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Mutations in voltage-gated ion channels are responsible for several types of epilepsy. Genetic epilepsies often exhibit variable severity in individuals with the same mutation, which may be due to variation in genetic modifiers. The Scn2aQ⁵⁴ transgenic mouse model has a sodium channel mutation and exhibits epilepsy with strain-dependent severity. We previously mapped modifier loci that influence Scn2aQ⁵⁴ phenotype severity and identified Kcnv2, encoding the voltage-gated potassium channel subunit Kv8.2, as a candidate modifier. In this study, we demonstrate a threefold increase in hippocampal Kcnv2 expression associated with more severe epilepsy. In vivo exacerbation of the phenotype by Kcnv2 transgenes supports its identification as an epilepsy modifier. The contribution of KCNV2 to human epilepsy susceptibility is supported by identification of two nonsynonymous variants in epilepsy patients that alter function of Kv2.1/Kv8.2 heterotetrameric potassium channels. Our results demonstrate that altered potassium subunit function influences epilepsy susceptibility and implicate Kcnv2 as an epilepsy gene.

Ocean warming will cause widespread changes in species richness and assemblage composition over coming decades, with important implications for both conservation management and international ocean governance. Anticipating the effect of climate change on biodiversity, in particular on changes in community composition, is crucial for adaptive ecosystem management 1 but remains a critical knowledge gap 2 . Here, we use climate velocity trajectories 3 , together with information on thermal tolerances and habitat preferences, to project changes in global patterns of marine species richness and community composition under IPCC Representative Concentration Pathways 4 (RCPs) 4.5 and 8.5. Our simple, intuitive approach emphasizes climate connectivity, and enables us to model over 12 times as many species as previous studies 5 , 6 . We find that range expansions prevail over contractions for both RCPs up to 2100, producing a net local increase in richness globally, and temporal changes in composition, driven by the redistribution rather than the loss of diversity. Conversely, widespread invasions homogenize present-day communities across multiple regions. High extirpation rates are expected regionally (for example, Indo-Pacific), particularly under RCP8.5, leading to strong decreases in richness and the anticipated formation of no-analogue communities where invasions are common. The spatial congruence of these patterns with contemporary human impacts 7 , 8 highlights potential areas of future conservation concern. These results strongly suggest that the millennial stability of current global marine diversity patterns, against which conservation plans are assessed, will change rapidly over the course of the century in response to ocean warming.

Climate change is driving changes in the physical and chemical properties of the ocean that have consequences for marine ecosystems. Here, we review evidence for the responses of marine life to recent climate change across ocean regions, from tropical seas to polar oceans. We consider observed changes in calcification rates, demography, abundance, distribution and phenology of marine species. We draw on a database of observed climate change impacts on marine species, supplemented with evidence in the Fifth Assessment Report of the Intergovernmental Panel on Climate Change. We discuss factors that limit or facilitate species’ responses, such as fishing pressure, the availability of prey, habitat, light and other resources, and dispersal by ocean currents. We find that general trends in species responses are consistent with expectations from climate change, including poleward and deeper distributional shifts, advances in spring phenology, declines in calcification and increases in the abundance of warm-water species. The volume and type of evidence of species responses to climate change is variable across ocean regions and taxonomic groups, with much evidence derived from the heavily-studied north Atlantic Ocean. Most investigations of marine biological impacts of climate change are of the impacts of changing temperature, with few observations of effects of changing oxygen, wave climate, precipitation (coastal waters) or ocean acidification. Observations of species responses that have been linked to anthropogenic climate change are widespread, but are still lacking for some taxonomic groups (e.g., phytoplankton, benthic invertebrates, marine mammals).

As ocean temperatures rise, species distributions are tracking towards historically cooler regions in line with their thermal affinity1,2. However, different responses of species to warming and changed species interactions make predicting biodiversity redistribution and relative abundance a challenge3,4. Here, we use three decades of fish and plankton survey data to assess how warming changes the relative dominance of warm-affinity and cold-affinity species5,6. Regions with stable temperatures (for example, the Northeast Pacific and Gulf of Mexico) show little change in dominance structure, while areas with warming (for example, the North Atlantic) see strong shifts towards warm-water species dominance. Importantly, communities whose species pools had diverse thermal affinities and a narrower range of thermal tolerance showed greater sensitivity, as anticipated from simulations. The composition of fish communities changed less than expected in regions with strong temperature depth gradients. There, species track temperatures by moving deeper2,7, rather than horizontally, analogous to elevation shifts in land plants8. Temperature thus emerges as a fundamental driver for change in marine systems, with predictable restructuring of communities in the most rapidly warming areas using metrics based on species thermal affinities. The ready and predictable dominance shifts suggest a strong prognosis of resilience to climate change for these communities.

