ANKHD1 regulates cell cycle progression and proliferation in multiple myeloma cells

ANKHD1 is a multiple ankyrin repeat containing protein, highly expressed in cancers, such as acute leukemia. the present study was undertaken to determine the expression and functional significance of ANKHD1 in human Multiple Myeloma (MM). We found that ANKHD1 is highly expressed in MM patient cells and cell lines. in vitro, lentiviral mediated ANKHD1-shRNA inhibited proliferation and delayed S to G2M cell cycle progression in glucocorticoid resistant (U266) and sensitive (MM1S) MM cells. Further ANKHD1 silencing resulted in upregulation of cyclin dependent kinase inhibitor p21 irrespective of the p53 status of the MM cell lines. These data suggest that ANKHD1 might have a role in MM cell proliferation and cell cycle progression by regulating expression of p21. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.Instituto Nacional de Ciencia e Tecnologia do Sangue(INCTS)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Campinas Hemoctr Unicamp, Hematol & Hemotherapy Ctr, Inst Nacl Ciencia & Tecnol Sangue, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, BrazilWeb of Scienc

Marco metodológico y tecnológico para la gestión del conocimiento organizativo que dé soporte al despliegue de buenas prácticas de Ingeniería del software

Hoy en día nos encontramos inmersos en una sociedad que está en constante cambio, donde los paradigmas creados por los padres de la automatización y formalización de procesos de la era moderna, Henry Ford y Frederick Taylor, han dejado de ser totalmente válidos; cuando a principios del siglo XX la capacidad productiva se basaba mayormente en la fuerza física, hoy en los albores del siglo XII el paradigma es muy distinto, ya que la productividad de la sociedad actual, llamada “del conocimiento” se basa en buena medida en la capacidad de las organizaciones para gestionar de la manera más eficiente lo que saben, es decir, su propio conocimiento. En una sociedad, en donde un activo de mucho valor es el conocimiento, surge la necesidad de crear nuevos modelos y paradigmas para la gestión del mismo, sin embargo, esto conlleva superar diversos retos, tanto metodológicos como tecnológicos, es por ello que en esta tesis doctoral, se presenta Promise Framework,una propuesta de marco metodológico y tecnológico para la gestión del conocimiento organizativo, el cual está focalizado en su práctica efectiva en el ámbito de la ingeniería del software, para conseguir que el conocimiento de las organizaciones de desarrollo de software sea usable, útil, accesible y cuantificable. • Usable, de modo que el conocimiento organizativo pueda ser usado y reutilizado en la gestión de proyectos en el seno de la organización. • Útil, ya que sólo en el caso de que el conocimiento que esté disponible sea útil, la transferencia del mismo será efectiva. • Accesible, de modo que el conocimiento organizativo pueda ser recuperado eficiente y eficazmente. • Cuantificable, de modo que los activos de conocimiento de la organización puedan valorarse en función de su aportación a la consecución de los objetivos estratégicos. A lo largo de esta tesis doctoral se presenta una descripción de cada uno de los componentes de Promise Framework: • Modelo de Madurez y Capacidad del Conocimiento Organizativo (Modelo Altus): El cual tiene por objetivo principal sentar las bases sobre las cuales se valorará el conocimiento organizativo, así como los mecanismos para asegurar su accesibilidad, usabilidad y aprendizaje por parte de todos los miembros de la organización. • Marco metodológico: El cual define el método general de trabajo que debe implementarse dentro de una organización para utilizar Promise Framework y poder llevar a cabo la gestión y valoración de su conocimiento. • Marco tecnológico: El cual define un conjunto de herramientas de software, principalmente herramientas basadas en tecnologías Web 2.0 y gestores de bases de datos, a través de las cuales se implementa de manera práctica el marco metodológico y se facilita la captura de información para llevar a cabo la valoración de la madurez del conocimiento organizativo. La validación experimental de la propuesta presentada en esta tesis doctoral se ha definido en torno a la potencial utilidad de Promise Framework dentro de una organización de desarrollo de software para dar soporte a la gestión del conocimiento organizativo (creación, uso, reutilización, valoración y transferencia) en grupos de trabajo conformados por ingenieros de software junior de nueva incorporación; bajo esta premisa, la validación experimenta de esta tesis doctoral se ha llevado a cabo en un contexto universitario, al proporcionar un entorno de experimentación adecuado, ya que el perfil de los alumnos universitarios satisface los criterios de un ingeniero de software junior. -----------------------------------------------------------------------------------------------------------------------------------------------Nowadays we are immersed in a constantly changing society, where the paradigms proposed by Henry Ford and Frederick Taylor, fathers of the automation and formalization of processes in the modern era, are no longer entirely valid; at the beginning of the 20th century the productive capacity was mainly based on physical strength. Today on the beginning of the 21st century the paradigm is quite different, productivity in the current society, that is called “the knowledge society”, is mainly based on the capability of organizations to effectively manage what they know, that is, their knowledge. In a society where the most valuable asset is knowledge, a need to create new models and paradigms to manage knowledge arises, it implies to overcome several methodological and technological challenges, for that reason, this doctoral thesis presents Promise Framework, a methodological and technological framework proposal for organizational knowledge management, that is focused to be deployed on software development organizations, and is aimed to help software organizations to make their knowledge usable, useful, accessible and measurable. • Usable, allowing to all the members of an organization to use and reuse organizational knowledge in projects execution. • Useful, easing knowledge transference and fostering work effectiveness. • Accessible, allowing knowledge access without complexity to all the members of an organization. • Measurable, allowing assessing the quality of knowledge assets in terms of their contribution to fulfill the strategic objectives of an organization. The organizational knowledge management framework presented in this work is composed by three main components, which are detailed throughout this doctoral thesis. • Altus Model: Capability and Maturity Model for Organizational Knowledge. This model is aimed to offer a mechanism to assess the maturity of organizational knowledge and the capability of an organization to manage its knowledge. • Methodological Framework. Defines the general workflow of Promise Framework by setting the rules that need to be followed by an organization to manage its knowledge. • Technological Framework. Defines a set of technological tools to deploy Promise Framework in an organization and ease the knowledge gathering, coding, storage and recovering. The experimental validation of the proposal presented in this doctoral thesis was conducted to corroborate if Promise Framework is useful within a software organization to support the creation, use, reuse, assessment, and transference of knowledge when a software project is executed by junior software engineers that are coordinated by senior software engineers. Under this context, this validation was conducted on a university environment, where last year students of a Computer Science degree played the role of junior software engineers and the lecturers played the role of senior software engineers

Modulation of subventricular zone oligodendrogenesis: a role for hemopressin?

Neural stem cells (NSCs) from the subventricular zone (SVZ) have been indicated as a source of new oligodendrocytes to use in regenerative medicine for myelin pathologies. Indeed, NSCs are multipotent cells that can self-renew and differentiate into all neural cell types of the central nervous system. In normal conditions, SVZ cells are poorly oligodendrogenic, nevertheless their oligodendrogenic potential is boosted following demyelination. Importantly, progressive restriction into the oligodendrocyte fate is specified by extrinsic and intrinsic factors, endocannabinoids being one of these factors. Although a role for endocannabinoids in oligodendrogenesis has already been foreseen, selective agonists and antagonists of cannabinoids receptors produce severe adverse side effects. Herein, we show that hemopressin (Hp),a modulator of CB1 receptors, increased oligodendroglial differentiation in SVZ neural stem/progenitor cell cultures derived from neonatal mice. The original results presented in this work suggest that Hp and derivates may be of potential interest for the development of future strategies to treat demyelinating diseases

Novel HIV-1 Knockdown Targets Identified by an Enriched Kinases/Phosphatases shRNA Library Using a Long-Term Iterative Screen in Jurkat T-Cells

HIV-1 is a complex retrovirus that uses host machinery to promote its replication. Understanding cellular proteins involved in the multistep process of HIV-1 infection may result in the discovery of more adapted and effective therapeutic targets. Kinases and phosphatases are a druggable class of proteins critically involved in regulation of signal pathways of eukaryotic cells. Here, we focused on the discovery of kinases and phosphatases that are essential for HIV-1 replication but dispensable for cell viability. We performed an iterative screen in Jurkat T-cells with a short-hairpin-RNA (shRNA) library highly enriched for human kinases and phosphatases. We identified 14 new proteins essential for HIV-1 replication that do not affect cell viability. These proteins are described to be involved in MAPK, JNK and ERK pathways, vesicular traffic and DNA repair. Moreover, we show that the proteins under study are important in an early step of HIV-1 infection before viral integration, whereas some of them affect viral transcription/translation. This study brings new insights for the complex interplay of HIV-1/host cell and opens new possibilities for antiviral strategies

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA

Brain-behaviour modes of covariation in healthy and clinically depressed young people

Abstract: Understanding how variations in dimensions of psychometrics, IQ and demographics relate to changes in brain connectivity during the critical developmental period of adolescence and early adulthood is a major challenge. This has particular relevance for mental health disorders where a failure to understand these links might hinder the development of better diagnostic approaches and therapeutics. Here, we investigated this question in 306 adolescents and young adults (14–24 y, 25 clinically depressed) using a multivariate statistical framework, based on canonical correlation analysis (CCA). By linking individual functional brain connectivity profiles to self-report questionnaires, IQ and demographic data we identified two distinct modes of covariation. The first mode mapped onto an externalization/internalization axis and showed a strong association with sex. The second mode mapped onto a well-being/distress axis independent of sex. Interestingly, both modes showed an association with age. Crucially, the changes in functional brain connectivity associated with changes in these phenotypes showed marked developmental effects. The findings point to a role for the default mode, frontoparietal and limbic networks in psychopathology and depression

Brain structural covariance networks in obsessive-compulsive disorder : a graph analysis from the ENIGMA Consortium

In the largest brain structural covariance study of OCD to date, Yun et al. show a less segregated organization of structural covariance networks and a reorganization of brain hubs, including cingulate and orbitofrontal regions, in OCD. The findings point to altered trajectories of brain development and maturation. Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z -score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

Genome-wide association study of placental weight in 65,405 newborns and 113,620 parents reveals distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth

Stress and worry in the 2020 coronavirus pandemic: Relationships to trust and compliance with preventive measures across 48 countries in the COVIDiSTRESS global survey

The COVIDiSTRESS global survey collects data on early human responses to the 2020 COVID-19 pandemic from 173 429 respondents in 48 countries. The open science study was co-designed by an international consortium of researchers to investigate how psychological responses differ across countries and cultures, and how this has impacted behaviour, coping and trust in government efforts to slow the spread of the virus. Starting in March 2020, COVIDiSTRESS leveraged the convenience of unpaid online recruitment to generate public data. The objective of the present analysis is to understand relationships between psychological responses in the early months of global coronavirus restrictions and help understand how different government measures succeed or fail in changing public behaviour. There were variations between and within countries. Although Western Europeans registered as more concerned over COVID-19, more stressed, and having slightly more trust in the governments' efforts, there was no clear geographical pattern in compliance with behavioural measures. Detailed plots illustrating between-countries differences are provided. Using both traditional and Bayesian analyses, we found that individuals who worried about getting sick worked harder to protect themselves and others. However, concern about the coronavirus itself did not account for all of the variances in experienced stress during the early months of COVID-19 restrictions. More alarmingly, such stress was associated with less compliance. Further, those most concerned over the coronavirus trusted in government measures primarily where policies were strict. While concern over a disease is a source of mental distress, other factors including strictness of protective measures, social support and personal lockdown conditions must also be taken into consideration to fully appreciate the psychological impact of COVID-19 and to understand why some people fail to follow behavioural guidelines intended to protect themselves and others from infection. The Stage 1 manuscript associated with this submission received in-principle acceptance (IPA) on 18 May 2020. Following IPA, the accepted Stage 1 version of the manuscript was preregistered on the Open Science Framework at https://osf.io/g2t3b. This preregistration was performed prior to data analysis