Resultados preliminares en la formación de docentes y alumnos como investigadores científicos iniciales

Junto con el inicio de la pandemia por COVID-19, que tantos cambios ocasionó en la actividad cotidiana y profesional de las personas, se inició el proyecto titulado ‘Formación de docentes y alumnos de grado como Investigadores Científicos Iniciales en las áreas de Informática y Ciencias de la Computación’, en el cual se buscó organizar y fortalecer el proceso de formación de investigadores en el Departamento de Ingeniería de Sistemas de Información de la UTN-Facultad Regional Mendoza, incluyendo a alumnos y docentes. En rigor, los responsables del mismo hemos venido realizando dicha tarea desde el año 2008, aunque sin el marco y formalidad de un proyecto marco específico. En este artículo se comenta la razón del mismo y los resultados preliminares obtenidos tras la experiencia de este trabajo que concluirá a fines del actual ciclo 2022. Obviamente, las observaciones y conclusiones no pueden dejar de considerar la situación excepcional experimentada en el ámbito académico en relación al aislamiento y distanciamiento por COVID-19, y al impacto que las restricciones impuestas tuvieron en el desarrollo de los proyectos y las diversas actividades de investigación, también indirectamente afectadas por los cambios en la docencia.Red de Universidades con Carreras en Informátic

Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription

In leiomyosarcoma class IIa HDACs (histone deacetylases) bind MEF2 and convert these transcription factors into repressors to sustain proliferation. Disruption of this complex with small molecules should antagonize cancer growth. NKL54, a PAOA (pimeloylanilide o-aminoanilide) derivative, binds a hydrophobic groove of MEF2, which is used as a docking site by class IIa HDACs. However, NKL54 could also act as HDAC inhibitor (HDACI). Therefore, it is unclear which activity is predominant. Here, we show that NKL54 and similar derivatives are unable to release MEF2 from binding to class IIa HDACs. Comparative transcriptomic analysis classifies these molecules as HDACIs strongly related to SAHA/vorinostat. Low expressed genes are upregulated by HDACIs, while abundant genes are repressed. This transcriptional resetting correlates with a reorganization of H3K27 acetylation around the transcription start site (TSS). Among the upregulated genes there are several BH3-only family members, thus explaining the induction of apoptosis. Moreover, NKL54 triggers the upregulation of MEF2 and the downregulation of class IIa HDACs. NKL54 also increases the binding of MEF2D to promoters of genes that are upregulated after treatment. In summary, although NKL54 cannot outcompete MEF2 from binding to class IIa HDACs, it supports MEF2-dependent transcription through several actions, including potentiation of chromatin binding

Three-dimensional analysis of the Plio-Pleistocene seismic sequences in the Venice Lagoon (Italy)

Integrated seismic and well data provide for the first time a picture of the geological evolution of the Venice area over the last 5 Ma and a 3D subsoil model, which is fundamental to prediction of the anthropogenic uplift of Venice by seawater injection. A Pliocene southward prograding complex formed a shelf–slope system, whereas subsidence related to the Apennine foredeep development led to the establishment of a Early Pleistocene deep-water environment, favouring the accumulation of a thick turbidite succession. The NE progradation of the palaeo-Po river delta during the Middle Pleistocene promoted a drastic environmental revolution, followed by the deposition of cyclothems linked to glacio-eustatic changes

Folding of Class IIa HDAC Derived Peptides into α-helices Upon Binding to Myocyte Enhancer Factor-2 in Complex with DNA

Interaction of transcription factor myocyte enhancer factor-2 (MEF2) family members with class IIa histone deacetylases (HDACs) has been implicated in a wide variety of diseases. Though considerable knowledge on this topic has been accumulated over the years, a high resolution and detailed analysis of the binding mode of multiple class IIa HDAC derived peptides with MEF2D is still lacking. To fulfil this gap, we report here the crystal structure of MEF2D in complex with double strand DNA and four different class IIa HDAC derived peptides, namely HDAC4, HDAC5, HDAC7 and HDAC9. All class IIa HDAC derived peptides form extended amphipathic α-helix structures that fit snugly in the hydrophobic groove of MEF2D domain. Binding mode of class IIa HDAC derived peptides to MEF2D is very similar and occur primarily through nonpolar interactions mediated by highly conserved branched hydrophobic amino acids. Further studies revealed that class IIa HDAC derived peptides are unstructured in solution and appear to adopt a folded α-helix structure only upon binding to MEF2D. Comparison of our peptide-protein complexes with previously characterized structures of MEF2 bound to different co-activators and co-repressors, highlighted both differences and similarities, and revealed the adaptability of MEF2 in protein–protein interactions. The elucidation of the three-dimensional structure of MEF2D in complex with multiple class IIa HDAC derived peptides provide not only a better understanding of the molecular basis of their interactions but also have implications for the development of novel antagonist