The COVID-19 pandemic has strained health system capacity worldwide due to a surge of hospital admissions, while mitigation measures have simultaneously reduced patients' access to health care, affecting the diagnosis and treatment of other diseases such as cancer. We estimated the impact of delayed diagnosis on cancer outcomes in Chile using a novel modelling approach to inform policies and planning to mitigate the forthcoming cancer-related health impacts of the pandemic in Chile. We developed a microsimulation model of five cancers in Chile (breast, cervix, colorectal, prostate, and stomach) for which reliable data were available, which simulates cancer incidence and progression in a nationally representative virtual population, as well as stage-specific cancer detection and survival probabilities. We calibrated the model to empirical data on monthly detected cases, as well as stage at diagnosis and 5-year net survival. We accounted for the impact of COVID-19 on excess mortality and cancer detection by month during the pandemic, and projected diagnosed cancer cases and outcomes of stage at diagnosis and survival up to 2030. For comparison, we simulated a no COVID-19 scenario in which the impacts of COVID-19 on excess mortality and cancer detection were removed. Our modelling showed a sharp decrease in the number of diagnosed cancer cases during the COVID-19 pandemic, with a large projected short-term increase in future diagnosed cases. Due to the projected backlog in diagnosis, we estimated that in 2021 there will be an extra 3198 cases (95% uncertainty interval [UI] 1356–5017) diagnosed among the five modelled cancers, an increase of nearly 14% compared with the no COVID-19 scenario, falling to a projected 10% increase in 2022 with 2674 extra cases (1318–4032) diagnosed. As a result of delayed diagnosis, we found a worse stage distribution for detected cancers in 2020–22, which is estimated to lead to 3542 excess cancer deaths (95% UI 2236–4816) in 2022–30, compared with the no COVID-19 scenario, among the five modelled cancers, most of which (3299 deaths, 2151–4431) are projected to occur before 2025. In addition to a large projected surge in diagnosed cancer cases, we found that delays in diagnosis will result in worse cancer stage at presentation, leading to worse survival outcomes. These findings can help to inform surge capacity planning and highlight the importance of ensuring appropriate health system capacity levels to detect and care for the increased cancer cases in the coming years, while maintaining the timeliness and quality of cancer care. Potential delays in treatment and adverse impacts on quality of care, which were not considered in this model, are likely to contribute to even more excess deaths from cancer than projected. Harvard TH Chan School of Public Health. For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

The conservation and sustainable use of marine resources is a highlighted goal on a growing number of national and international policy agendas. Unfortunately, efforts to assess progress, as well as to strategically plan and prioritize new marine conservation measures, have been hampered by the lack of a detailed, comprehensive biogeographic system to classify the oceans. Here we report on a new global system for coastal and shelf areas: the Marine Ecoregions of the World, or MEOW, a nested system of 12 realms, 62 provinces, and 232 ecoregions. This system provides considerably better spatial resolution than earlier global systems, yet it preserves many common elements and can be cross-referenced to many regional biogeographic classifications. The designation of terrestrial ecoregions has revolutionized priority setting and planning for terrestrial conservation; we anticipate similar benefits from the use of a coherent and credible marine system.

Massed synchronised neuronal firing is detrimental to information processing. When networks of task-irrelevant neurons fire in unison, they mask the signal generated by task-critical neurons. On a macroscopic level, such synchronisation can contribute to alpha/beta (8–30 Hz) oscillations. Reducing the amplitude of these oscillations, therefore, may enhance information processing. Here, we test this hypothesis. Twenty-one participants completed an associative memory task while undergoing simultaneous EEG-fMRI recordings. Using representational similarity analysis, we quantified the amount of stimulus-specific information represented within the BOLD signal on every trial. When correlating this metric with concurrently-recorded alpha/beta power, we found a significant negative correlation which indicated that as post-stimulus alpha/beta power decreased, stimulus-specific information increased. Critically, we found this effect in three unique tasks: visual perception, auditory perception, and visual memory retrieval, indicating that this phenomenon transcends both stimulus modality and cognitive task. These results indicate that alpha/beta power decreases parametrically track the fidelity of both externally-presented and internally-generated stimulus-specific information represented within the cortex.

Chromosomal instability (CIN) is a driver of cancer metastasis 1 – 4 , yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell–cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS–STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation. Chromosomal instability in cancer is linked to endoplasmic reticulum stress signalling, immune suppression and metastasis, which is mediated by the cGAS–STING pathway, suppression of which can reduce metastasis.

Diatoms are unicellular algae that accumulate significant amounts of triacylglycerols as storage lipids when their growth is limited by nutrients. Using biochemical, physiological, bioinformatics, and reverse genetic approaches, we analyzed how the flux of carbon into lipids is influenced by nitrogen stress in a model diatom, Phaeodactylum tricornutum . Our results reveal that the accumulation of lipids is a consequence of remodeling of intermediate metabolism, especially reactions in the tricarboxylic acid and the urea cycles. Specifically, approximately one-half of the cellular proteins are cannibalized; whereas the nitrogen is scavenged by the urea and glutamine synthetase/glutamine 2-oxoglutarate aminotransferase pathways and redirected to the de novo synthesis of nitrogen assimilation machinery, simultaneously, the photobiological flux of carbon and reductants is used to synthesize lipids. To further examine how nitrogen stress triggers the remodeling process, we knocked down the gene encoding for nitrate reductase, a key enzyme required for the assimilation of nitrate. The strain exhibits 40–50% of the mRNA copy numbers, protein content, and enzymatic activity of the wild type, concomitant with a 43% increase in cellular lipid content. We suggest a negative feedback sensor that couples photosynthetic carbon fixation to lipid biosynthesis and is regulated by the nitrogen assimilation pathway. This metabolic feedback enables diatoms to rapidly respond to fluctuations in environmental nitrogen availability. Significance When starved for nutrients, diatoms redirect carbon toward biosynthesis of storage lipids, triacylglycerols (TAGs). We examined how this modification is achieved in the diatom Phaeodactylum tricornutum. Under nitrogen stress, the cells cannibalized their photosynthetic apparatus while recycling intracellular nitrogen and redirecting it to synthesize nitrogen assimilation enzymes. Simultaneously, they allocated newly fixed carbon toward lipids. In contrast, a nitrate reductase knocked-down strain shunted ∼40% more carbon toward TAGs than the wild type without losing photosynthetic capacity. Our results show that diatoms can remodel their intermediate metabolism on environmental cues and reveal that a key signal in this remodeling is associated with nitrogen assimilation. This insight informs a strategy of developing a much more efficient pathway to produce algal-based biofuels.

Global maps constructed using climate-change velocities to derive spatial trajectories for climatic niches between 1960 and 2100 show past and future shifts in ecological climate niches; properties of these trajectories are used to infer changes in species distributions, and thus identify areas that will act as climate sources and sinks, and geographical barriers to species migrations. Species mobility in a changing climate To survive in a changing climate, a species may need to move in order to stay in an area with a constant average temperature. Such mobility would depend on an ability to keep pace with a moving climate — and on the absence of physical barriers to migration. These authors use the velocity of climate change to construct a global map of how ecological climate niches have shifted in recent decades and go on to predict changes in species distribution to the end of this century. The map indicates areas that will act as climate sources and sinks, and geographical barriers likely to impede species migration. The data show that geographical connections and physical barriers — mostly coasts — have profound effects on the expected ability of organisms to track their preferred climate. This work underlines the importance of migration corridors linking warmer and cooler areas as a means of maintaining biodiversity. The reorganization of patterns of species diversity driven by anthropogenic climate change, and the consequences for humans 1 , are not yet fully understood or appreciated 2 , 3 . Nevertheless, changes in climate conditions are useful for predicting shifts in species distributions at global 4 and local scales 5 . Here we use the velocity of climate change 6 , 7 to derive spatial trajectories for climatic niches from 1960 to 2009 (ref. 7 ) and from 2006 to 2100, and use the properties of these trajectories to infer changes in species distributions. Coastlines act as barriers and locally cooler areas act as attractors for trajectories, creating source and sink areas for local climatic conditions. Climate source areas indicate where locally novel conditions are not connected to areas where similar climates previously occurred, and are thereby inaccessible to climate migrants tracking isotherms: 16% of global surface area for 1960 to 2009, and 34% of ocean for the ‘business as usual’ climate scenario (representative concentration pathway (RCP) 8.5) 8 representing continued use of fossil fuels without mitigation. Climate sink areas are where climate conditions locally disappear, potentially blocking the movement of climate migrants. Sink areas comprise 1.0% of ocean area and 3.6% of land and are prevalent on coasts and high ground. Using this approach to infer shifts in species distributions gives global and regional maps of the expected direction and rate of shifts of climate migrants, and suggests areas of potential loss of species richness.