Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local ...microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.
A storage‐discharge relation tells us how discharge will change when new water enters a hydrologic system but not which water is released. Does an incremental increase in discharge come from faster ...turnover of older water already in storage? Or are the recent inputs rapidly delivered to the outlet, “short‐circuiting” the bulk of the system? Here I demonstrate that the concepts of storage‐discharge relationships and transit time distributions can be unified into a single relationship that can usefully address these questions: the age‐ranked storage‐discharge relation. This relationship captures how changes in total discharge arise from changes in the turnover rate of younger and older water in storage and provides a window into both the celerity and velocity of water in a catchment. This leads naturally to a distinction between cases where an increase in total discharge is accompanied by an increase (old water acceleration), no change (old water steadiness), or a decrease in the rate of discharge of older water in storage (old water suppression). The simple theoretical case of a power law age‐ranked storage‐discharge relations is explored to illustrate these cases. Example applications to data suggest that the apparent presence of old water acceleration or suppression is sensitive to the functional form chosen to fit to the data, making it difficult to draw decisive conclusions. This suggests new methods are needed that do not require a functional form to be chosen and provide age‐dependent uncertainty bounds.
Key Points
Storage‐discharge relations and transit time distributions are unified in a single relationship capturing both celerity and velocity effects
Empirical data and theory suggest old water release may be accelerated or suppressed at high discharge or catchments wetness
Robust inferences about oldest water turnover require new approaches to functional estimation with age‐dependent uncertainty
Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan ...of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.
Bedrock fracture systems facilitate weathering, allowing fresh mineral surfaces to interact with corrosive waters and biota from Earth's surface, while simultaneously promoting drainage of chemically ...equilibrated fluids. We show that topographic perturbations to regional stress fields explain bedrock fracture distributions, as revealed by seismic velocity and electrical resistivity surveys from three landscapes. The base of the fracture-rich zone mirrors surface topography where the ratio of horizontal compressive tectonic stresses to near-surface gravitational stresses is relatively large, and it parallels the surface topography where the ratio is relatively small. Three-dimensional stress calculations predict these results, suggesting that tectonic stresses interact with topography to influence bedrock disaggregation, groundwater flow, chemical weathering, and the depth of the "critical zone" in which many biogeochemical processes occur.
The annotation of the mammalian protein-coding genome is incomplete. Arbitrary size restriction of open reading frames (ORFs) and the absolute requirement for a methionine codon as the sole initiator ...of translation have constrained the identification of potentially important transcripts with non-canonical protein-coding potential
. Here, using unbiased transcriptomic approaches in macrophages that respond to bacterial infection, we show that ribosomes associate with a large number of RNAs that were previously annotated as 'non-protein coding'. Although the idea that such non-canonical ORFs can encode functional proteins is controversial
, we identify a range of short and non-ATG-initiated ORFs that can generate stable and spatially distinct proteins. Notably, we show that the translation of a new ORF 'hidden' within the long non-coding RNA Aw112010 is essential for the orchestration of mucosal immunity during both bacterial infection and colitis. This work expands our interpretation of the protein-coding genome and demonstrates that proteinaceous products generated from non-canonical ORFs are crucial for the immune response in vivo. We therefore propose that the misannotation of non-canonical ORF-containing genes as non-coding RNAs may obscure the essential role of a multitude of previously undiscovered protein-coding genes in immunity and disease.
Over the last few years, a number of authors have suggested that, under certain circumstances, molecular oxygen (O2) or ozone (O3) generated by abiotic processes may accumulate to detectable ...concentrations in a habitable terrestrial planet's atmosphere, producing so-called "false positives" for life. But the models have occasionally disagreed with each other, with some predicting false positives, and some not, for the same apparent set of circumstances. We show here that photochemical false positives derive either from inconsistencies in the treatment of atmospheric and global redox balance or from the treatment (or lack thereof) of lightning. For habitable terrestrial planets with even trace amounts of atmospheric N2, NO produced by lightning catalyzes the recombination of CO and O derived from CO2 photolysis and should be sufficient to eliminate all reported false positives. Molecular oxygen thus remains a useful biosignature gas for Earth-like extrasolar planets, provided that the planet resides within the conventional liquid water habitable zone and has not experienced distinctly non-Earth-like, irrecoverable water loss.
PbSeTe-based quantum dot superlattice structures grown by molecular beam epitaxy have been investigated for applications in thermoelectrics. We demonstrate improved cooling values relative to the ...conventional bulk$(Bi,Sb)_{2}(Se,Te)_{3}$thermoelectric materials using a n-type film in a one-leg thermoelectric device test setup, which cooled the cold junction 43.7 K below the room temperature hot junction temperature of 299.7 K. The typical device consists of a substrate-free, bulk-like (typically 0.1 millimeter in thickness, 10 millimeters in width, and 5 millimeters in length) slab of nanostructured PbSeTe/PbTe as the n-type leg and a metal wire as the p-type leg.
