Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination.

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process

A new method to estimate cloud cover fraction over El Leoncito Observatory from an all-sky imager designed for upper atmosphere studies

A method for determining cloud cover fraction over El Leoncito Observatory (31.8°S, 69.3°W) is presented. Data from an all-sky imaging system, designed to measure nightglow originating from the mesosphere and thermosphere, is used to determine the fraction of the sky covered by clouds. More than 9,000 hr of observations from May 2006 to December 2010 are used to show that El Leoncito is clear approximately 75-80% of the time. No significant seasonal variations are observed. The optical ground-based data are compared with data from the Moderate Resolution Imaging Spectro-radiometer (MODIS) instrument on board the TERRA and AQUA satellites.Fil: Martinis, C.. University Of Boston; Estados Unidos de América;Fil: Wilson, J.. University of New Hampshire; Estados UnidosFil: Zablowski, P.. University Of Boston; Estados Unidos de América;Fil: Baumgardner, J.. University Of Boston; Estados Unidos de América;Fil: Aballay, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Garcia, Beatriz Elena. Universidad Tecnologica Nacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología En Detección y Astropartículas. Itedam - Subsede del Instituto de Tec. En Detección y Astropartículas Mendoza | Comisión Nacional de Energía Atómica. Instituto de Tecnología En Detección y Astropartículas. Itedam - Subsede del Instituto de Tec. En Detección y Astropartículas Mendoza | Universidad Nacional de San Martin. Instituto de Tecnología En Detección y Astropartículas. Itedam - Subsede del Instituto de Tec. En Detección y Astropartículas Mendoza. ; Argentina; ArgentinaFil: Ristori, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo Estratégico para la Defensa. Ministerio de Defensa. Unidad de Investigación y Desarrollo Estratégico para la Defensa; ArgentinaFil: Otero, Lidia Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo Estratégico para la Defensa. Ministerio de Defensa. Unidad de Investigación y Desarrollo Estratégico para la Defensa; Argentin

Conocimiento y destrezas iniciales de los alumnos que acceden a cursos introductorios de física en 6 universidades iberoamericanas : cambio a lo largo del primer curso e incidencia en el éxito académi

Este trabajo forma parte de un estudio más extenso, financiado por la AECID, sobre la formación inicial de los alumnos que acceden a cursos de Física en varias universidades iberoamericanas, y de su influencia en el rendimiento académico en el primer curso. La muestra incluye alumnos de las universidades de Alcalá (España), Católica del Norte (Antofagasta, Chile), Santiago (Chile), San Luis (Argentina), San Juan (Argentina) y Tecnológico de Monterrey (México). En primer lugar se ilustra el grado alcanzado en la comprensión de conceptos físicos básicos, en destrezas relevantes para el estudio de la Física y en la capacidad de razonamiento científico. En la segunda parte se muestra como varía la comprensión de los conceptos en el primer año universitario y se analiza mediante un estudio correlacional la influencia de la formación inicial en el éxito académico

Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia

Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-29-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p,0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL

Characterization of Human Herpesvirus 8 genomic integration and amplification events in a primary effusion lymphoma cell line

In this study, we investigated the integration of Human Herpesvirus 8 (HHV-8) into the human genome using the primary effusion lymphoma (PEL) cell line BC-3. Through next-generation sequencing (NGS) data from multiple independent sequencing runs, we identified two highly supported HHV-8 integrants. These integrants encompassed a region of human chromosome 12 that was amplified approximately 16-fold between the junctions. Significantly, these events could represent the first known instance of HHV-8 integration into a hybrid human-viral extrachromosomal chimeric circular DNA (eccDNA). The amplified fragment contained partial or complete copies of various human genes, including SELPLG and CORO1C. Analysis of long-read Nanopore data indicated that the CpGs at the SELPLG promoter were mostly unmethylated, suggesting that the additional copies of SELPLG within this eccDNA are likely transcriptionally active. Our findings suggest that viral insertion and eccDNA amplification could be crucial mechanisms in the development of HHV-8-related cancers. In conclusion, our study provides valuable insights into the molecular mechanisms involved in HHV-8-induced oncogenesis and emphasizes the importance of investigating viral integration and eccDNAs in cancer development. Furthermore, we highlight the necessity of employing multiple independent sequencing approaches to validate integration events and avoid false positives derived from library construction artifacts

MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations

The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML

Burdigalian deposits of the Santa Cruz formation in the Sierra Baguales, austral (magallanes) basin: Age, depositional environment and vertebrate fossils

A succession of marine and continental strata on the southern flank of Cerro Cono in the Sierra Baguales, northeast of Torres del Paine, can be correlated with stratigraphic units exposed along the southern border of the Lago Argentino region in Santa Cr

Synthetic Chemical Inducers and Genetic Decoupling Enable Orthogonal Control of the rhaBAD Promoter

External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly used inducible expression systems, but is marred by transient expression caused by degradation of the native inducer, l-rhamnose. To address this problem, 35 analogues of l-rhamnose were screened for induction of the rhaBAD promoter, but no strong inducers were identified. In the native configuration, an inducer must bind and activate two transcriptional activators, RhaR and RhaS. Therefore, the expression system was reconfigured to decouple the rhaBAD promoter from the native rhaSR regulatory cascade so that candidate inducers need only activate the terminal transcription factor RhaS. Rescreening the 35 compounds using the modified rhaBAD expression system revealed several promising inducers. These were characterized further to determine the strength, kinetics, and concentration-dependence of induction; whether the inducer was used as a carbon source by E. coli; and the modality (distribution) of induction among populations of cells. l-Mannose was found to be the most useful orthogonal inducer, providing an even greater range of induction than the native inducer l-rhamnose, and crucially, allowing sustained induction instead of transient induction. These findings address the key limitation of the rhaBAD expression system and suggest it may now be the most suitable system for many applications

Heart failure with recovered ejection fraction: Clinical characteristics, determinants and prognosis. CARDIOCHUS-CHOP registry

Background: The magnitude and the prognostic impact of recovering left ventricular ejection fraction (LVEF) in patients with heart failure (HF) and systolic dysfunction is unclear. The aim of this study was to evaluate the clinical characteristics and prognosis of patients with HFrecEF in an HF population. Methods: 449 consecutive patients were selected with the diagnosis of HF and an evaluation of LVEF in the 6 months prior to selection who were referred to two HF units. Patients with systolic dysfunction were only considered if a second echocardiogram was performed during the follow-up. Results: At the time of diagnosis, 207 patients had LVEF > 40% (HFpEF) and 242 had LVEF ≤ 40% (HFrEF). After 1 year, the LVEF was re-evaluated in all 242 patients with a LVEF ≤ 40%: in 126 (52%), the second LVEF was > 40% (HFrecEF), and the remaining 116 (48%) had LVEF ≤ 40% (HFrEF). After 1800 ± 900 days of follow-up patients with recovered LVEF had a significantly lower mortality rate (HFpEF vs. HFrecEF: hazard ratio [HR] = 2.286, 95% confidence interval [95% CI] 1.264–4.145, p = 0.019; HFrEF vs. HFrecEF: HR = 2.222, 95% CI 1.189–4.186, p < 0.001) and hospitalization rate (HFpEF vs. HFrecEF: HR = 1.411, 95% CI 1.046–1.903, p = 0.024; HFrEF vs. HFrecEF: HR = 1.388, 95% CI 1.002–1.924, p = 0.049). The following are predictors of LVEF recovery: younger age, lower functional class, treatment with renin–angiotensin–aldosterone system inhibitors and beta-blockers, absence of defibrillator use, and non-ischemic etiology. Conclusions: Patients with HF and reduced LVEF who were re-evaluated after 1 year, had significant improvement in their LVEF and had a more favourable prognosis than HF with preserved and reduced ejection fraction