When TADs go bad: chromatin structure and nuclear organisation in human disease

Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease

Constructing Memory through Television in Argentina

La televisión representa el pasado reciente de la Argentina a través de vínculos específicos con la memoria social: como un “emprendedor de la memoria” definiendo las agendas públicas, como un vehículo de transmisión intergeneracional sobre el pasado y como un creador de significados por medio de imágenes, sonidos y palabras, esto es, un “escenario para la memoria”. Un análisis de los vínculos entre televisión y memorias, construido alrededor de la desaparición forzada de personas durante la dictadura militar de 1976 a 1983, revela la manera compleja en la cual los obstáculos para relatar ese periodo trágico se combinan con el intento de vender un producto y entretener al espectador.Television represents Argentina’s recent past through three specific links with social memory: as an “entrepreneur of memory,” shaping public agendas, as a vehicle of intergenerational transmission of past events, and as a creator of meaning through images, sounds, and words, a “stage for memory”. An analysis in terms of the links between television and the memories constructed around the forced disappearance of persons during the 1976–1983 military dictatorship reveals the complex way in which the obstacles when narrating an extreme experience are combined with the attempt to sell a product and entertain the spectator.Fil: Feld, Claudia Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Sociales. Instituto de Desarrollo Económico y Social. Centro de Investigaciones Sociales; Argentin

Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection

The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. Here, we combine a multi-omics approach with longitudinal sampling to reveal temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients and associate specific immune trajectories with upper airway viral containment. We see a distinct systemic rather than local immune state associated with viral containment, characterized by interferon stimulated gene (ISG) upregulation across circulating immune cell subsets in non-pneumonic SARS-CoV2 infection. We report reduced cytotoxic potential of Natural Killer (NK) and T cells, and an immune-modulatory monocyte phenotype associated with protective immunity in COVID-19. Together, we show protective immune trajectories in SARS-CoV2 infection, which have important implications for patient prognosis and the development of immunomodulatory therapies

Unraveling the deep learning gearbox in optical coherence tomography image segmentation towards explainable artificial intelligence

Machine learning has greatly facilitated the analysis of medical data, while the internal operations usually remain intransparent. To better comprehend these opaque procedures, a convolutional neural network for optical coherence tomography image segmentation was enhanced with a Traceable Relevance Explainability (T-REX) technique. The proposed application was based on three components: ground truth generation by multiple graders, calculation of Hamming distances among graders and the machine learning algorithm, as well as a smart data visualization ('neural recording'). An overall average variability of 1.75% between the human graders and the algorithm was found, slightly minor to 2.02% among human graders. The ambiguity in ground truth had noteworthy impact on machine learning results, which could be visualized. The convolutional neural network balanced between graders and allowed for modifiable predictions dependent on the compartment. Using the proposed T-REX setup, machine learning processes could be rendered more transparent and understandable, possibly leading to optimized applications

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Abstract Background Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns. Results Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution. Conclusions We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

Taxonomy based on science is necessary for global conservation

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