Abstract
Recent progresses of genome-wide chromatin conformation capture techniques have shown that the genome is segmented into hierarchically organized spatial compartments. However, whether this ...non-random 3D organization only reflects or indeed contributes-and how-to the regulation of genome function remain to be elucidated. The observation in many species that 3D domains correlate strongly with the 1D epigenomic information along the genome suggests a dynamic coupling between chromatin organization and epigenetic regulation. Here, we posit that chromosome folding may contribute to the maintenance of a robust epigenomic identity via the formation of spatial compartments like topologically-associating domains. Using a novel theoretical framework, the living chromatin model, we show that 3D compartmentalization leads to the spatial colocalization of epigenome regulators, thus increasing their local concentration and enhancing their ability to spread an epigenomic signal at long-range. Interestingly, we find that the presence of 1D insulator elements, like CTCF, may contribute greatly to the stable maintenance of adjacent antagonistic epigenomic domains. We discuss the generic implications of our findings in the light of various biological contexts from yeast to human. Our approach provides a modular framework to improve our understanding and to investigate in details the coupling between the structure and function of chromatin.
Without a systematic SpO2i measurement, a normal breathing rate could mask profound hypoxia and make severity assessment in COVID-19 patients all the more difficult in an out-of-hospital setting. ......prehospital pulse oximetry might be used as a red flag for early detection of “silent hypoxemia” in COVID-19 patients. Predicting success of high-flow nasal cannula in pneumonia patients with hypoxemic respiratory failure: the utility of the ROX index.
Genomes of eukaryotes are partitioned into domains of functionally distinct chromatin states. These domains are stably inherited across many cell generations and can be remodeled in response to ...developmental and external cues, hence contributing to the robustness and plasticity of expression patterns and cell phenotypes. Remarkably, recent studies indicate that these 1D epigenomic domains tend to fold into 3D topologically associated domains forming specialized nuclear chromatin compartments. However, the general mechanisms behind such compartmentalization including the contribution of epigenetic regulation remain unclear. Here, we address the question of the coupling between chromatin folding and epigenome. Using polymer physics, we analyze the properties of a block copolymer model that accounts for local epigenomic information. Considering copolymers build from the epigenomic landscape of Drosophila, we observe a very good agreement with the folding patterns observed in chromosome conformation capture experiments. Moreover, this model provides a physical basis for the existence of multistability in epigenome folding at sub-chromosomal scale. We show how experiments are fully consistent with multistable conformations where topologically associated domains of the same epigenomic state interact dynamically with each other. Our approach provides a general framework to improve our understanding of chromatin folding during cell cycle and differentiation and its relation to epigenetics.
Although mortality due to COVID-19 is, for the most part, robustly tracked, its indirect effect at the population level through lockdown, lifestyle changes, and reorganisation of health-care systems ...has not been evaluated. We aimed to assess the incidence and outcomes of out-of-hospital cardiac arrest (OHCA) in an urban region during the pandemic, compared with non-pandemic periods.
We did a population-based, observational study using data for non-traumatic OHCA (N=30 768), systematically collected since May 15, 2011, in Paris and its suburbs, France, using the Paris Fire Brigade database, together with in-hospital data. We evaluated OHCA incidence and outcomes over a 6-week period during the pandemic in adult inhabitants of the study area.
