y mejores alumnos a las carreras técnicas de la universidad patrocinadora, actuando sobre una de las posibles razones por la merma de inscripción registrado en los recientes años. Por otra parte, el uso de esta tecnología como herramienta de estudio en las materias de las carreras de informática permitirá motivar a los alumnos de las mismas para participar en las asignaturas y así disminuir el índice de deserción, minimizar el tiempo de finalizado de la carrera, y extender las experiencias más allá de lo meramente formal. El desarrollo es lo suficientemente genérico como para que puedan participar alumnos de diferentes carreras, y diferentes niveles dentro de las mismas, favoreciendo la aplicación de los contenidos de cada materia en la solución de problemas concretos. Esto permite abordar un tema de gran importancia para la formación profesional, como es la integración curricular horizontal y vertical de los contenidos de varias asignaturas, lo cual hace posible que los alumnos comprendan el alcance y utilidad de los diferentes bloques curriculares y mejoren conceptualmente su articulación.Eje: Agentes y Sistemas InteligentesRed de Universidades con Carreras en Informática (RedUNCI

Transcriptional Hallmarks of Noonan Syndrome and Noonan-Like Syndrome with Loose Anagen Hair

Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is genetically heterogeneous, being caused by germline mutations affecting various genes implicated in the RAS signaling network. This network transduces extracellular signals into intracellular biochemical and transcriptional responses controlling cell proliferation, differentiation, metabolism, and senescence. To explore the transcriptional consequences of NS-causing mutations, we performed global mRNA expression profiling on peripheral blood mononuclear cells obtained from 23 NS patients carrying heterozygous mutations in PTPN11 or SOS1. Gene expression profiling was also resolved in five subjects with Noonan-like syndrome with loose anagen hair (NS/LAH), a condition clinically related to NS and caused by an invariant mutation in SHOC2. Robust transcriptional signatures were found to specifically discriminate each of the three mutation groups from 21 age- and sex-matched controls. Despite the only partial overlap in terms of gene composition, the three signatures showed a notable concordance in terms of biological processes and regulatory circuits affected. These data establish expression profiling of peripheral blood mononuclear cells as a powerful tool to appreciate differential perturbations driven by germline mutations of transducers involved in RAS signaling and to dissect molecular mechanisms underlying NS and other RASopathies. Hum Mutat 33:703–709, 2012. © 2012 Wiley Periodicals, Inc

Un sistema didáctico integrado para la enseñanza introductoria de robótica

Se presenta un sistema informático para la enseñanza introductoria de la robótica en escuelas de nivel medio y universitario. Está formado por un robot armado con componentes de bajo costo y por un conjunto de aplicaciones que permite programar y simular situaciones tales como la edición y resolución de laberintos.Eje: Tecnología informática aplicada en educaciónRed de Universidades con Carreras en Informática (RedUNCI

Un sistema didáctico integrado para la enseñanza introductoria de robótica

Se presenta un sistema informático para la enseñanza introductoria de la robótica en escuelas de nivel medio y universitario. Está formado por un robot armado con componentes de bajo costo y por un conjunto de aplicaciones que permite programar y simular situaciones tales como la edición y resolución de laberintos.Eje: Tecnología informática aplicada en educaciónRed de Universidades con Carreras en Informática (RedUNCI

LA PALAFITTA DI TOMBOLA DI CEREA (VR). LO SCAVO 1999.

