Propuesta didáctica para el desarrollo de las competencias comunicativas de los estudiantes de cuarto grado de educación primaria de una institución educativa pública de Santa Rosa, Atalaya, Ucayali

El presente trabajo de suficiencia profesional, ostenta un diseño de una propuesta didáctica para el desarrollo de las competencias comunicativas en los estudiantes de cuarto grado de educación primaria de una institución educativa pública en Atalaya – Ucayali, con el objetivo de mejorar los aprendizajes de las competencias comunicativas y todo está fundamentado en el Paradigma Sociocognitivo Humanista de: Jean Piaget, David Ausubel y Jerome Bruner (cognitivo), Lev Vygotsky y Reaven Feuerstein (social y cultural), Robert Sternberg, Martiniano Román y Eloísa Diez (Teoría de la Inteligencia) que dirigen a la comprensión y a la transformación del conocimiento en la enseñanza aprendizaje en cuanto al entorno educativo y a la práctica docente. Este trabajo de suficiencia está dividido en tres capítulos, en el primer capítulo presenta el diagnóstico de la institución educativa, los objetivos generales y específicos y la justificación; en el segundo capítulo se encuentran las teorías desarrolladas por los distintos autores que fundamentan el aspecto cognitivo, sociocultural y contextual que aportan a la acción pedagógica; y el tercer capítulo consta de la programación curricular; a través de esta propuesta, el estudiante logrará una vinculación con competencias, capacidades, destrezas y métodos; donde no solo va adquirir conocimientos, sino también aprenderá valores para que pueda socializar en este tiempo tan difícil que estamos viviendo.The present work of professional sufficiency, shows a design of a didactic proposal for the development of communicative competences in students of fourth grade of primary education of a public educational institution in Atalaya - Ucayali, with the aim of improving the learning of competences communicative and everything is based on the Humanist Sociocognitive Paradigm of: Jean Piaget, David Ausubel and Jerome Bruner (cognitive), Lev Vygotsky and Reaven Feuerstein (social and cultural), Robert Sternberg, Martiniano Román and Eloísa Diez (Intelligence Theory) that They lead to the understanding and transformation of knowledge in teaching-learning in terms of the educational environment and teaching practice. This sufficiency work is divided into three chapters, in the first chapter it presents the diagnosis of the educational institution, the general and specific objectives and the justification; in the second chapter are the theories developed by the different authors that support the cognitive, sociocultural and contextual aspect that they contribute to pedagogical action; and the third chapter consists of the curricular programming; Through this proposal, the student will achieve a link with competences, capacities, skills and methods; where you will not only acquire knowledge, but also learn values so that you can socialize in this difficult time that we are living

The Government-led initiative for liquified petroleum gas (LPG) scale-up in Cameroon: programme development and initial evaluation

In 2016, the government of Cameroon, a central African country heavily reliant on wood fuel for cooking, published a Masterplan for increasing primary use of LPG from 20% to 58% of households by 2035. Developed via a multi-sectoral committee with support from the Global LPG Partnership, the plan envisages a 400 million Euro investment program to 2030, focused on increasing LPG cylinder numbers, key infrastructure, and enhanced regulation. This case study describes the Masterplan process and investment proposals and draws on community studies and stakeholder interviews to identify factors likely to impact on the planned expansion of LPG use

Quiver Bundles and Wall Crossing for Chains

Holomorphic chains on a Riemann surface arise naturally as fixed points of the natural C*-action on the moduli space of Higgs bundles. In this paper we associate a new quiver bundle to the Hom-complex of two chains, and prove that stability of the chains implies stability of this new quiver bundle. Our approach uses the Hitchin-Kobayashi correspondence for quiver bundles. Moreover, we use our result to give a new proof of a key lemma on chains (due to \'Alvarez-C\'onsul, Garc\'ia-Prada and Schmitt), which has been important in the study of Higgs bundle moduli; this proof relies on stability and thus avoids the direct use of the chain vortex equations

Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

Funder: Alzheimer’s Research UK; doi: http://dx.doi.org/10.13039/501100002283Abstract: Despite the wealth of genomic and transcriptomic data in Parkinson’s disease (PD), the initial molecular events are unknown. Using LD score regression analysis, we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiological concentrations of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory response with time, including TNF-α production. ROS and cell death in primary neuronal cultures were significantly reduced by TLR4 antagonists revealing that an indirect inflammatory mechanism involving cytokines produced by glial cells makes a major contribution to neuronal death. Prolonged exposure to low levels of alpha-synuclein oligomers sensitizes TLR4 responsiveness in astrocytes and microglial, explaining how they become pro-inflammatory, and may be an early causative event in PD

Prediction of mechanistic subtypes of Parkinson’s using patient-derived stem cell models