Comparing the 521 OHCAs of the pandemic period (March 16 to April 26, 2020) to the mean of the 3052 total of the same weeks in the non-pandemic period (weeks 12–17, 2012–19), the maximum weekly OHCA incidence increased from 13·42 (95% CI 12·77–14·07) to 26·64 (25·72–27·53) per million inhabitants (p<0·0001), before returning to normal in the final weeks of the pandemic period. Although patient demographics did not change substantially during the pandemic compared with the non-pandemic period (mean age 69·7 years SD 17 vs 68·5 18, 334 males 64·4% vs 1826 59·9%), there was a higher rate of OHCA at home (460 90·2% vs 2336 76·8%; p<0·0001), less bystander cardiopulmonary resuscitation (239 47·8% vs 1165 63·9%; p<0·0001) and shockable rhythm (46 9·2% vs 472 19·1%; p<0·0001), and longer delays to intervention (median 10·4 min IQR 8·4–13·8 vs 9·4 min 7·9–12·6; p<0·0001). The proportion of patients who had an OHCA and were admitted alive decreased from 22·8% to 12·8% (p<0·0001) in the pandemic period. After adjustment for potential confounders, the pandemic period remained significantly associated with lower survival rate at hospital admission (odds ratio 0·36, 95% CI 0·24–0·52; p<0·0001). COVID-19 infection, confirmed or suspected, accounted for approximately a third of the increase in OHCA incidence during the pandemic.
A transient two-times increase in OHCA incidence, coupled with a reduction in survival, was observed during the specified time period of the pandemic when compared with the equivalent time period in previous years with no pandemic. Although this result might be partly related to COVID-19 infections, indirect effects associated with lockdown and adjustment of health-care services to the pandemic are probable. Therefore, these factors should be taken into account when considering mortality data and public health strategies.
The French National Institute of Health and Medical Research (INSERM)
The 3D organization of chromosomes is crucial for regulating gene expression and cell function. Many experimental and polymer modeling efforts are dedicated to deciphering the mechanistic principles ...behind chromosome folding. Chromosomes are long and densely packed-topologically constrained-polymers. The main challenges are therefore to develop adequate models and simulation methods to investigate properly the multi spatio-temporal scales of such macromolecules. Here, we proposed a generic strategy to develop efficient coarse-grained models for self-avoiding polymers on a lattice. Accounting accurately for the polymer entanglement length and the volumic density, we show that our simulation scheme not only captures the steady-state structural and dynamical properties of the system but also tracks the same dynamics at different coarse-graining. This strategy allows a strong power-law gain in numerical efficiency and offers a systematic way to define reliable coarse-grained null models for chromosomes and to go beyond the current limitations by studying long chromosomes during an extended time period with good statistics. We use our formalism to investigate in details the time evolution of the 3D organization of chromosome 3R (20 Mbp) in drosophila during one cell cycle (20 hours). We show that a combination of our coarse-graining strategy with a one-parameter block copolymer model integrating epigenomic-driven interactions quantitatively reproduce experimental data at the chromosome-scale and predict that chromatin motion is very dynamic during the cell cycle.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Although our understanding of the involvement of heterochromatin architectural factors in shaping nuclear organization is improving, there is still ongoing debate regarding the role of ...active genes in this process. In this study, we utilize publicly-available Micro-C data from mouse embryonic stem cells to investigate the relationship between gene transcription and 3D gene folding. Our analysis uncovers a nonmonotonic - globally positive - correlation between intragenic contact density and Pol II occupancy, independent of cohesin-based loop extrusion. Through the development of a biophysical model integrating the role of transcription dynamics within a polymer model of chromosome organization, we demonstrate that Pol II-mediated attractive interactions with limited valency between transcribed regions yield quantitative predictions consistent with chromosome-conformation-capture and live-imaging experiments. Our work provides compelling evidence that transcriptional activity shapes the 4D genome through Pol II-mediated micro-compartmentalization.
