Dyrk1A Influences Neuronal Morphogenesis Through Regulation of Cytoskeletal Dynamics in Mammalian Cortical Neurons

Down syndrome (DS) is the most frequent genetic cause of mental retardation. Cognitive dysfunction in these patients is correlated with reduced dendritic branching and complexity, along with fewer spines of abnormal shape that characterize the cortical neuronal profile of DS. DS phenotypes are caused by the disruptive effect of specific trisomic genes. Here, we report that overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A, DYRK1A, is sufficient to produce the dendritic alterations observed in DS patients. Engineered changes in Dyrk1A gene dosage in vivo strongly alter the postnatal dendritic arborization processes with a similar progression than in humans. In cultured mammalian cortical neurons, we determined a reduction of neurite outgrowth and synaptogenesis. The mechanism underlying neurite dysgenesia involves changes in the dynamic reorganization of the cytoskeleton

Metabolic Imbalance Effect on Retinal Müller Glial Cells Reprogramming Capacity: Involvement of Histone Deacetylase SIRT6

Retinal Müller glial cells (MGs) are among the first to demonstrate metabolic changes during retinal disease and are a potential source of regenerative cells. In response to a harmful stimulus, they can dedifferentiate acquiring neural stem cells properties, proliferate and migrate to the damaged retinal layer and differentiate into lost neurons. However, it is not yet known how this reprogramming process is regulated in mammals. Since glucose and oxygen are important regulatory elements that may help directing stem cell fate, we aimed to study the effect of glucose variations and oxidative stress in Müller cells reprogramming capacity and analyze the participation the histone deacetylase SIRT6, as an epigenetic modulator of this process. We found that the combination of high glucose and oxidative stress induced a decrease in the levels of the marker glutamine synthetase, and an increase in the migration capacity of the cells suggesting that these experimental conditions could induce some degree of dedifferentiation and favor the migration ability. High glucose induced an increase in the levels of the pluripotent factor SOX9 and a decrease in SIRT6 levels accompanied by the increase in the acetylation levels of H3K9. Inhibiting SIRT6 expression by siRNA rendered an increase in SOX9 levels. We also determined SOX9 levels in retinas from mice with a conditional deletion of SIRT6 in the CNS. To further understand the mechanisms that regulate MGs response under metabolic impaired conditions, we evaluated the gene expression profile and performed Gene Ontology enrichment analysis of Müller cells from a murine model of Diabetes. We found several differentially expressed genes and observed that the transcriptomic change involved the enrichment of genes associated with glucose metabolism, cell migration, development and pluripotency. We found that many functional categories affected in cells of diabetic animals were directly related to SIRT6 function. Transcription factors enrichment analysis allowed us to predict several factors, including SOX9, that may be involved in the modulation of the differential expression program observed in diabetic MGs. Our results underline the heterogeneity of Müller cells response and the challenge that the study of metabolic impairment in vivo represents.Fil: Sanhueza Salas, L. Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: García Venzor, Alfredo. Ben Gurion University of the Negev; IsraelFil: Beltramone, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Capurro, Claudia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Toiber, Debra. Ben Gurion University of the Negev; IsraelFil: Silberman, Dafne Magalí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

The histone deacetylase SIRT6, a critical modulator of metabolism and tumorigenesis

Efficient glucose metabolism is critical for maintaining cel-lular viability. Under normal nutrient and oxygen condi-tions, glucose is converted to pyruvate, entering the mitochondria for oxidative phosphorylation and ATP pro-duction. Under hypoxia or nutrient stress, metabolism is switched to glycolysis, increasing lactate production and reducing mitochondrial respiration, a switch known to play an important role in cancer cells, as defined by Otto Warburg decades ago. Little is known whether chromatin plays a role in carbohydrate flux. The yeast Sir2 protein is an NAD-dependent histone deacetylase that senses the metabolic status of the cell and functions as a chromatin silencer to promote lifespan and genomic stability. Recently, we discovered that the mammalian SIRT6 is a chromatin factor that influences glucose metabolism an

Paternidad en adolescentes en conflicto con la ley: Historias de vida

The main aim of this article is to understand how adolescents in conflict with the law construct their ideas around fatherhood. To explore this issue, an exploratory and qualitative study was carried out. Life stories were constructed through in-depth interviews. The sample consisted of 3 adolescents in conflict with the law. Through the interpretative content analysis, we obtained the following categories: 1) family of origin experiences, 2) risk and criminal conduct, 3) trajectory of fatherhood: pregnancy and child`s birth, 4) intergenerational transmission of violence, and 5) reconstituted families. Participants' discourses included a trajectory of their own experiences as children and the decision to prevent the intergenerational transmission of violence and emotional deprivation. Within the reconstituted families that these adolescents established, their main parental role was to replace the biological father. This role can promote rigid beliefs and patterns of interaction with the intention of conceiving themselves as a nuclear family without considering previous family history. This research is a contribution to the study of fatherhood, not only biological but also acquired. It will also contribute to the field of psychotherapeutic treatment for adolescent parents in conflict with the law, who are in the process of social reintegration.El propósito de este artículo es analizar la construcción de la paternidad de adolescentes en conflicto con la ley. Por lo anterior, se realizó un estudio exploratorio y cualitativo; se construyeron historias de vida a través de la técnica de entrevista a profundidad. La muestra se conformó por 3 adolescentes en conflicto con la ley. Con la información obtenida se llevó a cabo un análisis de contenido interpretativo mediante el cual se obtuvieron 5 categorías: 1) experiencias en la familia de origen; 2) conductas de riesgo y delictivas; 3) curso de la paternidad: embarazo y nacimiento de su hijo; 4) transmisión intergeneracional de la violencia; y 5) familia reconstituida. En los discursos de los participantes se reconoce un transitar entre sus propias experiencias como hijos y la decisión de interrumpir la transmisión intergeneracional de la violencia y carencia afectiva. El estudio es una contribución al análisis de la paternidad, no sólo biológica sino también adquirida, lo que implica un elemento de mayor complejidad al brindar tratamiento psicoterapéutico a los padres adolescentes en conflicto con la ley que se encuentran en proceso de reinserción social

Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity

Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations (‘‘TH– Vglut2 Class1’’) also expressed the dopamine transporter (DAT) gene while one did not ("TH–Vglut2 Class2"), and the remaining population did not express TH at all ("TH-Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 are

N-Acetylcholinesterase-Induced Apoptosis in Alzheimer's Disease

Background: Alzheimer’s disease (AD) involves loss of cholinergic neurons and Tau protein hyper-phosphorylation. Here, we report that overexpression of an N-terminally extended ‘‘synaptic’ ’ acetylcholinesterase variant, N-AChE-S is causally involved in both these phenomena. Methodology and Principal Findings: In transfected primary brain cultures, N-AChE-S induced cell death, morphological impairments and caspase 3 activation. Rapid internalization of fluorescently labeled fasciculin-2 to N-AChE-S transfected cells indicated membranal localization. In cultured cell lines, N-AChE-S transfection activated the Tau kinase GSK3, induced Tau hyper-phosphorylation and caused apoptosis. N-AChE-S-induced cell death was suppressible by inhibiting GSK3 or caspases, by enforced overexpression of the anti-apoptotic Bcl2 proteins, or by AChE inhibition or silencing. Moreover, inherent N-AChE-S was upregulated by stressors inducing protein misfolding and calcium imbalances, both characteristic of AD; and in cortical tissues from AD patients, N-AChE-S overexpression coincides with Tau hyper-phosphorylation. Conclusions: Together, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to ACh

Pro-apoptotic protein–protein interactions of the extended N-AChE terminus

The N-terminally extended “synaptic” acetylcholinesterase variant N-AChE-S operates to promote apoptosis; however, the protein partners involved in this function remain unknown. Here, we report that when microinjected to fertilized mouse oocytes, N-AChE-S caused embryonic death as early as the zygotic stage. To identify the putative protein partners involved, we first tried yeast two hybrid screening, but this approach failed, probably because of the N-AChE-S-induced lethality. In contrast, sequence analysis and a corresponding peptide array revealed possible partners, which were validated by co-immunoprecipitation. These include the kinases GSK3, Aurora and GAK, the membrane integrin receptors, and the death receptor FAS. Each of these could potentially modulate N-AChE-S-induced apoptosis with possible therapeutic value for the treatment of Alzheimer’s disease

El crédito como detonador del desarrollo en dos comunidades rurales de puebla, Mexico

Within a strategy of territorial development, credit is a very important element in productive activities, since its good use allows reducing the poverty and increasing the local competitiveness. However, the availability of resources in the credit market in México is scarce, since commercial banking and of development do not consider it to be a priority. With the objective of analyzing the access to credit as a pathway for rural development, a study in the municipalities in Domingo Arenas and San Andrés Calpan, Puebla, México, was carried out; 252 structured surveys were applied to various actors in the municipalities mentioned, recorded as results; in the case of established businesses, the main source of financing was internal and came from utilities of their own obtained through the sale of their products or from their labor. There is a generalized idea that the interests that institutions take on are quite high, and also, those who have received credit allot part of these resources to consumption expenditure, generating in some cases scarce capitalization.Keywords: territorial development, productive activities, financing

The 2021 FASEB science research conference on NAD metabolism and signaling

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