Oncogenic signals prime cancer cells for toxic cell overgrowth during a G1 cell cycle arrest.

CDK4/6 inhibitors are remarkable anti-cancer drugs that can arrest tumor cells in G1 and induce their senescence while causing only relatively mild toxicities in healthy tissues. How they achieve this mechanistically is unclear. We show here that tumor cells are specifically vulnerable to CDK4/6 inhibition because during the G1 arrest, oncogenic signals drive toxic cell overgrowth. This overgrowth causes permanent cell cycle withdrawal by either preventing progression from G1 or inducing genotoxic damage during the subsequent S-phase and mitosis. Inhibiting or reverting oncogenic signals that converge onto mTOR can rescue this excessive growth, DNA damage, and cell cycle exit in cancer cells. Conversely, inducing oncogenic signals in non-transformed cells can drive these toxic phenotypes and sensitize the cells to CDK4/6 inhibition. Together, this demonstrates that cell cycle arrest and oncogenic cell growth is a synthetic lethal combination that is exploited by CDK4/6 inhibitors to induce tumor-specific toxicity.

CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence.

Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2- breast cancer. We demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. We propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal.

CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long-lasting effects on tumour growth. Here, we demonstrate that a prolonged G1 arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53-dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.

Recommendations for quantifying and reducing uncertainty in climate projections of species distributions.

Projecting the future distributions of commercially and ecologically important species has become a critical approach for ecosystem managers to strategically anticipate change, but large uncertainties in projections limit climate adaptation planning. Although distribution projections are primarily used to understand the scope of potential change-rather than accurately predict specific outcomes-it is nonetheless essential to understand where and why projections can give implausible results and to identify which processes contribute to uncertainty. Here, we use a series of simulated species distributions, an ensemble of 252 species distribution models, and an ensemble of three regional ocean climate projections, to isolate the influences of uncertainty from earth system model spread and from ecological modeling. The simulations encompass marine species with different functional traits and ecological preferences to more broadly address resource manager and fishery stakeholder needs, and provide a simulated true state with which to evaluate projections. We present our results relative to the degree of environmental extrapolation from historical conditions, which helps facilitate interpretation by ecological modelers working in diverse systems. We found uncertainty associated with species distribution models can exceed uncertainty generated from diverging earth system models (up to 70% of total uncertainty by 2100), and that this result was consistent across species traits. Species distribution model uncertainty increased through time and was primarily related to the degree to which models extrapolated into novel environmental conditions but moderated by how well models captured the underlying dynamics driving species distributions. The predictive power of simulated species distribution models remained relatively high in the first 30 years of projections, in alignment with the time period in which stakeholders make strategic decisions based on climate information. By understanding sources of uncertainty, and how they change at different forecast horizons, we provide recommendations for projecting species distribution models under global climate change.

Marine heatwaves disrupt ecosystem structure and function via altered food webs and energy flux.

The prevalence and intensity of marine heatwaves is increasing globally, disrupting local environmental conditions. The individual and population-level impacts of prolonged heatwaves on marine species have recently been demonstrated, yet whole-ecosystem consequences remain unexplored. We leveraged time series abundance data of 361 taxa, grouped into 86 functional groups, from six long-term surveys, diet information from a new diet database, and previous modeling efforts, to build two food web networks using an extension of the popular Ecopath ecosystem modeling framework, Ecotran. We compare ecosystem models parameterized before and after the onset of recent marine heatwaves to evaluate the cascading effects on ecosystem structure and function in the Northeast Pacific Ocean. While the ecosystem-level contribution (prey) and demand (predators) of most functional groups changed following the heatwaves, gelatinous taxa experienced the largest transformations, underscored by the arrival of northward-expanding pyrosomes. We show altered trophic relationships and energy flux have potentially profound consequences for ecosystem structure and function, and raise concerns for populations of threatened and harvested species.

An updated end-to-end ecosystem model of the Northern California Current reflecting ecosystem changes due to recent marine heatwaves.

