Cohesin alters immune response gene expression primarily by transcriptional burst frequency modulation

Transcription is an intermittent process that occurs in bursts. The frequency and the number of messenger RNAs (mRNAs) produced by these bursts determine expression levels and shape cell-to-cell variability. Burst dynamics are modulated by productive encounters between enhancers and promoters, which can be facilitated by the cohesin complex through loop ex-trusion. In experimental systems, cohesin deficiency disrupts cell-type-specific expression pro-grams more severely than constitutive gene expression. Cohesin loss of function increases the self-renewal of hematopoietic progenitor stem cells (HPSCs), and cohesin-related mutations are frequent in cancers, such as AML. Cohesin defects in human AML, mouse HSPC and mature myeloid cells lead to a transcriptional state characterised by the reduced expression of inducible inflammatory genes and the elevated expression ofMyctargets and oxidative phosphorylation (OXPHOS) genes. In this thesis, I combine RNAseq, GROseq, scRNAseq, and smFISH to explore how cohesin depletion affects transcriptional parameters at steady-state and during cell-state transitions. Using primary macrophages as a model system, I find that loss of cohesin alters the dynamics of transcriptional bursts without measurably increasing cell-to-cell variability in scRNAseq. I show that expression changes triggered by LPS are primarily orchestrated through the modulation of burst frequencies, and this modulation is blunted in cohesin-deficient macrophages. An increase in burst frequency can have consequences not just for individual cells, but also for their neighbours. Specifically, the frequency of transcriptionalIfnb1bursts determines the number of cells that produceIfnb1-encoded type I interferon (IFN), which through paracrine signalling can alter IFN-dependent expression in neighbouring cells. Co-culture with cohesin-deficient macrophages reduces LPS-induced gene expression in wildtype (WT) macrophages, indicating that cohesin defects can buffer inflammatory responses and impair cell-state transitions due to the defective control of burst frequencies. I speculate that these features contribute to the somatic selection of cohesin mutations in cancer.Open Acces

Advances in behavioral genetics modeling using Mplus: Applications of factor mixture modeling to twin data.

This article discusses new latent variable techniques developed by the authors. As an illustration, a new factor mixture model is applied to the monozygotic-dizygotic twin analysis of binary items measuring alcohol-use disorder. In this model, heritability is simultaneously studied with respect to latent class membership and within-class severity dimensions. Different latent classes of individuals are allowed to have different heritability for the severity dimensions. The factor mixture approach appears to have great potential for the genetic analyses of heterogeneous populations. Generalizations for longitudinal data are also outlined

Descriptive analysis of postmarket surveillance data for hip implants

Purpose: Recent safety issues involving medical devices have highlighted the need for better postmarket surveillance (PMS) evaluation. This article aims to describe and to assess the quality of the PMS data for a medical device and, finally, to provide recommendations to improve the data gathering process. Methods: A descriptive analysis of medical device reports (MDRs) on the use of MRA, a specific type of hip implant replacement submitted to the Food and Drug Administration Manufacturer and User Facility Device Experience database from 1 January 2008 to 31 December 2017. The number of reports was described as the number of MDRs per unique MDR number and stratified by different variables. The quality was assessed by the level of completeness of the collected PMS data. Results: The total number of reports related to MRA was 2377, and the number of MDRs per year ranged between 84 in 2009 and 452 in 2017. Most of the reports were reported by manufacturer Depuy Johnson & Johnson and were reported by a physician. In 44.9% of the reports, the device problem was reported as “Unknown.” When the device problem was known, in the majority of cases, it was related to an implant fracture. The quality of the collected data was assessed as low due to missing information. Conclusion: The underlying data should meet high quality standards to generate more evidence and to ensure a timely signal generation. This case study shows that the completeness and quality of the MDRs can be improved. The authors propose the development of tools to ensure a more dynamic complaint data collection to contribute to this enhancement