Parkinson’s disease is a common, incurable neurodegenerative disorder that is clinically heterogeneous: it is likely that different cellular mechanisms drive the pathology in different individuals. So far it has not been possible to define the cellular mechanism underlying the neurodegenerative disease in life. We generated a machine learning-based model that can simultaneously predict the presence of disease and its primary mechanistic subtype in human neurons. We used stem cell technology to derive control or patient-derived neurons, and generated different disease subtypes through chemical induction or the presence of mutation. Multidimensional fluorescent labelling of organelles was performed in healthy control neurons and in four different disease subtypes, and both the quantitative single-cell fluorescence features and the images were used to independently train a series of classifiers to build deep neural networks. Quantitative cellular profile-based classifiers achieve an accuracy of 82%, whereas image-based deep neural networks predict control and four distinct disease subtypes with an accuracy of 95%. The machine learning-trained classifiers achieve their accuracy across all subtypes, using the organellar features of the mitochondria with the additional contribution of the lysosomes, confirming the biological importance of these pathways in Parkinson’s. Altogether, we show that machine learning approaches applied to patient-derived cells are highly accurate at predicting disease subtypes, providing proof of concept that this approach may enable mechanistic stratification and precision medicine approaches in the future

Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading.

The protein alpha-synuclein (αS) self-assembles into small oligomeric species and subsequently into amyloid fibrils that accumulate and proliferate during the development of Parkinson's disease. However, the quantitative characterization of the aggregation and spreading of αS remains challenging to achieve. Previously, we identified a conformational conversion step leading from the initially formed oligomers to more compact oligomers preceding fibril formation. Here, by a combination of single-molecule fluorescence measurements and kinetic analysis, we find that the reaction in solution involves two unimolecular structural conversion steps, from the disordered to more compact oligomers and then to fibrils, which can elongate by further monomer addition. We have obtained individual rate constants for these key microscopic steps by applying a global kinetic analysis to both the decrease in the concentration of monomeric protein molecules and the increase in oligomer concentrations over a 0.5-140-µM range of αS. The resulting explicit kinetic model of αS aggregation has been used to quantitatively explore seeding the reaction by either the compact oligomers or fibrils. Our predictions reveal that, although fibrils are more effective at seeding than oligomers, very high numbers of seeds of either type, of the order of 10(4), are required to achieve efficient seeding and bypass the slow generation of aggregates through primary nucleation. Complementary cellular experiments demonstrated that two orders of magnitude lower numbers of oligomers were sufficient to generate high levels of reactive oxygen species, suggesting that effective templated seeding is likely to require both the presence of template aggregates and conditions of cellular stress.We thank Dr. Nadia Shivji and Beata Blaszczyk for ɑS protein expression, Dr. Peter Jönsson for help with preliminary TIRFM imaging experiments, Chris Taylor for help with preliminary autodilution experiments and Prof. Michel Goedert for critical reading of the manuscript. M.I. is funded by Dr. Tayyeb-Hussain Scholarship. G.A.G. is funded by the Schiff Foundation . S.G. is funded through a Wellcome Trust Intermediate Clinical Fellowship. Funding from the Frances and Augustus Newman Foundation, the European Research Council and the Biothechnology and Biophysical Sciences Research Council is gratefully acknowledged.This is the author accepted manuscript. The final version is available from the National Academy of Sciences via http://dx.doi.org/10.1073/pnas.152412811

Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein

The protein alpha-synuclein (αS) self-assembles into toxic beta-sheet aggregates in Parkinson’s disease, while it is proposed that αS forms soluble alpha-helical multimers in healthy neurons. Here, we have made αS multimers in vitro using arachidonic acid (ARA), one of the most abundant fatty acids in the brain, and characterized them by a combination of bulk experiments and single-molecule Fӧrster resonance energy transfer (sm-FRET) measurements. The data suggest that ARA-induced oligomers are alpha-helical, resistant to fibril formation, more prone to disaggregation, enzymatic digestion and degradation by the 26S proteasome, and lead to lower neuronal damage and reduced activation of microglia compared to the oligomers formed in the absence of ARA. These multimers can be formed at physiologically-relevant concentrations, and pathological mutants of αS form less multimers than wild-type αS. Our work provides strong biophysical evidence for the formation of alpha-helical multimers of αS in the presence of a biologically relevant fatty acid, which may have a protective role with respect to the generation of beta-sheet toxic structures during αS fibrillation.M.I. acknowledges Dr. Tayyeb-Hussain Scholarship. L.T. has been recipient of a grant PAT Post Doc Outgoing 2009 7th Framework Program Marie Curie COFUND actions. C.D.H. and C.E.B. acknowledge funding from Alzheimer’s Research UK. Augustus Newman Foundation is acknowledged

Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

Funder: Alzheimer's Research UK (ARUK); doi: https://doi.org/10.13039/501100002283Abstract: The molecular events causing memory loss and neuronal cell death in Alzheimer’s disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD

α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease.

Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease