Finding the pathology of major depression through effects on gene interaction networks

The disease signature of major depressive disorder is distributed across multiple physical scales and investigative specialties, including genes, cells and brain regions. No single mechanism or pathway currently implicated in depression can reproduce its diverse clinical presentation, which compounds the difficulty in finding consistently disrupted molecular functions. We confront these key roadblocks to depression research - multi-scale and multi-factor pathology - by conducting parallel investigations at the levels of genes, neurons and brain regions, using transcriptome networks to identify collective patterns of dysfunction. Our findings highlight how the collusion of multi-system deficits can form a broad-based, yet variable pathology behind the depressed phenotype. For instance, in a variant of the classic lethality-centrality relationship, we show that in neuropsychiatric disorders including major depression, differentially expressed genes are pushed out to the periphery of gene networks. At the level of cellular function, we develop a molecular signature of depression based on cross-species analysis of human and mouse microarrays from depression-affected areas, and show that these genes form a tight module related to oligodendrocyte function and neuronal growth/structure. At the level of brain-region communication, we find a set of genes and hormones associated with the loss of feedback between the amygdala and anterior cingulate cortex, based on a novel assay of interregional expression synchronization termed "gene coordination". These results indicate that in the absence of a single pathology, depression may be created by dysynergistic effects among genes, cell-types and brain regions, in what we term the "floodgate" model of depression. Beyond our specific biological findings, these studies indicate that gene interaction networks are a coherent framework in which to understand the faint expression changes found in depression and complex neuropsychiatric disorders

Differentially Expressed Genes in Major Depression Reside on the Periphery of Resilient Gene Coexpression Networks

The structure of gene coexpression networks reflects the activation and interaction of multiple cellular systems. Since the pathology of neuropsychiatric disorders is influenced by diverse cellular systems and pathways, we investigated gene coexpression networks in major depression, and searched for putative unifying themes in network connectivity across neuropsychiatric disorders. Specifically, based on the prevalence of the lethality–centrality relationship in disease-related networks, we hypothesized that network changes between control and major depression-related networks would be centered around coexpression hubs, and secondly, that differentially expressed (DE) genes would have a characteristic position and connectivity level in those networks. Mathematically, the first hypothesis tests the relationship of differential coexpression to network connectivity, while the second “hybrid” expression-and-network hypothesis tests the relationship of differential expression to network connectivity. To answer these questions about the potential interaction of coexpression network structure with differential expression, we utilized all available human post-mortem depression-related datasets appropriate for coexpression analysis, which spanned different microarray platforms, cohorts, and brain regions. Similar studies were also performed in an animal model of depression and in schizophrenia and bipolar disorder microarray datasets. We now provide results which consistently support (1) that genes assemble into small-world and scale-free networks in control subjects, (2) that this efficient network topology is largely resilient to changes in depressed subjects, and (3) that DE genes are positioned on the periphery of coexpression networks. Similar results were observed in a mouse model of depression, and in selected bipolar- and schizophrenia-related networks. Finally, we show that baseline expression variability contributes to the propensity of genes to be network hubs and/or to be DE in disease. In summary, our results suggest that the small-world and scale-free properties of gene networks are resilient to pathological changes in major depression, and that the network structure may constrain the extent to which a gene may be DE in the illness, hence informing further gene-network-based mechanistic studies of neuropsychiatric disorders

The Interaction of Intrinsic Dynamics and Network Topology in Determining Network Burst Synchrony

The pre-Bötzinger complex (pre-BötC), within the mammalian respiratory brainstem, represents an ideal system for investigating the synchronization properties of complex neuronal circuits via the interaction of cell-type heterogeneity and network connectivity. In isolation, individual respiratory neurons from the pre-BötC may be tonically active, rhythmically bursting, or quiescent. Despite this intrinsic heterogeneity, coupled networks of pre-BötC neurons en bloc engage in synchronized bursting that can drive inspiratory motor neuron activation. The region's connection topology has been recently characterized and features dense clusters of cells with occasional connections between clusters. We investigate how the dynamics of individual neurons (quiescent/bursting/tonic) and the betweenness centrality of neurons’ positions within the network connectivity graph interact to govern network burst synchrony, by simulating heterogeneous networks of computational model pre-BötC neurons. Furthermore, we compare the prevalence and synchrony of bursting across networks constructed with a variety of connection topologies, analyzing the same collection of heterogeneous neurons in small-world, scale-free, random, and regularly structured networks. We find that several measures of network burst synchronization are determined by interactions of network topology with the intrinsic dynamics of neurons at central network positions and by the strengths of synaptic connections between neurons. Surprisingly, despite the functional role of synchronized bursting within the pre-BötC, we find that synchronized network bursting is generally weakest when we use its specific connection topology, which leads to synchrony within clusters but poor coordination across clusters. Overall, our results highlight the relevance of interactions between topology and intrinsic dynamics in shaping the activity of networks and the concerted effects of connectivity patterns and dynamic heterogeneities

Deodoro Roca en la Revista Universidad Nacional de Córdoba (1915-1920). Un análisis crítico del discurso. A cien años de la Reforma Universitaria de 1918

Trabajo Final para optar al grado académico de Licenciatura en Comunicación Social, Universidad Nacional de Córdoba (inédita). Calificación 9 (nueve)Los números de las Revistas analizadas están online en el Portal de Revistas UNC https://revistas.unc.edu.ar/index.php/REUNC/issue/archiveEl presente trabajo tiene por objetivo principal, analizar tres discursos de Deodoro Roca publicados en la Revista Universidad Nacional de Córdoba entre 1915-1920. ¿Por qué el tema y el período? Según veremos a continuación, en el año 1918, ocurrió un hecho histórico en Córdoba que hasta la actualidad, sigue influyendo en la educación universitaria argentina: la Reforma Universitaria. Este suceso fue resultado de un conjunto de circunstancias y actores que permitieron cambios no sólo en la Universidad, sino también, aspirar a una reforma social. Es una investigación que está situada desde el paradigma crítico, bajo una lógica cualitativa. Se intenta comprender la construcción discursiva-política de uno de los líderes reformistas en ese período, que es anterior y posterior a la Reforma. Para ello, se exponen dos instancias de análisis: una para el soporte gráfico, y otra para los discursos desde una mirada semiótica. Se utiliza una perspectiva teórica novedosa en el campo disciplinar de la comunicación denominada Análisis Crítico del Discurso (ACD), que permite adecuar la metodología a partir de categorías semióticas, que proporcionan una manera de abordar las publicaciones seleccionadas, entendiéndolas como producción de sentidos en un momento determinado. Dichas categorías están divididas en dos, una principal, denominada “Ideales Reformistas”, y otras seis subcategorías: acontecimientos, escenario, actores, tiempo, intención y conocimiento compartido. Es a través del análisis de las categorías discursivas y del soporte gráfico, que se explica el surgimiento de un discurso considerado aquí de resistencia frente a la hegemonía discursiva del siglo XX

Development of a Microfluidic Immunoassay for Determination of Kinase Phosphorylation

Extracellular signal-related kinases 1 and 2 (ERK1/2) are signaling proteins involved in cell survival and proliferation and are overactive/phosphorylated (forming pERK1/2) in approximately 1/3 of human cancers. Measuring pERK1/2:ERK1/2 is therefore common in cancer-related research, but conventional methods are some combination of slow, expensive, and labor-intensive, and large samples are often required. Microfluidic devices offer the possibility of determining pERK1/2:ERK1/2 rapidly, with lower costs, and with substantially reduced labor and reagent requirements compared to conventional methods. This would facilitate more expedient medical decisions and increase experimental throughput in research that requires determining pERK1/2:ERK1/2, such as that related to tumor cell signaling and anti-cancer drug development. This dissertation describes the development of a microfluidic immunoassay for determining the ratio of pERK1/2:ERK1/2 in human cell lysate. Early experiments used antibody-coated beads loaded into chips with poly(dimethylsiloxane) (PDMS) microwell arrays. The fluorophore, assay buffer, incubation protocol, and capture antibody used in all subsequent experiments were chosen here, but these experiments suffered from high (>10%) coefficients of variance. To improve the sensitivity and clinical relevance of the pERK1/2:ERK1/2 assay, the assay was systematically examined until it was determined that the process of loading beads into the PDMS arrays was mechanically damaging their capture antibodies. The next chapter introduced a new chip design for performing pERK1/2:ERK1/2 assays without harsh mechanical loading. These chips were used to optimize assay conditions and determine pERK1/2:ERK1/2 in human Jurkat cell lysate at physiologically relevant concentrations. Further improvement of the assay called for automation to minimize labor/user interaction during experiments, and this required valves to control fluid flow on-chip. The next chapter therefore focused on developing computer-controlled, Peltier-based freeze-thaw valves for microfluidic chips. In the final chapter, these valves were coupled with a chip design for assaying up to 8 samples simultaneously. These chips could be used to perform multiple replicate measurements of a sample or to produce a calibration curve on the same device used to measure samples. Finally, the 8-sample chips were used with the freeze-thaw valves to determine pERK1/2:ERK1/2 in cell lysate with automated fluid control, marking a significant advance toward the realization of automated kinase assays.Doctor of Philosoph

Políticas públicas de comunicación en Argentina: desarmando los sentidos de estudiantes y docentes de comunicación sobre la LSCA

The following paper presents the results of a research project that studies the ideas around communication as a right from students and teachers of the Communication Sciences Faculty (FCC) of the National University of Córdoba (UNC) from Argentina. This inquiry appears from the need to understand what happened to the academic community in the years in which the Audiovisual Communication Services Law (LSCA) was effectively implemented —sanctioned in 2009— with its modifications over time. This law sought to regulate and demonopolize multimedia powers and challenge the idea that information is not a commodity. In order to approach the ideas —perceptions, meanings and evaluations— of the students and teachers, two questionnaires were carried out for the students and in-depth interviews for the teachers. The results were that the students do not have a clear and precise knowledge about the Law like the teachers do, but only those who were involved in the subject and have proposed/participated in activities around the Law’s implementation. Finally, teachers and students pointed out that the enactment of the law was valuable in terms of democratic matters. However, they expressed a feeling that the Law was a dispute between the Government of Cristina Fernandez de Kirchner and the Clarín group, and it could not be carried out with a real implementation.En el siguiente trabajo de investigación se exponen los resultados de un proyecto de investigación que estudia las ideas que giran en torno a la comunicación como derecho desde estudiantes y docentes de la Facultad de Ciencias de la Comunicación (FCC) de la Universidad Nacional de Córdoba (UNC) de Argentina. Esta indagación surge por la necesidad de comprender qué pasó con la comunidad académica en los años en que se implementó efectivamente la Ley de Servicios de Comunicación Audiovisual (LSCA) —sancionada en 2009— y sus modificaciones a lo largo del tiempo. Esta ley buscaba regular y desmonopolizar los poderes multimediáticos y disputar la concepción hegemónica de que la información es una mercancía. Para poder aproximarnos a las ideas —percepciones, significaciones y valoraciones— de las y los estudiantes y docentes, se realizaron dos cuestionarios para los primeros y entrevistas en profundidad para los segundos. Los resultados fueron que los estudiantes no poseen conocimientos claros y precisos sobre la Ley y los docentes sí, pero sólo aquellos/as que estuvieron involucrados/as en la temática y han propuesto/participado en actividades en torno a la implementación o actualización de la Ley. Finalmente, tanto las y los docentes como estudiantes señalaron que es valiosa la sanción de la Ley en cuanto a avances en materia democrática. Sin embargo, manifestaron una sensación de que la Ley quedó como una disputa entre el Gobierno de Cristina Fernandez de Kirchner y el grupo Clarín, y no se pudo llevar adelante su real puesta en práctica

Repensar las prácticas de investigación en tiempos de pandemia : entre continuidades y reconfiguraciones

El presente trabajo tiene como objetivo exponer aspectos vinculados a la experiencia de transformación desarrolladas por las prácticas de investigación en un escenario inédito a escala mundial producido por la pandemia provocada por el Covid 19 durante el bienio 2020-2022. Dichas prácticas fueron llevadas a cabo como parte de un proyecto actualmente en curso denominado “Prácticas de escritura en contextos de formación docente inicial y en primeras inserciones profesionales de estudiantes/egresados de Profesorados en Comunicación Social y en Ciencias Biológicas de la UNC". Su propósito es estudiar las diversas escrituras desarrolladas por estudiantes en etapas avanzadas de la formación docente inicial de dos profesorados y, luego, como profesores en los primeros ejercicios profesionales a fin de identificar continuidades y distanciamientos. La investigación está radicada en la Facultad de Ciencias de la Comunicación (FCC) de la Universidad Nacional de Córdoba (UNC) y forma parte de un Programa de investigación que nuclea otros tres proyectos. Asimismo, se inscribe en una línea de estudio que, a lo largo de más de dos décadas, se orientó a estudiar los procesos de formación en educación superior, las prácticas letradas y su vinculación con campos profesionales. El proyecto está acreditado y financiado por la Secretaría de Ciencia y Tecnología de dicha casa de estudios en el marco del Programa de Docentes Investigadores con un interés explícito en articular la investigación con docencia y extensión. A partir de lo expuesto, en primer lugar, se describen algunas notas distintivas del estudio: su finalidad, período de ejecución, estado de avance y perfil de su equipo. En segundo término, se exponen algunas estrategias desarrolladas para dar continuidad al cronograma de actividades a través de tecnologías y plataformas incorporadas para poder desarrollar acciones al interior del equipo. En tercer término, se presentan acciones vinculadas al trabajo de campo y las reconfiguraciones que tuvo al igual que los instrumentos utilizados, soportes, lenguajes, géneros y plataformas incluidos para poder avanzar en la segunda fase del proyecto que correspondía a los años 2020/2021. En cuarto lugar, se comparten cuestiones vinculadas a la reprogramación de la agenda de presentaciones en eventos académico científicos inicialmente previstos – sobre todo los planificados para el 2020-. Estas mutaciones de las prácticas investigativas repentinas de la presencialidad hacia la virtualidad representaron no solo un desafío para el equipo, sino también, una profunda reflexión sobre ellas. Implicaron, como se señaló, una reformulación de cronogramas, formas de comunicación entre sus integrantes, reprogramar agendas, lugares y maneras de participar en eventos científicos y de comunicar resultados y de trabajo de campo que impactaron profundamente en el “hacer". Por esta razón, interesa recuperar y visibilizar estas estrategias, acciones y decisiones puestas en juego en la excepcional situación aludida en tanto constituyeron una construcción de conocimiento del equipo que interpeló, enriqueció y diversificó el repertorio de experiencias como investigadores en un entrecruzamiento que se venía gestando pero se vio inesperadamente profundizado entre la cultura académico-científica y la cultura digital.Fil: Cagnolo, Susana . Universidad Nacional de Córdoba.Fil: Gaiteri, Jorge. Universidad Nacional de Córdoba.Fil: Giménez, Laura . Universidad Nacional de Córdoba

Ricardo Rojas y Deodoro Roca. Intercambios epistolares

The objective of this article is to make known some private letters, unknown until now, exchanged between Deodoro Roca and Ricardo Rojas, while we consider the epistle as a historical source that allows us to understand ideas, recover ideological matrices of certain historical, cultural, political moments, and even aspects of the daily or private life of an important personality. The work is divided in three parts. In the first, we made a brief biographical sketch about Rojas; then, we make a historical journey through the epistolary exchanges that we have, which allowed us to reconstruct and verify the principles of a long friendship between both, concerned about their country, education and art. Finally, we analyze the decision of both to participate actively in politics, after the coup d'état of September 6, 1930, when General José Félix Uriburu overthrew the government of Hipólito Yrigoyen, although the two took different positions.El presente artículo tiene como objetivo dar a conocer algunas cartas privadas, hasta hoy desconocidas, intercambiadas entre Deodoro Roca y Ricardo Rojas, en tanto consideramos la epístola como una fuente histórica que permite comprender ideas, recuperar matrices ideológicas de determinados momentos históricos, culturales, políticos, e incluso, aspectos de la vida cotidiana o privada de una personalidad importante. El trabajo se divide en tres partes. En la primera, hicimos un breve esbozo biográfico sobre Rojas; luego, realizamos un recorrido histórico a través de los intercambios epistolares que poseemos, los que nos permitieron reconstruir y comprobar los principios de una larga amistad entre ambos, preocupados por su país, la educación y el arte. Finalmente, nos ocupamos de analizar la decisión de ambos de participar activamente en política, después del golpe de Estado del 6 de setiembre de 1930, cuando el General José Félix Uriburu derrocó al gobierno de Hipólito Yrigoyen, aunque los dos tomaron posturas diferentes

The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia

Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relationship to a wide range of clinical, molecular and neuropathological features. Because the effect size of individual variants is typically small, we utilized a polygenic (overall) risk approach to identify the global impact of Alzheimer's dementia susceptibility variants. Under this approach, each individual has a polygenic risk score (PRS) that we related to clinical, molecular and neuropathological phenotypes. Applying this approach to 1,272 individuals who came to autopsy from one of two longitudinal aging cohorts, we observed that an individual's PRS was associated with cognitive decline and brain pathologies including beta-amyloid, tau-tangles, hippocampal sclerosis, and TDP-43, MIR132, four proteins including VGF, IGFBP5, and STX1A, and many chromosomal regions decorated with acetylation on histone H3 lysine 9 (H3K9Ac). While excluding the APOE/TOMM40 region (containing the single largest genetic risk factor for late-onset Alzheimer's dementia) in the calculation of the PRS resulted in a slightly weaker association with the molecular signatures, results remained significant. These PRS-associated brain pathologies and molecular signatures appear to mediate genetic risk, as they attenuated the association of the PRS with cognitive decline. Notably, the PRS induced changes in H3K9Ac throughout the genome, implicating it in large-scale chromatin changes. Thus, the PRS for Alzheimer's dementia (AD-PRS) showed effects on diverse clinical, molecular, and pathological systems, ranging from the epigenome to specific proteins. These convergent targets of a large number of genetic risk factors for Alzheimer's dementia will help define the experimental systems and models needed to test therapeutic targets, which are expected to be broadly effective in the aging population that carries diverse genetic risks for Alzheimer's dementia