Diferenciación por nivel de habilidad en varones y mujeres adultos

Despite the increasing importance of the ability-level differentiation hypothesis, no study has been conducted to clarify the role played by sex regarding this issue. A battery of cognitive tests was administered to a sample of 10,247 participants (6,068 males and 4,179 females). Results show a differentiation effect in males (around 2%) but not in females. Therefore, the ability-level differentiation hypothesis is substantiated for males onlyA pesar de la importancia creciente de la hipótesis de la diferenciación por nivel, ningún estudio se ha dirigido a clarificar el papel que la variable sexo juega con respecto a este asunto. En el presente estudio, una batería de pruebas cognitivas se administró a una muestra de 10.247 participantes (6.068 varones y 4.179 mujeres). Se encuentra un efecto de diferenciación en hombres (alrededor de un 2%), que no se replica en mujeres. Por consiguiente, la hipótesis de la diferenciación por nivel de habilidad sólo se mantiene en la muestra de varonesThis research was supported by a grant funded by the Spanish «Ministerio de Educación y Cultura», Grant Nº BSO2000-004

Evaluating the Safety Profile of Non-Active Implantable Medical Devices Compared with Medicines

Recent safety issues involving non-active implantable medical devices (NAIMDs) have highlighted the need for better pre-market and post-market evaluation. Some stakeholders have argued that certain features of medicine safety evaluation should also be applied to medical devices. Our objectives were to compare the current processes and methodologies for the assessment of NAIMD safety profiles with those for medicines, identify potential gaps, and make recommendations for the adoption of new methodologies for the ongoing benefit–risk monitoring of these devices throughout their entire life cycle. A literature review served to examine the current tools for the safety evaluation of NAIMDs and those for medicines. We searched MEDLINE using these two categories. We supplemented this search with Google searches using the same key terms used in the MEDLINE search. Using a comparative approach, we summarized the new product design, development cycle (preclinical and clinical phases), and post-market phases for NAIMDs and drugs. We also evaluated and compared the respective processes to integrate and assess safety data during the life cycle of the products, including signal detection, signal management, and subsequent potential regulatory actions. The search identified a gap in NAIMD safety signal generation: no global program exists that collects and analyzes adverse events and product quality issues. Data sources in real-world settings, such as electronic health records, need to be effectively identified and explored as additional sources of safety information, particularly in some areas such as the EU and USA where there are plans to implement the unique device identifier (UDI). The UDI and other initiatives will enable more robust follow-up and assessment of long-term patient outcomes. The safety evaluation system for NAIMDs differs in many ways from those for drugs, but both systems face analogous challenges with respect to monitoring real-world usage. Certain features of the drug safety evaluation process could, if adopted and adapted for NAIMDs, lead to better and more systematic evaluations of the latter

Mejora de la adhesión terapéutica en el paciente polimedicado. Un estudio comparativo descriptivo

Con el objetivo de valorar la mejora en la adherencia al tratamiento en pacientes polimedicados, se llevó a cabo un estudio observacional descriptivo comparativo en base a dos estudios diferentes. Como primera línea se realizó un estudio transversal descriptivo a pacientes polimedicados (con 4 o más medicamentos prescritos), con el objetivo de evaluar el cumplimiento/incumplimiento en esta población. Tras este primer estudio, se llevó a cabo otro estudio transversal descriptivo, con el mismo objetivo de evaluación, esta vez en pacientes polimedicados usuarios de sistemas personalizados de dosificación (SPD). En pacientes polimedicados usuarios de SPD se observó un cumplimiento terapéutico cercano al 55%; mientras que en pacientes polimedicados sin SPD dicho valor fue menor al 45%. La mejora del cumplimiento no fue de la magnitud esperada, lo que llevó a la conclusión de que la presencia del sistema SPD por sí solo no supone una mejora en la adhesión, sino que debe acompañarse de una serie de actividades. Es de vital importancia la funcionalidad conjunta de todos los profesionales sanitarios, que permitiría conocer la función cognitiva del paciente, mejorar la educación sanitaria del mismo, o realizar un seguimiento de la adhesión al tratamiento en este grupo de personas. Algún ejemplo de dichas actividades son el Programa de atención al mayor polimedicado de la Comunidad de Madrid o el realizado por el Sistema Nacional de Salud Británico