The Northern California Current is a highly productive marine upwelling ecosystem that is economically and ecologically important. It is home to both commercially harvested species and those that are federally listed under the U.S. Endangered Species Act. Recently, there has been a global shift from single-species fisheries management to ecosystem-based fisheries management, which acknowledges that more complex dynamics can reverberate through a food web. Here, we have integrated new research into an end-to-end ecosystem model (i.e., physics to fisheries) using data from long-term ocean surveys, phytoplankton satellite imagery paired with a vertically generalized production model, a recently assembled diet database, fishery catch information, species distribution models, and existing literature. This spatially-explicit model includes 90 living and detrital functional groups ranging from phytoplankton, krill, and forage fish to salmon, seabirds, and marine mammals, and nine fisheries that occur off the coast of Washington, Oregon, and Northern California. This model was updated from previous regional models to account for more recent changes in the Northern California Current (e.g., increases in market squid and some gelatinous zooplankton such as pyrosomes and salps), to expand the previous domain to increase the spatial resolution, to include data from previously unincorporated surveys, and to add improved characterization of endangered species, such as Chinook salmon (Oncorhynchus tshawytscha) and southern resident killer whales (Orcinus orca). Our model is mass-balanced, ecologically plausible, without extinctions, and stable over 150-year simulations. Ammonium and nitrate availability, total primary production rates, and model-derived phytoplankton time series are within realistic ranges. As we move towards holistic ecosystem-based fisheries management, we must continue to openly and collaboratively integrate our disparate datasets and collective knowledge to solve the intricate problems we face. As a tool for future research, we provide the data and code to use our ecosystem model.

Incorporating climate science in applications of the US endangered species act for aquatic species.

Aquatic species are threatened by climate change but have received comparatively less attention than terrestrial species. We gleaned key strategies for scientists and managers seeking to address climate change in aquatic conservation planning from the literature and existing knowledge. We address 3 categories of conservation effort that rely on scientific analysis and have particular application under the U.S. Endangered Species Act (ESA): assessment of overall risk to a species; long-term recovery planning; and evaluation of effects of specific actions or perturbations. Fewer data are available for aquatic species to support these analyses, and climate effects on aquatic systems are poorly characterized. Thus, we recommend scientists conducting analyses supporting ESA decisions develop a conceptual model that links climate, habitat, ecosystem, and species response to changing conditions and use this model to organize analyses and future research. We recommend that current climate conditions are not appropriate for projections used in ESA analyses and that long-term projections of climate-change effects provide temporal context as a species-wide assessment provides spatial context. In these projections, climate change should not be discounted solely because the magnitude of projected change at a particular time is uncertain when directionality of climate change is clear. Identifying likely future habitat at the species scale will indicate key refuges and potential range shifts. However, the risks and benefits associated with errors in modeling future habitat are not equivalent. The ESA offers mechanisms for increasing the overall resilience and resistance of species to climate changes, including establishing recovery goals requiring increased genetic and phenotypic diversity, specifying critical habitat in areas not currently occupied but likely to become important, and using adaptive management. Incorporación de las Ciencias Climáticas en las Aplicaciones del Acta Estadunidense de Especies en Peligro para Especies Acuáticas.

Do species' traits predict recent shifts at expanding range edges?

Although some organisms have moved to higher elevations and latitudes in response to recent climate change, there is little consensus regarding the capacity of different species to track rapid climate change via range shifts. Understanding species' abilities to shift ranges has important implications for assessing extinction risk and predicting future community structure. At an expanding front, colonization rates are determined jointly by rates of reproduction and dispersal. In addition, establishment of viable populations requires that individuals find suitable resources in novel habitats. Thus, species with greater dispersal ability, reproductive rate and ecological generalization should be more likely to expand into new regions under climate change. Here, we assess current evidence for the relationship between leading-edge range shifts and species' traits. We found expected relationships for several datasets, including diet breadth in North American Passeriformes and egg-laying habitat in British Odonata. However, models generally had low explanatory power. Thus, even statistically and biologically meaningful relationships are unlikely to be of predictive utility for conservation and management. Trait-based range shift forecasts face several challenges, including quantifying relevant natural history variation across large numbers of species and coupling these data with extrinsic factors such as habitat fragmentation and availability.

Using time series analysis to characterize evolutionary and plastic responses to environmental change: a case study of a shift toward earlier migration date in sockeye salmon.

Environmental change can shift the phenotype of an organism through either evolutionary or nongenetic processes. Despite abundant evidence of phenotypic change in response to recent climate change, we typically lack sufficient genetic data to identify the role of evolution. We present a method of using phenotypic data to characterize the hypothesized role of natural selection and environmentally driven phenotypic shifts (plasticity). We modeled historical selection and environmental predictors of interannual variation in mean population phenotype using a multivariate state-space model framework. Through model comparisons, we assessed the extent to which an estimated selection differential explained observed variation better than environmental factors alone. We applied the method to a 60-year trend toward earlier migration in Columbia River sockeye salmon Oncorhynchus nerka, producing estimates of annual selection differentials, average realized heritability, and relative cumulative effects of selection and plasticity. We found that an evolutionary response to thermal selection was capable of explaining up to two-thirds of the phenotypic trend. Adaptive plastic responses to June river flow explain most of the remainder. This method is applicable to other populations with time series data if selection differentials are available or can be reconstructed. This method thus augments our toolbox for predicting responses to environmental change.

Differential impacts of freshwater and marine covariates on wild and hatchery Chinook salmon marine survival.

Large-scale atmospheric conditions in the Northeast Pacific Ocean affect both the freshwater environment in the Columbia River Basin and marine conditions along the coasts of Oregon, Washington, and British Columbia, resulting in correlated conditions in the two environments. For migrating species, such as salmonids that move through multiple habitats, these correlations can amplify the impact of good or poor physical conditions on growth and survival, as movements among habitats may not alleviate effects of anomalous conditions. Unfortunately, identifying the mechanistic drivers of salmon survival in space and time is hindered by these cross-habitat correlations. To address this issue, we modeled the marine survival of Snake River spring/summer Chinook salmon with multiple indices of the marine environment and an explicit treatment of the effect of arrival timing from freshwater to the ocean, and found that both habitats contribute to marine survival rates. We show how this particular carryover effect of freshwater conditions on marine survival varies by year and rearing type (hatchery or wild), with a larger effect for wild fish. As environmental conditions change, incorporating effects from both freshwater and marine habitats into salmon survival models will become more important, and has the additional benefit of highlighting how management actions that affect arrival timing may improve marine survival.

Environmentally triggered shifts in steelhead migration behavior and consequences for survival in the mid-Columbia River.

The majority of Columbia River summer-run steelhead encounter high river temperatures (near or > 20°C) during their spawning migration. While some steelhead pass through the mid-Columbia River in a matter of days, others use tributary habitats as temperature refuges for periods that can last months. Using PIT tag detection data from adult return years 2004-2016, we fit 3-component mixture models to differentiate between "fast", "slow", and "overwintering" migration behaviors in five aggregated population groups. Fast fish migrated straight through the reach on average in ~7-9 days while slow fish delayed their migration for weeks to months, and overwintering fish generally took ~150-250 days. We then fit covariate models to examine what factors contributed to the probability of migration delay during summer months (slow or overwintering behaviors), and to explore how migration delay related to mortality. Finally, to account for the impact of extended residence times in the reach for fish that delayed, we compared patterns in estimated average daily rates of mortality between migration behaviors and across population groups. Results suggest that migration delay was primarily triggered by high river temperatures but temperature thresholds for delay were lowest just before the seasonal peak in river temperatures. While all populations groups demonstrated these general patterns, we documented substantial variability in temperature thresholds and length of average delays across population groups. Although migration delay was related to higher reach mortality, it was also related to lower average daily mortality rates due to the proportional increase in reach passage duration being larger than the associated increase in mortality. Lower daily mortality rates suggest that migration delay could help mitigate the impacts of harsh migration conditions, presumably through the use of thermal refuges, despite prolonged exposure to local fisheries. Future studies tracking individual populations from their migration through reproduction could help illuminate the full extent of the tradeoffs between different migration behaviors.

Climate change threatens Chinook salmon throughout their life cycle.

Widespread declines in Atlantic and Pacific salmon (Salmo salar and Oncorhynchus spp.) have tracked recent climate changes, but managers still lack quantitative projections of the viability of any individual population in response to future climate change. To address this gap, we assembled a vast database of survival and other data for eight wild populations of threatened Chinook salmon (O. tshawytscha). For each population, we evaluated climate impacts at all life stages and modeled future trajectories forced by global climate model projections. Populations rapidly declined in response to increasing sea surface temperatures and other factors across diverse model assumptions and climate scenarios. Strong density dependence limited the number of salmon that survived early life stages, suggesting a potentially efficacious target for conservation effort. Other solutions require a better understanding of the factors that limit survival at sea. We conclude that dramatic increases in smolt survival are needed to overcome the negative impacts of climate change for this threatened species.

Can mechanism inform species' distribution models?

Two major approaches address the need to predict species distributions in response to environmental changes. Correlative models estimate parameters phenomenologically by relating current distributions to environmental conditions. By contrast, mechanistic models incorporate explicit relationships between environmental conditions and organismal performance, estimated independently of current distributions. Mechanistic approaches include models that translate environmental conditions into biologically relevant metrics (e.g. potential duration of activity), models that capture environmental sensitivities of survivorship and fecundity, and models that use energetics to link environmental conditions and demography. We compared how two correlative and three mechanistic models predicted the ranges of two species: a skipper butterfly (Atalopedes campestris) and a fence lizard (Sceloporus undulatus). Correlative and mechanistic models performed similarly in predicting current distributions, but mechanistic models predicted larger range shifts in response to climate change. Although mechanistic models theoretically should provide more accurate distribution predictions, there is much potential for improving their flexibility and performance.

Interacting effects of density and temperature on body size in multiple populations of Chinook salmon.

1. The size individuals attain reflects complex interactions between food availability and quality, environmental conditions and ecological interactions. A statistical interaction between temperature and the density of conspecifics is expected to arise from various ecological dynamics, including bioenergetic constraints, if population density affects mean consumption rate or activity level. Density effects on behaviour or size-selective predation could also generate this pattern. This interaction plays an important role in bioenergetic models, in particular, and yet has not been documented in natural populations. 2. The lengths of 131 286 juvenile wild Chinook salmon (Oncorhynchus tshawytscha) across 13 populations spread throughout the Salmon River Basin, Idaho, USA over 15 years were compared to test whether juvenile density alters the relationship between body size and temperature. 3. Strong evidence for a negative interaction between mean summer temperature and density emerged, despite the relatively cool temperatures in this high elevation habitat. Growth correlated positively with temperature at lower densities, but the correlation was negative at the highest densities. 4. This is the first study to document this interaction at such a large spatial and temporal scale, and suggests that warmer temperatures might intensify some density-dependent processes. How climate change will affect individual growth rates in these populations will depend intimately on ecological conditions, particularly food availability and population dynamics. More broadly, the conditions that led to the interactions observed in our study - limited food availability and temperatures that ranged above those optimal for growth - likely exist for many other natural populations, and warrant broader exploration.

Snake River sockeye and Chinook salmon in a changing climate: Implications for upstream migration survival during recent extreme and future climates.

