Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Ten new insights in climate science 2023

Non-technical summary: We identify a set of essential recent advances in climate change research with high policy relevance, across natural and social sciences: (1) looming inevitability and implications of overshooting the 1.5°C warming limit, (2) urgent need for a rapid and managed fossil fuel phase-out, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future contribution of natural carbon sinks, (5) intertwinedness of the crises of biodiversity loss and climate change, (6) compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems. Technical summary The IPCC Assessment Reports offer the scientific foundation for international climate negotiations and constitute an unmatched resource for climate change researchers. However, the assessment cycles take multiple years. As a contribution to cross- and interdisciplinary understanding across diverse climate change research communities, we have streamlined an annual process to identify and synthesise essential research advances. We collected input from experts on different fields using an online questionnaire and prioritised a set of ten key research insights with high policy relevance. This year we focus on: (1) looming overshoot of the 1.5°C warming limit, (2) urgency of phasing-out fossil fuels, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future of natural carbon sinks, (5) need for join governance of biodiversity loss and climate change, (6) advances in the science of compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems. We first present a succinct account of these Insights, reflect on their policy implications, and offer an integrated set of policy relevant messages. This science synthesis and science communication effort is also the basis for a report targeted to policymakers as a contribution to elevate climate science every year, in time for the UNFCCC COP. Social media summary We highlight recent and policy-relevant advances in climate change research - with input from more than 200 experts 1

A precautionary public health protection strategy for the possible risk of childhood leukaemia from exposure to power frequency magnetic fields

<p>Abstract</p> <p>Background</p> <p>Epidemiological evidence showing a consistent association between the risk of childhood leukaemia and exposure to power frequency magnetic fields has been accumulating. This debate considers the additional precautionary intervention needed to manage this risk, when it exceeds the protection afforded by the exposure guidelines as recommended by the International Commission on Non-Ionizing Radiation Protection.</p> <p>Methods</p> <p>The Bradford-Hill Criteria are guidelines for evaluating the scientific evidence that low frequency magnetic fields cause childhood leukaemia. The criteria are used for assessing the strength of scientific evidence and here have been applied to considering the strength of evidence that exposures to extremely low frequency magnetic fields may increase the risk of childhood leukaemia. The applicability of precaution is considered using the risk management framework outlined in a European Commission (EC) communication on the Precautionary Principle. That communication advises that measures should be proportionate, non-discriminatory, consistent with similar measures already taken, based on an examination of the benefits and costs of action and inaction, and subject to review in the light of new scientific findings.</p> <p>Results</p> <p>The main evidence for a risk is an epidemiological association observed in several studies and meta-analyses; however, the number of highly exposed children is small and the association could be due to a combination of selection bias, confounding and chance. Corroborating experimental evidence is limited insofar as there is no clear indication of harm at the field levels implicated; however, the aetiology of childhood leukaemia is poorly understood. Taking a precautionary approach suggests that low-cost intervention to reduce exposure is appropriate. This assumes that if the risk is real, its impact is likely to be small. It also recognises the consequential cost of any major intervention. The recommendation is controversial in that other interpretations of the data are possible, and low-cost intervention may not fully alleviate the risk.</p> <p>Conclusions</p> <p>The debate shows how the EC risk management framework can be used to apply the Precautionary Principle to small and uncertain public health risks. However, despite the need for evidence-based policy making, many of the decisions remain value driven and therefore subjective.</p

Ten New Insights in Climate Science 2023/2024

Non-technical summary: We identify a set of essential recent advances in climate change research with high policy relevance, across natural and social sciences: (1) looming inevitability and implications of overshooting the 1.5°C warming limit, (2) urgent need for a rapid and managed fossil fuel phase-out, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future contribution of natural carbon sinks, (5) intertwinedness of the crises of biodiversity loss and climate change, (6) compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems. Technical summary: The IPCC Assessment Reports offer the scientific foundation for international climate negotiations and constitute an unmatched resource for climate change researchers. However, the assessment cycles take multiple years. As a contribution to cross- and interdisciplinary understanding across diverse climate change research communities, we have streamlined an annual process to identify and synthesise essential research advances. We collected input from experts on different fields using an online questionnaire and prioritised a set of ten key research insights with high policy relevance. This year we focus on: (1) looming overshoot of the 1.5°C warming limit, (2) urgency of phasing-out fossil fuels, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future of natural carbon sinks, (5) need for join governance of biodiversity loss and climate change, (6) advances in the science of compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems. We first present a succinct account of these Insights, reflect on their policy implications, and offer an integrated set of policy relevant messages. This science synthesis and science communication effort is also the basis for a report targeted to policymakers as a contribution to elevate climate science every year, in time for the UNFCCC COP. Social media summary: We highlight recent and policy-relevant advances in climate change research - with input from more than 200 experts

Physical aspects of precision in genetic regulation

The process by which transcription factors (TFs) locate specific DNA binding sites is stochastic and as such, is subject to a considerable level of noise. TFs diffuse in the three-dimensional nuclear space, but can also slide along the DNA. It was proposed that this sliding facilitates the TF molecules arriving to their binding site, by effectively reducing the dimensionality of diffusion. However, the possible implications of DNA sliding on the accuracy by which the nuclear concentration of TFs can be estimated were not examined. Here, we calculate the mean and the variance of the number of TFs that bind to their binding site in reduced and partially reduced diffusion dimensionality regimes. We find that a search process which combines three-dimensional diffusion in the nucleus with one-dimensional sliding along the DNA can reduce the noise in TF binding and in this way enables a better estimation of the TF concentration inside the nucleus

Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms

Approximately 20% of patients with myeloproliferative neoplasms (MPN) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classified as either type I or type II. While type II CALR-mutant proteins retain many of the Ca2+ binding sites present in the wild-type protein, type I CALR-mutant proteins lose these residues. The functional consequences of this differential loss of Ca2+ binding sites remain unexplored. Here, we show that the loss of Ca2+ binding residues in the type I mutant CALR protein directly impairs its Ca2+ binding ability, which in turn leads to depleted endoplasmic reticulum (ER) Ca2+ and subsequent activation of the IRE1α/XBP1 pathway of the unfolded protein response. Genetic or pharmacologic inhibition of IRE1α/XBP1 signaling induces cell death in type I mutant but not type II mutant or wild-type CALR-expressing cells, and abrogates type I mutant CALR-driven MPN disease progression in vivo. Significance: Current targeted therapies for CALR-mutated MPNs are not curative and fail to differentiate between type I- versus type II-driven disease. To improve treatment strategies, it is critical to identify CALR mutation type-specific vulnerabilities. Here we show that IRE1α/XBP1 represents a unique, targetable dependency specific to type I CALR-mutated MPNs