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River flow is mainly controlled by climate, physiography and regulations, but their relative importance over large landmasses is poorly understood. Here we show from computational modelling that hydropower regulation is a key driver of flow regime change in snow-dominated regions and is more important than future climate changes. This implies that climate adaptation needs to include regulation schemes. The natural river regime in snowy regions has low flow when snow is stored and a pronounced peak flow when snow is melting. Global warming and hydropower regulation change this temporal pattern similarly, causing less difference in river flow between seasons. We conclude that in snow-fed rivers globally, the future climate change impact on flow regime is minor compared to regulation downstream of large reservoirs, and of similar magnitude over large landmasses. Our study not only highlights the impact of hydropower production but also that river regulation could be turned into a measure for climate adaptation to maintain biodiversity on floodplains under climate change. Global warming and hydropower regulations are major threats to future fresh-water availability and biodiversity. Here, the authors show that their impact on flow regime over a large landmass result in similar changes, but hydropower is more critical locally and may have potential for climate adaptation in floodplains.

Matter-wave interferometers provide an opportunity to measure whether quantum superpositions exist at macroscopic length scales or only at microscopically small scales; now such instruments have demonstrated quantum interference of wave packets separated by 54 cm. Macroscopic quantum superposition Matter-wave interferometers, which allow for the observation of interference pattern of atomic wave packets that are split and recombined, have proven to be useful tools in precision metrology and fundamental research. These interferometers provide an opportunity to measure whether quantum superpositions exist at macroscopic length scales or only at microscopically small scales. But a truly macroscopic scale that would be necessary for such a test had not been reached in matter-wave interferometers to date. Here the authors show quantum interference of wave packets separated by 54 cm. Their matter-wave interferometer also promises increased sensitivity in precision tests, for example, when measuring the equivalence principle or measuring gravity. The quantum superposition principle allows massive particles to be delocalized over distant positions. Though quantum mechanics has proved adept at describing the microscopic world, quantum superposition runs counter to intuitive conceptions of reality and locality when extended to the macroscopic scale 1 , as exemplified by the thought experiment of Schrödinger’s cat 2 . Matter-wave interferometers 3 , which split and recombine wave packets in order to observe interference, provide a way to probe the superposition principle on macroscopic scales 4 and explore the transition to classical physics 5 . In such experiments, large wave-packet separation is impeded by the need for long interaction times and large momentum beam splitters, which cause susceptibility to dephasing and decoherence 1 . Here we use light-pulse atom interferometry 6 , 7 to realize quantum interference with wave packets separated by up to 54 centimetres on a timescale of 1 second. These results push quantum superposition into a new macroscopic regime, demonstrating that quantum superposition remains possible at the distances and timescales of everyday life. The sub-nanokelvin temperatures of the atoms and a compensation of transverse optical forces enable a large separation while maintaining an interference contrast of 28 per cent. In addition to testing the superposition principle in a new regime, large quantum superposition states are vital to exploring gravity with atom interferometers in greater detail. We anticipate that these states could be used to increase sensitivity in tests of the equivalence principle 8 , 9 , 10 , 11 , 12 , measure the gravitational Aharonov–Bohm effect 13 , and eventually detect gravitational waves 14 and phase shifts associated with general relativity 12 .

Up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis; here, in a systematic and nationwide study of 1,133 children with severe, undiagnosed developmental disorders, and their parents, exome sequencing and array-based detection of chromosomal rearrangements reveals novel genes causing developmental disorders, increasing the proportion of children that can now be diagnosed to 31%. Gene linkage to developmental disorders Until recently, the discovery of the genetic causes of monogenic disorders has been predominantly phenotype-driven. Up to half of all children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. This publication from The Deciphering Developmental Disorders Study presents a UK-wide systematic genetic analysis of 1,133 children with severe, undiagnosed developmental disorders, and their parents. Exome sequencing and array-based detection of chromosomal rearrangements revealed 12 previously unknown developmental disorder genes and increased the proportion of children that could be diagnosed by 10%. Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders 1 , up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach 2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Climate change impacts on water availability and hydrological extremes are major concerns as regards the Sustainable Development Goals. Impacts on hydrology are normally investigated as part of a modelling chain, in which climate projections from multiple climate models are used as inputs to multiple impact models, under different greenhouse gas emissions scenarios, which result in different amounts of global temperature rise. While the goal is generally to investigate the relevance of changes in climate for the water cycle, water resources or hydrological extremes, it is often the case that variations in other components of the model chain obscure the effect of climate scenario variation. This is particularly important when assessing the impacts of relatively lower magnitudes of global warming, such as those associated with the aspirational goals of the Paris Agreement. In our study, we use ANOVA (analyses of variance) to allocate and quantify the main sources of uncertainty in the hydrological impact modelling chain. In turn we determine the statistical significance of different sources of uncertainty. We achieve this by using a set of five climate models and up to 13 hydrological models, for nine large scale river basins across the globe, under four emissions scenarios. The impact variable we consider in our analysis is daily river discharge. We analyze overall water availability and flow regime, including seasonality, high flows and low flows. Scaling effects are investigated by separately looking at discharge generated by global and regional hydrological models respectively. Finally, we compare our results with other recently published studies. We find that small differences in global temperature rise associated with some emissions scenarios have mostly significant impacts on river discharge-however, climate model related uncertainty is so large that it obscures the sensitivity of the hydrological system.