The Polycomb system via the methylation of the lysine 27 of histone H3 (H3K27) plays central roles in the silencing of many lineage-specific genes during development. Recent experimental evidence ...suggested that the recruitment of histone modifying enzymes like the Polycomb repressive complex 2 (PRC2) at specific sites and their spreading capacities from these sites are key to the establishment and maintenance of a proper epigenomic landscape around Polycomb-target genes. Here, to test whether such mechanisms, as a minimal set of qualitative rules, are quantitatively compatible with data, we developed a mathematical model that can predict the locus-specific distributions of H3K27 modifications based on previous biochemical knowledge. Within the biological context of mouse embryonic stem cells, our model showed quantitative agreement with experimental profiles of H3K27 acetylation and methylation around Polycomb-target genes in wild-type and mutants. In particular, we demonstrated the key role of the reader-writer module of PRC2 and of the competition between the binding of activating and repressing enzymes in shaping the H3K27 landscape around transcriptional start sites. The predicted dynamics of establishment and maintenance of the repressive trimethylated H3K27 state suggest a slow accumulation, in perfect agreement with experiments. Our approach represents a first step towards a quantitative description of PcG regulation in various cellular contexts and provides a generic framework to better characterize epigenetic regulation in normal or disease situations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over the past decade, advances in molecular methods have strikingly improved the resolution at which nuclear genome folding can be analyzed. This revealed a wealth of conserved features organizing ...the one dimensional DNA molecule into tridimensional nuclear domains. In this review, we briefly summarize the main findings and highlight how models based on polymer physics shed light on the principles underlying the formation of these domains. Finally, we discuss the mechanistic similarities allowing self-organization of these structures and the functional importance of these in the maintenance of transcriptional programs.
Recent years have seen a flurry of activity in the fields of quantum computing and quantum complexity theory, which aim to understand the computational capabilities of quantum systems by applying the ...toolbox of computational complexity theory. This paper explores the conceptually rich and technologically useful connection between the dynamics of free quantum particles and complexity theory. I review results on the computational power of two simple quantum systems, built out of noninteracting bosons (linear optics) or noninteracting fermions. These rudimentary quantum computers display radically different capabilities—while free fermions are easy to simulate on a classical computer, and therefore devoid of nontrivial computational power, a free-boson computer can perform tasks expected to be classically intractable. To build the argument for these results, I introduce concepts from computational complexity theory. I describe some complexity classes, starting with P and NP and building up to the less common #P and polynomial hierarchy, and the relations between them. I identify how probabilities in free-bosonic and free-fermionic systems fit within this classification, which then underpins their difference in computational power. This paper is aimed at graduate or advanced undergraduate students with a Physics background, hopefully serving as a soft introduction to this exciting and highly evolving field.
Os últimos anos presenciaram uma atividade crescente nas áreas de computação quântica e teoria de complexidade quântica. Essas áreas têm como objetivo analisar a complexidade e as capacidades computacionais de diversos sistemas quânticos através do uso das ferramentas desenvolvidas, ao longo das últimas décadas, no contexto da teoria de complexidade computacional. Este artigo explora as conexões conceitualmente ricas e tecnologicamente úteis entre a dinâmica de partículas quânticas livres e a teoria da complexidade. Eu reviso resultados sobre a complexidade computacional da simulação de dois sistemas quânticos simples, construídos com bósons não interagentes (ou seja, óptica linear), ou com férmions não interagentes. Tais sistemas podem ser vistos como tipos rudimentares de computadores quânticos, com potencialidades radicalmente distintas: por um lado, sabe-se que férmions livres são facilmente simulados por um computador clássico e, portanto, desprovidos de poder computacional não trivial; por outro lado, existe forte evidência de que um computador construído a partir de bósons livres pode realizar uma tarefa que é classicamente intratável (ou seja, é capaz de demonstrar vantagem ou supremacia quântica). A fim de construir os argumentos que fundamentam esses resultados, este artigo oferece uma introdução básica a alguns conceitos do campo da teoria da complexidade computacional. Para isso, eu descrevo algumas classes de complexidade e as relações entre elas, partindo das bem conhecidas P e NP, e avançando para as classes #P e a hierarquia polinomial. Identifico então como as probabilidades de transição nos sistemas de bósons livres e de férmions livres se encaixam nessa classificação, o que fundamenta a diferença em seu poder computacional. Este artigo foi pensado para estudantes no fim da graduação e na pós-graduação, com formação em Física. Espero que ele sirva como uma introdução leve a este campo fascinante e em rápido desenvolvimento.
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