Self-Organization, Optical, and Electrical Properties of -Quinquethiophene-Dinucleotide Conjugates

The synthesis and properties of (5')TA(3')-t5 (8a) and (5')CG(3')-t5 (8b) conjugates, in which the self-complementary dinucleotides TA and CG are covalently bound to the central ring of alpha-quinquethiophene (t5), are described. According to molecular mechanics calculations, the preferred conformation of both 8 a and 8b is that with the dinucleotide folded over the planar t5 backbone, with the nucleobases facing t5 at stacking distance. The calculations show that the aggregation process of 8 a and 8b is driven by a mix of nucleobase-thiophene interactions, hydrogen bonding between nucleobases (non Watson-Crick (W&C) in TA, and W&C in CG), van der Waals, and electrostatic interactions. While 8b is scarcely soluble in any solvents, 8a is soluble in water, indicating that the aggregates of the former are more stable than those of the latter. Microfluidic-induced self-assembly studies of 8a showed the formation of lamellar, spherulitic, and dendritic supramolecular structures, depending on the concentration and solvent evaporation time. The self-assembled structures displayed micrometer dimensions in the. v plane of the substrate and nanometer dimensions in the z direction. Spatially resolved confocal microscopy and spectroscopy showed that the aggregates were characterized by intense fluorescence emission. Cast films of 8a from water solutions showed chirality transfer from the dinucleotide to t5. The hole mobility of the cast films of 8a was estimated using a two-electrode device under high vacuum and found to be up to two orders of magnitude greater than those previously measured for dinucleotide-quarterthiophene conjugates under the same experimental conditions

Three-dimensional analysis of the Plio-Pleistocene seismic sequences in the Venice Lagoon (Italy)

<p>Integrated seismic and well data provide for the first time a picture of the geological evolution of the Venice area over the last 5 Ma and a 3D subsoil model, which is fundamental to prediction of the anthropogenic uplift of Venice by seawater injection. A Pliocene southward prograding complex formed a shelf–slope system, whereas subsidence related to the Apennine foredeep development led to the establishment of a Early Pleistocene deep-water environment, favouring the accumulation of a thick turbidite succession. The NE progradation of the palaeo-Po river delta during the Middle Pleistocene promoted a drastic environmental revolution, followed by the deposition of cyclothems linked to glacio-eustatic changes. </p

Clinicopathological and genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy.

We report on two Italian families with an early-adult onset autosomal dominant disorder, characterized by leukoencephalopathy, migraine, psychiatric disturbances, stroke and dementia. These findings fulfill the diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. Moreover, to confirm the CADASIL gene location to 19p12, we performed a linkage analysis with four microsatellite markers. The results of the genetic study gave positive but not significant lod scores, indicating only weak evidence of a linkage with 19p12. In one autopsy case, we found extensive ischemic changes due to the selective involvement of the small muscular arteries of the cerebral white matter. The lesions consisted of a thickening of the media with deposition of granular eosinophilic material. Ultrastructural examination of the arterial walls showed graded damage to smooth muscle cells, mostly of the longitudinal layer, and an abnormal proliferation of basal lamina components. Immunocytochemical analysis showed strong reactivity using antibodies to collagen IV and smooth myosin proteins. The results suggest a primary involvement of the smooth muscle cells of small cerebral arteries, with a secondary alteration of basal lamina components and elastic tissue

Marco para desarrollar nuevas unidades de proyectos e incorporar docentes y alumnos en actividades de investigación