We investigate how the effectiveness of green infrastructure (GI) to mitigate the frequency and magnitude of significant discharge events and combined sewer overflows (CSOs) depend on both climate ...and sewershed characteristics and propose a theoretical framework for a holistic assessment of GI's efficacy. The framework is based on the comparison of three characteristic timescales that control the production of peak discharge: rainfall duration (tr), travel time in the sewer network (tn), and the duration of rain that would be required to fill the GI's storage (tGI). Storm events can then be characterized by two ratios of these timescales: Tn = tn/tGI and Tr = tr/tGI. A third dimensionless number characterizes critical storms during which adverse events (such as CSOs) occur and allows us to identify the combinations of Tn and Tr for which GI may substantially mitigate those events. The results of numerical experiments with the model demonstrate that the storms for which GI can substantially reduce peak discharge and CSO volume typically occur in a narrow band of Tn and Tr. Within that band, the efficacy of GI may depend on the location of GI within the sewershed if network routing substantially affects the timing and magnitude of flood peaks. The proposed framework is applied to examine the efficacy of GI using historical precipitation data from two major U.S. cities: Philadelphia, PA, and Seattle, WA, and the results of this comparative analysis suggest that GI location is an important control on catchment‐scale GI efficacy in Philadelphia, but less so in Seattle.
Plain Language Summary
Combined sewer overflows (CSO) occur when storm rainfall exceeds the capacity of the sewer system to drain it. Green infrastructure (GI) is intended to mitigate the occurrence and severity of CSOs. But how effective will it be in helping to manage CSOs? Here we present a theoretical framework to address this question, by focusing on the major physical controls on the efficacy of GI for managing CSOs, including the relative roles of climate, the size of the sewershed, and the location of the GI within it. The framework is based on three characteristic timescales: storm duration, travel time to the overflow location, and time required to fill GI storage. We use the framework to explore how GI might work differently in different places. The results show that GI is most effective under certain combinations of climate and sewershed conditions, and that the location of GI within the sewershed can be very critical. The latter effect was found to be more evident, for example, in Philadelphia, PA, than in Seattle, WA, due to differences in storm duration and intensity between these two places. In these ways, the proposed framework can support green infrastructure planning by providing insights on location‐effectiveness tradeoffs.
Key Points
The ability of GI to mitigate peak discharge depends on the climate and sewershed characteristics, as well as its design
We propose a simple framework for capturing these controls in terms of timescales and three dimensionless numbers
GI efficacy in treating CSO volume and frequency may depend on the precipitation pattern and the location of GI within a sewershed
There have been repeated calls for a Darwinian approach to hydrologic science, or for a synthesis of Darwinian and Newtonian approaches, to deepen understanding of the hydrologic system in the larger ...landscape context, and so develop a better basis for predictions now and in an uncertain future. But what exactly makes a Darwinian approach to hydrology "Darwinian"? While there have now been a number of discussions of Darwinian approaches, many referencing Harte (2002), the term is potentially a source of confusion because its connections to Darwin remain allusive rather than explicit. Here we suggest that the Darwinian approach to hydrology follows the example of Charles Darwin by focusing attention on the patterns of variation in populations and seeking hypotheses that explain these patterns in terms of the mechanisms and conditions that determine their historical development. These hypotheses do not simply catalog patterns or predict them statistically - they connect the present structure with processes operating in the past. Nor are they explanations presented without independent evidence or critical analysis - Darwin's hypotheses about the mechanisms underlying present-day variation could be independently tested and validated. With a Darwinian framework in mind, it is easy to see that a great deal of hydrologic research has already been done that contributes to a Darwinian hydrology - whether deliberately or not. We discuss some practical and philosophical issues with this approach to hydrologic science: how are explanatory hypotheses generated? What constitutes a good hypothesis? How are hypotheses tested? "Historical" sciences - including paleohydrology - have long grappled with these questions, as must a Darwinian hydrologic science. We can draw on Darwin's own example for some answers, though there are ongoing debates about the philosophical nature of his methods and reasoning. Darwin used a range of methods of historical reasoning to develop explanatory hypotheses: extrapolating mechanisms, space for time substitution, and looking for signatures of history. Some of these are already in use, while others are not and could be used to develop new insights. He sought explanatory hypotheses that intelligibly unified disparate facts, were testable against evidence, and had fertile implications for further research. He provided evidence to support his hypotheses by deducing corollary conditions ("if explanation A is true, then B will also be true") and comparing these to observations. While a synthesis of the Darwinian and Newtonian approaches remains a goal, the Darwinian approach to hydrologic science has significant value of its own. The Darwinian hydrology that has been conducted already has not been coordinated or linked into a general body of theory and knowledge, but the time is coming when this will be possible.
Globally, many different kinds of water resources management issues call for policy- and infrastructure-based responses. Yet responsible decision-making about water resources management raises a ...fundamental challenge for hydrologists: making predictions about water resources on decadal- to century-long timescales. Obtaining insight into hydrologic futures over 100 yr timescales forces researchers to address internal and exogenous changes in the properties of hydrologic systems. To do this, new hydrologic research must identify, describe and model feedbacks between water and other changing, coupled environmental subsystems. These models must be constrained to yield useful insights, despite the many likely sources of uncertainty in their predictions. Chief among these uncertainties are the impacts of the increasing role of human intervention in the global water cycle - a defining challenge for hydrology in the Anthropocene. Here we present a research agenda that proposes a suite of strategies to address these challenges from the perspectives of hydrologic science research. The research agenda focuses on the development of co-evolutionary hydrologic modeling to explore coupling across systems, and to address the implications of this coupling on the long-time behavior of the coupled systems. Three research directions support the development of these models: hydrologic reconstruction, comparative hydrology and model-data learning. These strategies focus on understanding hydrologic processes and feedbacks over long timescales, across many locations, and through strategic coupling of observational and model data in specific systems. We highlight the value of use-inspired and team-based science that is motivated by real-world hydrologic problems but targets improvements in fundamental understanding to support decision-making and management. Fully realizing the potential of this approach will ultimately require detailed integration of social science and physical science understanding of water systems, and is a priority for the developing field of sociohydrology.
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