La palafitta \ue8 stata scoperta nel 1955 all'interno della Valle del Menago, poche centinaia di metri a Sud del gruppo di case di Tombola di Cerea (VR). Dopo un primo scavo effettuato nello stesso anno da parte di Francesco Zorzi, direttore del Museo Civico di Storia Naturale di Verona, le ricerche sono riprese nel 1999 da parte della Soprintendenza Archeologica del Veneto. I risultati di queste ricerche hanno accertato che l'abitato preistorico era posto su palafitta all'interno di un ambiente di tipo palustre. Sono conservati solo dei pali verticali e alcune travi orizzontali, che fanno ipotizzare l'esistenza di una piattaforma lignea. Gli elementi strutturali della palafitta trovano confronti in altri abitati d'ambiente umido della media et\ue0 del Bronzo. L\u2019inquadramento geomorfologico finalizzato alla ricostruzione paleogeografica mostra che il sito si colloca al centro della Paleovalle del f. Menago, un\u2019incisione larga alcune centinaia di metri e profonda oltre una decina di metri, alla base di un potente spessore di torbe. Gli studi pregressi, relativi all\u2019origine della profonda incisione generata dall\u2019omonimo fiume di risorgiva, si richiamano principalmente a fattori geodinamici legati a linee tettoniche sepolte, quali moventi principali per le incisioni causate dalle diversione di canali di rotta atesini richiamati verso il bacino delle Valli Grandi Veronesi, verificatesi in et\ue0 tardoglaciale-olocenica antica. L\u2019analisi di nuove litostratigrafie rilevate su esposizioni individuate all\u2019interno della paleovalle, ha condotto a riscontrare la presenza di uno spesso e pressoch\ue9 continuo riempimento di sedimenti organico-torbosi, che contrassegnano gli accrescimenti e le sedimentazioni verificatesi a partire dai livelli basali della stazione palafitticola, deposizioni che sono perdurate sino a date piuttosto recenti. Una serie di dettagliati confronti operati con i termini delle sequenze di riempimento torboso-detritiche del bacino che si sviluppava all\u2019esterno delle arginature del vicino e coevo sito di Fondo Paviani, ha portato a verificare un\u2019analoga evoluzione negli accrescimenti che contrassegnano i tratti superiori di queste due importanti successioni alluvio-organiche. Si giunge in definitiva a far intervenire una medesima incidenza di fattori antropici e climatici quali concause principali nello sviluppo dei riempimenti sommitali della Paleovalle del Menago, in corrispondenza della stazione palafitticola della Tombola di Cerea e del sito arginato di Fondo Paviani. Lo scavo ha restituito un notevole quantitativo di materiale ceramico (ca. 620 kg) e una percentuale minoritaria di manufatti in bronzo, terracotta e osso-corno. Il presente contributo si concentra sull'analisi crono-tipologica dei materiali focalizzando l'attenzione sulla ceramica di impasto medio-fine ai fini dell'inquadramento complessivo e del confronto con materiale proveniente da siti geograficamente limitrofi. Le datazioni assolute delle strutture lignee, ottenute dall\u2019applicazione della dendrocronologia e dal radiocarbonio, collocano gli elementi verticali di Tombola di Cerea nella seconda met\ue0 del XV secolo cal BC, o al pi\uf9 tardi nei primi decenni del XIV secolo cal BC; essi sono stati ottenuti da alberi di quercia abbattuti in momenti successivi, a intervalli di circa 10 anni. Le ricerche archeobotaniche hanno compreso un\u2019analisi palinologica condotta su 18 campioni presi da una carota prelevata all'interno dell\u2019abitato palafitticolo, ed un\u2019analisi carpologica e xilo-antracologica su due campioni provenienti da unit\ue0 stratigrafiche cronologicamente corrispondenti alla parte basale della carota. L\u2019analisi dei resti vegetali ha permesso di disegnare il quadro ambientale dell\u2019insediamento. Il luogo era ricco di ambienti umidi soprattutto ripariali, con boscaglie d\u2019igrofile e con elofite, con situazioni di prati periodicamente inondati e fossati poco profondi. La presenza antropica \ue8 suggerita dalla coltivazioni di cereali e altri indicatori antropogenici. Inoltre i dati carpologici e/o pollinici testimoniano la disponibilit\ue0 nell\u2019area di varie piante con frutti eduli, come prugnolo, nocciolo, ribes, noce e vite. Il ritrovamento di reperti di Baldellia ranuncoloides -una specie oggi minacciata sottolinea come le ricerche archeobotaniche forniscano informazioni anche dal punto di vista naturalistico utili per conoscere meglio la storia di specie oggi in rarefazione. L\u2019insieme faunistico \ue8 composto complessivamente da 1995 reperti ossei. Quasi l\u201980% dei resti \ue8 stato identificato a livello specifico. La maggior parte dei resti appartiene alle specie domestiche: bue, pecora, capra e maiale, seguite da cavallo e cane. La distribuzione delle classi d\u2019et\ue0 mostra come l\u2019allevamento degli Ungulati fosse finalizzato non solo all\u2019ottenimento di carni, ma anche alla produzione di latte e lana. La pratica della caccia, volta allo sfruttamento di specie di ambiente forestale (cervo, capriolo, cinghiale), appare un\u2019attivit\ue0 marginale. Le tracce di macellazione sono numerose e attestano l\u2019utilizzo di strumenti sia litici sia metallici. Durante lo studio sono stati riconosciuti 18 manufatti in materia dura animale, ben conservati, che hanno permesso l\u2019identificazione delle tracce di lavorazione utili per la ricostruzione delle catene operative.The pile dwelling was discovered in 1955 in the valley of the river Menago, just a few hundred meters south of the settlement of Tombola di Cerea (VR). A first excavation was carried out that very year by Francesco Zorzi, director of the Museo Civico di Storia Naturale of Verona; the digging has been resumed in 1999 by the Soprintendenza Archeologica of Veneto. The results of these excavations have ascertained that the prehistoric dwelling site was built in a marshy environment. Only some vertical poles and some horizontal beams were preserved, which leads to the hypothesis that there existed a wooden platform on which the sheds were standing. The structural elements of the palafitte find correspondents in others settlements in moist environment from the Middle Bronze Age. The paleogeographic reconstruction of the immediate hinterland confirm the location of the site at the center of the Menago River Paleovalley, an incision a few hundred meters wide and more than ten meters deep, at the base of a thick layer of peat. Previous studies, related to the origin of the deep incision generated by the homonymous spring-line river, mainly refer to geodynamic factors linked to buried tectonic lines, as main motives for the incisions caused by the diversion of Adige breach-channels captured towards the basin of Great Veronese Valleys, which occurred in the late Lateglacial-Holocene age. The analysis of new lithostratigraphies detected on exposures inside the paleovalley, has led to find the presence of a thick and almost continuous filling of organic-peaty sediments, which mark the accretions and the sedimentations verified starting from the basal levels of the pile-dwelling site, depositions that have lasted until fairly recent dates. A series of detailed comparisons made with the terms of the peat-debris-filling sequences of the basin that developed outside the embankments of the near and coeval Fondo Paviani site, led to verify a similar evolution in the growths that mark the upper reaches of these two important alluvio-organic successions. Ultimately, is claimed that the same incidence, of anthropogenic and climatic factors, is involved as the main contributors to the development of the upper fills of the Menago Paleovalley, in correspondence with the pile-dwelling station of the Tombola di Cerea and the embanked site of Fondo Paviani. A great number of ceramic fragments (ca 620 kg) and a smaller amount of bronze, terracotta and bone-horn artefacts had been found. This paper focus on chrono-typological analysis of the archaeological finds, in particular on ceramic of the medium-fine tipe. The goal is the overall classification artefacts, accompanied by a comparison made from materials found in geographically nearbysites. Dendrochronology and radiocarbon allow to date the wooden structures to the second half of the 15th Century cal BC, or in the first decades of the 14th Century cal BC at the latest; the vertical posts come from oak tree felled down once about every ten years. Archaeobotanical study includes pollen analysis carried out on 18 subsamples taken from a core collected in the pile-dwelling settlement and carpological and xilo-anthacological analysis, from 2 samples taken from layers (stratigraphic units) corresponding to the bottom of the core. The results allows to draw the environmental framework of the settlement. The pollen diagram shows that the landscape was rich of wet environments: ponds, wet grassland and hygrophilous wood. The human activity was suggested by a number of anthropogenic indicators: cereal fields, ruderals and weeds. Seeds/fruits and pollen data testify to the presence in the area of edible fruits from plants such as blackthorn, hazelnut, currant, walnut and grapevine. The finds of Baldellia ranuncoloides \u2013 a threatened plants today - underline that the archaeobotanical research provide naturalistic information that allow us to better understand the history of plant species becoming rare today. The faunal assemblage is composed by 1995 bone remains. More than 80% of the faunal remains was identified at species level. Domestic animals are the most frequent. Age at death highlights different breeding strategies focused on meat consumption and secondary products. Hunting was barely practiced on wild ungulates (red deer, roe deer, wild boar). Several anthropic marks were identified on the faunal remains emphasizing the use of lithic and metal tools. During the analysis 18 animal hard material artefacts were identified. The good state of preservation allowed us to identify working traces linked to the reduction sequences of the tools

Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator

Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus.Methods and results In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%.Conclusion Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC