Letras en territorio o territorios de letras : experiencias de formación en territorio en el Profesorado Universitario en Letras

En 2015 se inicia el dictado de las cátedras Taller de la Práctica Docente I y II en el Profesorado Universitario en Letras de la FCH UNSL. Los contenidos mínimos planteados en el plan de estudio requerían una formación de grado en territorios tanto en espacios formales como no formales. En aquellos años, como docentes de ambos espacios curriculares, pensamos y llevamos a cabo propuestas de formación donde lxs estudiantes pudieran desarrollar prácticas educativas y prácticas docentes en territorios. Nos propusimos como punto de partida contemplar las necesidades y demandas de la comunidad, y que estas se articularan con las necesidades de formación de la carrera de grado. Para lograr este cometido decidimos como equipo de cátedra formar parte como materia asociada del Centro de Prácticas Pedagógicas y Sociocomunitarias de la FCH de la UNSL, que establece un trabajo mancomunado con las organizaciones sociales y escuelas de sectores populares de la ciudad de San Luis. En este trabajo queremos compartir, en primer lugar, los posicionamientos de nuestra propuesta que se asienta en el modelo de aprendizaje en movimiento y se sostiene en los principios de: diálogo de saberes, construcción colectiva de conocimiento, organización popular, resistencia y pensamiento crítico. En segundo lugar, compartiremos las interpelaciones, las enseñanzas y los aprendizajes de los diferentes actores de esta propuesta (comunidad, estudiantes, docentes y universidad) en los que fuimos inventando, entre la comunidad y la universidad, nombres, espacios y tareas tanto para las actividades que lxs referentes de la comunidad realizan en la academia como de aquellas que realizan los equipos docentes y estudiantes en la comunidad. Por último, presentaremos los viejos y nuevos interrogantes que la academia y la comunidad nos planteamos cuando el trabajo conjunto, desde el aprendizaje en movimiento, comienza a transitar el camino desde el discurso a la práctica efectiva.Fil: Figueroa, Paola Susana. Universidad Nacional de San Luis.Fil: Cichero, Anuar David. Universidad Nacional de San Luis

Exhaustive CoMFA and CoMSIA analyses around different chemical entities: a ligand-based study exploring the affinity and selectivity profiles of 5-HT1A ligands

The 5-hydroxytryptamine (5-HT1A) receptors represent an attractive target in drug discovery. In particular, 5-HT1A agonists and partial agonists are deeply investigated for their potential role in the treatment of anxiety, depression, ischaemic brain disorder and more recently, of pain. On the other hand, 5-HT1A antagonists have been revealed promising compounds in cognition disorders and, lately, in cancer. Thus, the discovery of 5HT1A ligands is nowadays an appealing research activity in medicinal chemistry. In this work, Comparative Molecular Fields Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied on an in-house library of 5-HT1A ligands bearing different chemical scaffolds in order to elucidate their affinity and selectivity for the target. Following this procedure, a number of structural modifications have been drawn for the development of much more effective 5-HT1AR ligands

Benzimidazole-based derivatives as privileged scaffold developed for the treatment of the RSV infection: a computational study exploring the potency and cytotoxicity profiles

Respiratory syncytial virus (RSV) has been identified as a main cause of hospitalisation in infants and children. To date, the current therapeutic arsenal is limited to ribavirin and palivizumab with variable efficacy. In this work, starting from a number of in-house series of previously described anti-RSV agents based on the benzimidazole scaffold, with the aim at gaining a better understanding of the related chemical features involved in potency and safety profiles, we applied a computational study including two focussed comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results allowed us to derive useful suggestions for the design of derivatives and also to set up statistical models predicting the potency and selectivity index (SI1/4CC50/EC50) of any new analogue prior to synthesis. Accordingly, here, we discuss preliminary results obtained through the applied exhaustive QSAR analyses, leading to design and synthesise more effective anti-RSV agents

Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1

open15siGenetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion-like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome-maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS.openCapponi, Simona; Geuens, Thomas; Geroldi, Alessandro; Origone, Paola; Verdiani, Simonetta; Cichero, Elena; Adriaenssens, Elias; De Winter, Vicky; Bandettini di Poggio, Monica; Barberis, Marco; Chiò, Adriano; Fossa, Paola; Mandich, Paola; Bellone, Emilia; Timmerman, VincentCapponi, Simona; Geuens, Thomas; Geroldi, Alessandro; Origone, Paola; Verdiani, Simonetta; Cichero, Elena; Adriaenssens, Elias; De Winter, Vicky; BANDETTINI DI POGGIO, MONICA LAURA; Barberis, Marco; Chiò, Adriano; Fossa, Paola; Mandich, Paola; Bellone, Emilia; Timmerman, Vincen

Fluorometric detection of protein-ligand engagement: The case of phosphodiesterase5

Phosphodiesterases (PDEs) regulate the intracellular levels of cAMP and cGMP. The great clinical success of the PDE5 inhibitors, Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) has led to an increasing interest for this class of enzymes. Recent studies have shown a correlation between tumor growth and PDE5 overexpression, making PDE5-selective inhibitors promising candidates for cancer treatment. The search for such inhibitors rests today on radioactive assays. In this work, we exploit the conserved catalytic domain of the enzyme and propose a faster and safer method for detecting the binding of ligands and evaluate their affinities. The new approach takes advantage of Förster Resonance Energy Transfer (FRET) between, as the donor, a fluorescein-like diarsenical probe able to covalently bind a tetracysteine motif fused to the recombinant PDE5 catalytic domain and, as the acceptor, a rhodamine probe covalently bound to the pseudosubstrate cGMPS. The FRET efficiency decreases when a competitive ligand binds the PDE5 catalytic site and displaces the cGMPS-rhodamine conjugate. We have structurally investigated the PDE5/cGMPS-rhodamine complex by molecular modelling and have used the FRET signal to quantitatively characterize its binding equilibrium. Competitive displacement experiments were carried out with tadalafil and cGMPS. An adaptation of the competitive-displacement equilibrium model yielded the affinities for PDE5 of the incoming ligands, nano- and micromolar, respectively

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking diculties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family

Identification of a high affinity binding site for abscisic acid on human lanthionine synthetase component C-like protein 2

Lanthionine synthetase component C-like protein 2 (LANCL2) has been identified as the mammalian receptor mediating the functional effects of the universal stress hormone abscisic acid (ABA) in mammals. ABA stimulates insulin independent glucose uptake in myocytes and adipocytes via LANCL2 binding in vitro, improves glucose tolerance in vivo and induces brown fat activity in vitro and in vivo. The emerging role of the ABA/LANCL2 system in glucose and lipid metabolism makes it an attractive target for pharmacological interventions in diabetes mellitus and the metabolic syndrome. The aim of this study was to investigate the presence of ABA binding site(s) on LANCL2 and identify the amino acid residues involved in ABA binding. Equilibrium binding assays ([3H]-ABA saturation binding and surface plasmon resonance analysis) suggested multiple ABA-binding sites, prompting us to perform a computational study that indicated one putative high-affinity and two low-affinity binding sites. Site-directed mutagenesis (single mutant R118I, triple mutants R118I/R22I/K362I and R118I/S41A/E46I) and equilibrium binding experiments on the mutated LANCL2 proteins identified a high-affinity ABA-binding site involving R118, with a KD of 2.6 nM ± 1.2 nM, as determined by surface plasmon resonance. Scatchard plot analysis of binding curves from both types of equilibrium binding assays revealed a Hill coefficient >1, suggesting cooperativity of ABA binding to LANCL2. Identification of the high-affinity ABA-binding site is expected to allow the design of ABA agonists/antagonists, which will help to understand the role of the ABA/LANCL2 system in human physiology and disease

Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study

The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work we describe design, the synthesis and SAR study of a new series of compounds (1-16) obtained by introducing specific structural changes at key points of our lead-compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogs, namely 1 and 2, showed potent functional activity in in vitro and in vivo models

Anales del III Congreso Internacional de Vivienda y Ciudad "Debate en torno a la nueva agenda urbana"

Acta de congresoEl III Congreso Internacional de Vivienda y Ciudad “Debates en torno a la NUEVa Agenda Urbana”, ha sido una apuesta de alto compromiso por acercar los debates centrales y urgentes que tensionan el pleno ejercicio del derecho a la ciudad. Para ello las instituciones organizadoras (INVIHAB –Instituto de Investigación de Vivienda y Hábitat y MGyDH-Maestría en Gestión y Desarrollo Habitacional-1), hemos convidado un espacio que se concretó con potencia en un debate transdisciplinario. Convocó a intelectuales de prestigio internacional, investigadores, académicos y gestores estatales, y en una metodología de innovación articuló las voces académicas con las de las organizaciones sociales y/o barriales en el Foro de las Organizaciones Sociales que tuvo su espacio propio para dar voz a quienes están trabajando en los desafíos para garantizar los derechos a la vivienda y los bienes urbanos en nuestras ciudades del Siglo XXI

In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies

Small heat-shock proteins, possessing chaperone-like activity, represented crucial proteins actively involved in maintain protein homeostasis, which act to prevent improper polypeptide aggregation and deposition of misfolded proteins. In this context, a number of mutations concerning the HspB1 protein proved to be associated with the development of several neuropathologies. Unfortunately, molecular mechanisms underlying the onset of these diseases and in particular the changes induced by the mutations in HspB1 structure, remain poorly characterized. On the other hand, more recent studies demonstrated that HspB1 overexpression leads to an overactive chaperone activity, which in turn contributes to the anticancer agent resistance. On these basis, Hsp27 could represent a good innovative target for development of novel cancer therapy. Therefore, in this work a computational study, based on the homology model of the complete Hsp27 protein and of several pathological mutant forms, was developed. Finally, the derived model was employed to perform, for the first time, docking simulations on a recently identified Hsp27 inhibitor, disclosing a new useful panorama to be exploited for the further development of new compounds