El presente proyecto, que es la continuación de una primera experiencia realizada desde el 2020 al 2022, propone la formación de investigadores como objetivo primordial y a la vez define un marco globalizador que permita la coexistencia de diversas unidades de proyectos que de otra manera no tendrían la posibilidad de llegar a la instancia de conformar un proyecto independiente. Dicho Marco constituirá un espacio de promoción de ideas e iniciativas para la iniciación en la investigación, tanto para estudiantes de grado como para docentes. Ofrece la posibilidad de realizar prácticas de investigación específicas como un primer peldaño que permita acceder a distintos elementos (categorización, recursos económicos, acompañamiento de los directores del proyecto y miembros con más experiencia, posibilidad de obtención de becas y, fundamentalmente, un contexto que guíe y enmarque la experiencia para favorecer su concreción). Es importante remarcar que normalmente no todo docente (menos aún los estudiantes) logra involucrarse y participar formalmente dentro de un proyecto de investigación dado que los requisitos para la conformación de grupos, la solicitud de financiamiento, y/o su incorporación a actividades de investigación suelen convertirse en un obstáculo. Por ende, permitir la incorporación de los mismos, guiar su trayecto formativo y posibilitar los medios económicos mínimos para desarrollar y dar a conocer sus propuestas, es el objetivo final del presente proyecto.Red de Universidades con Carreras en Informátic

Cytoplasmic HDAC4 regulates the membrane repair mechanism in Duchenne muscular dystrophy

Abstract Background Histone deacetylase 4 (HDAC4) is a stress‐responsive factor that mediates multiple cellular responses. As a member of class IIa HDACs, HDAC4 shuttles between the nucleus and the cytoplasm; however, HDAC4 cytoplasmic functions have never been fully investigated. Duchenne muscular dystrophy (DMD) is a genetic, progressive, incurable disorder, characterized by muscle wasting, which can be treated with the unspecific inhibition of HDACs, despite this approach being only partially effective. More efficient strategies may be proposed for DMD only after the different HDAC members will be characterized. Methods To fully understand HDAC4 functions, we generated dystrophic mice carrying a skeletal muscle‐specific deletion of HDAC4 (mdx;KO mice). The progression of muscular dystrophy was characterized in mdx and age‐matched mdx;KO mice by means of histological, molecular, and functional analyses. Satellite cells (SCs) from these mice were differentiated in vitro, to identify HDAC4 intrinsic functions influencing the myogenic potential of dystrophic SCs. Gain‐of‐function experiments revealed the cytoplasmic functions of HDAC4 in mdx;KO muscles. Results Histone deacetylase 4 increased in the skeletal muscles of mdx mice (~3‐fold; P < 0.05) and of DMD patients (n = 3, males, mean age 13.3 ± 1.5 years), suggesting that HDAC4 has a role in DMD. Its deletion in skeletal muscles importantly worsens the pathological features of DMD, leading to greater muscle fragility and degeneration over time. Additionally, it impairs SC survival, myogenic potential, and muscle regeneration, ultimately compromising muscle function (P < 0.05–0.001). The impaired membrane repair mechanism in muscles and SCs accounts for the mdx;KO phenotype. Indeed, the ectopic expression of Trim72, a major player in the membrane repair mechanism, prevents SC death (~20%; P < 0.01) and increases myogenic fusion (~40%; P < 0.01) in vitro; in vivo it significantly reduces myofibre damage (~10%; P < 0.005) and improves mdx;KO muscle function (P < 0.05). The mdx;KO phenotype is also fully rescued by restoring cytoplasmic levels of HDAC4, both in vitro and in vivo. The protective role of HDAC4 in the cytoplasm of mdx;KO muscles is, in part, independent of its deacetylase activity. HDAC4 expression correlates with Trim72 mRNA levels; furthermore, Trim72 mRNA decays more rapidly (P < 0.01) in mdx;KO muscle cells, compared with mdx ones. Conclusions Histone deacetylase 4 performs crucial functions in the cytoplasm of dystrophic muscles, by mediating the muscle repair response to damage, an important role in ensuring muscle homeostasis, probably by stabilizing Trim72 mRNA. Consequently, the cytoplasmic functions of HDAC4 should be stimulated rather than inhibited in muscular dystrophy treatments, a fact to be considered in future therapeutic approaches