Abilities that explain the Intelligence decline: Evidence from the WAIS-III

Las puntuaciones en los tests de inteligencia declinan con la edad, aunque el grado de declive depende de la naturaleza, fluida o cristalizada, de los tests. Sin embargo, pocas investigaciones han abordado la pregunta de qué aptitudes cognitivas son responsables de tal declive. El presente estudio se centra en esta cuestión. La combinación del análisis factorial jerárquico (procedimiento Schmid-Leiman) y el método de vectores correlacionados permite responder a esta pregunta. Ambos procedimientos han sido utilizados para analizar la muestra de estandarización española del WAIS-III. Los resultados muestran que tanto g como el factor manipulativo son responsables del declive en las puntuaciones. El factor verbal (Gc) no da cuenta de tal declive. Por lo tanto, estos resultados suponen una matización del modelo de aptitudes vulnerables y sostenibles propuesto por HornIntelligence test’s scores decline with age, but such decline change for fluid and crystallized tests. However, little effort has been put to investigate what cognitive abilities are responsible for such decline. The present paper focuses on that issue. A hierarchical factor analysis (performed through the Schmid-Leiman transformation) followed by the method of correlated vectors let us to answer that question. Both procedures were applied to the Spanish standardization sample of the WAIS-III. Results show that g and performance factors are responsible for the decrease on the scores. The verbal factor (Gc) does not account for such decline. Therefore, results draw a more fined-grained view about the Horn’s model distinguishing vulnerable and sustainable cognitive abilitiesLa investigación contenida en este artículo ha sido financiada por un proyecto de investigación concedido por el Ministerio español de Ciencia y Tecnología (Ref: BSO2000-0043

Memory span and general intelligence: a latent variable approach.

Abstract There are several studies showing that working memory and intelligence are strongly related. However, working memory tasks require simultaneous processing and storage, so the causes of their relationship with intelligence are currently a matter of discussion. The present study examined the simultaneous relationships among short-term memory (STM), working memory (WM), and general intelligence ( g). Two hundred and eight participants performed six verbal, quantitative, and spatial STM tasks, six verbal, quantitative, and spatial WM tasks, and eight tests measuring fluid, crystallized, spatial, and quantitative intelligence. Especial care is taken to avoid misrepresenting the relations among the constructs being studied because of specific task variance. Structural equation modelling (SEM) results revealed that (a) WM and g are (almost) isomorphic constructs, (b) the isomorphism vanishes when the storage component of WM is partialed out, and (c) STM and WM (with its storage component partialed out) predict g.

Influence of Main Ocular Variables in #TheDress Perception: An Ophthalmic Survey.

The objective of this study is to study the influence of ocular variables in the perception of #thedress and to develop a logistic regression model that could help predict it. This is a cross-sectional study on 1,100 subjects. People who did not report one of the two main perceptions were excluded from the study. Dress perception was codified as 0 (white&gold) or 1 (black&blue). The association between dress perception and demographic and main ocular variables (age, gender, binocular visual acuity, grade of nuclear cataract, crystalline lens status [phakic/pseudophakic], spherical equivalent, and ocular health status) was tested using logistic regression. Receiver operation curves were used to test the predictive value of the model. Several variables were found to be related with dress perception. The best model included three variables—Age: adjusted odds ratio (OR) = 1.02 (1.01–1.03), p = 0.08; ocular refraction: adjusted OR = 1.07 (1.02–1.12), p = 0.009; and nuclear cataract grade: adjusted OR = 1.45 (1.05–1.99), p = 0.026. The predictive value of the model was low (area under the curve = 0.62). Older age, nuclear cataract grade, and hyperopia were associated with black&blue perception. The predictive capacity of the developed model was poor. Only a small proportion of the variability in the #thedress perception can be explained by ocular examination.post-print667 K