The kinematic mechanisms associated with elevated externally applied valgus knee moments during non-contact sidestepping and subsequent anterior cruciate ligament (ACL) injury risk are not well understood. To address this issue, the residual reduction algorithm (RRA) in OpenSim was used to create nine subject-specific, full-body (37 degrees of freedom) torque-driven simulations of athletic males performing unplanned sidestep (UnSS) sport tasks. The RRA was used again to produce an optimized kinematic solution with reduced peak valgus knee torques during the weight acceptance phase of stance. Pre-to-post kinematic optimization, mean peak valgus knee moments were significantly reduced by 44.2Nm (p=0.045). Nine of a possible 37 upper and lower body kinematic changes in all three planes of motion were consistently used during the RRA to decrease peak valgus knee moments. The generalized kinematic strategy used by all nine simulations to reduce peak valgus knee moments and subsequent ACL injury risk during UnSS was to redirect the whole-body center of mass medially, towards the desired direction of travel.

Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell—mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.

Nutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of cancer and inflammatory diseases. MIF is constitutively present in several cell types and non-lymphoid tissues and is secreted after acute stress or inflammation. MIF triggers the release of proinflammatory cytokines, overrides the anti-inflammatory effects of glucocorticoids, and exerts chemokine function, resulting in increased migration and recruitment of leukocytes into inflamed tissue. Despite this, MIF is a challenging target for therapeutic intervention because of its ubiquitous nature and presence in the circulation and tissue of healthy individuals. Oxidized MIF (oxMIF) is an immunologically distinct disease-related structural isoform found in the plasma and tissues of patients with inflammatory diseases and in solid tumor tissues. MIF converts to oxMIF in an oxidizing, inflammatory environment. This review discusses the biology and activity of MIF and the potential for autoimmune disease and cancer modification by targeting oxMIF. Anti-oxMIF antibodies reduce cancer cell invasion/migration, angiogenesis, proinflammatory cytokine production, and ERK and AKT activation. Anti-oxMIF antibodies also elicit apoptosis and alter immune cell function and/or migration. When co-administered with a glucocorticoid, anti-oxMIF antibodies produced a synergistic response in inflammatory models. Anti-oxMIF antibodies therefore counterregulate biological activities attributed to MIF. oxMIF expression has been observed in inflammatory diseases (eg, sepsis, psoriasis, asthma, inflammatory bowel disease, and systemic lupus erythematosus) and oxMIF has been detected in ovarian, colorectal, lung, and pancreatic cancers. In contrast to MIF, oxMIF is specifically detected in plasma and/or tissues of diseased patients, but not in healthy individuals. Therefore, as a druggable isoform of MIF, oxMIF represents a potential new therapeutic target in inflammatory diseases and cancer. Fully human, monoclonal anti-oxMIF antibodies have been shown to selectively bind oxMIF in preclinical and phase I studies; however, additional clinical assessments are necessary to validate their use as either a monotherapy or in combination with standard-of-care regimens (ie, immunomodulatory agents/checkpoint inhibitors, anti-angiogenic drugs, chemotherapeutics, and glucocorticoids).

The paper investigates climate change impacts on streamflow seasonality for a set of eleven representative large river basins covering all continents and a wide range of climatic and physiographic settings. Based on an ensemble of nine regional hydrological models driven by climate projections derived from five global circulation models under four representative concentration pathways, we analyzed the median and range of projected changes in seasonal streamflow by the end of the twenty-first century and examined the uncertainty arising from the different members of the modelling chain. Climate change impacts on the timing of seasonal streamflow were found to be small except for two basins. In many basins, we found an acceleration of the existing seasonality pattern, i.e. high-flows are projected to increase and/or low-flows are projected to decrease. In some basins the hydrologic projections indicate opposite directions of change which cancel out in the ensemble median, i.e., no robust conclusions could be drawn. In the majority of the basins, differences in projected streamflow seasonality between the low emission pathway and the high emission pathway are small with the exception of four basins. For these basins our results allow conclusions on the potential benefits (or adverse effects) of avoided GHG emissions for the seasonal streamflow regime.