In 2015, the Pacific marine heat wave, low river flows, and record high water temperatures in the Columbia River Basin contributed to a near-complete failure of the adult migration of endangered Snake River sockeye salmon (Oncorhynchus nerka, NOAA Fisheries 2016). These extreme weather events may become the new normal due to anthropogenic climate change, with catastrophic consequences for endangered species. Existing anthropogenic pressures may amplify vulnerability to climate change, but these potential synergies have rarely been quantified. We examined factors affecting survival of endangered sockeye (Oncorhynchus nerka) and threatened Chinook salmon (O. tshawytscha) as they migrated upstream through eight dams and reservoirs to spawning areas in the Snake River Basin. Our extensive database included histories of 17,279 individual fish that migrated since 2004. A comparison between conditions in 2015 and daily temperatures and flows in a regulated basin forced by output from global climate models showed that 2015 did have many characteristics of projected future mean conditions. To evaluate potential salmon responses, we modeled migration timing and apparent survival under historical and future climate scenarios (2040s). For Chinook salmon, adult survival from the first dam encountered to spawning grounds dropped by 4-15%, depending on the climate scenario. For sockeye, survival dropped by ~80% from their already low levels. Through sensitivity analyses, we observed that the adult sockeye migration would need to shift more than 2 weeks earlier than predicted to maintain survival rates typical of those seen during 2008-2017. Overall, the greater impacts of climate change on adult sockeye compared with adult Chinook salmon reflected differences in life history and environmental sensitivities, which were compounded for sockeye by larger effect sizes from other anthropogenic factors. Compared with Chinook, sockeye was more negatively affected by a history of juvenile transportation and by similar temperatures and flows. The largest changes in temperature and flow were projected to be upstream from the hydrosystem, where direct mitigation through hydrosystem management is not an option. Unfortunately, Snake River sockeye have likely lost much of their adaptive capacity with the loss of the wild population. Further work exploring habitat restoration or additional mitigation actions is urgently needed.

Climate change effects on biodiversity, ecosystems, ecosystem services, and natural resource management in the United States.

Climate change is a pervasive and growing global threat to biodiversity and ecosystems. Here, we present the most up-to-date assessment of climate change impacts on biodiversity, ecosystems, and ecosystem services in the U.S. and implications for natural resource management. We draw from the 4th National Climate Assessment to summarize observed and projected changes to ecosystems and biodiversity, explore linkages to important ecosystem services, and discuss associated challenges and opportunities for natural resource management. We find that species are responding to climate change through changes in morphology and behavior, phenology, and geographic range shifts, and these changes are mediated by plastic and evolutionary responses. Responses by species and populations, combined with direct effects of climate change on ecosystems (including more extreme events), are resulting in widespread changes in productivity, species interactions, vulnerability to biological invasions, and other emergent properties. Collectively, these impacts alter the benefits and services that natural ecosystems can provide to society. Although not all impacts are negative, even positive changes can require costly societal adjustments. Natural resource managers need proactive, flexible adaptation strategies that consider historical and future outlooks to minimize costs over the long term. Many organizations are beginning to explore these approaches, but implementation is not yet prevalent or systematic across the nation.

Division of labour between PP2A-B56 isoforms at the centromere and kinetochore.

PP2A-B56 is a serine/threonine phosphatase complex that regulates several major mitotic processes, including sister chromatid cohesion, kinetochore-microtubule attachment and the spindle assembly checkpoint. We show here that these key functions are divided between different B56 isoforms that localise to either the centromere or kinetochore. The centromeric isoforms rely on a specific interaction with Sgo2, whereas the kinetochore isoforms bind preferentially to BubR1 and other proteins containing an LxxIxE motif. In addition to these selective binding partners, Sgo1 helps to anchor PP2A-B56 at both locations: it collaborates with BubR1 to maintain B56 at the kinetochore and it helps to preserve the Sgo2/B56 complex at the centromere. A series of chimaeras were generated to map the critical region in B56 down to a small C-terminal loop that regulates the key interactions and defines B56 localisation. Together, this study describes how different PP2A-B56 complexes utilise isoform-specific interactions to control distinct processes during mitosis.

Climate vulnerability assessment for Pacific salmon and steelhead in the California Current Large Marine Ecosystem.

Major ecological realignments are already occurring in response to climate change. To be successful, conservation strategies now need to account for geographical patterns in traits sensitive to climate change, as well as climate threats to species-level diversity. As part of an effort to provide such information, we conducted a climate vulnerability assessment that included all anadromous Pacific salmon and steelhead (Oncorhynchus spp.) population units listed under the U.S. Endangered Species Act. Using an expert-based scoring system, we ranked 20 attributes for the 28 listed units and 5 additional units. Attributes captured biological sensitivity, or the strength of linkages between each listing unit and the present climate; climate exposure, or the magnitude of projected change in local environmental conditions; and adaptive capacity, or the ability to modify phenotypes to cope with new climatic conditions. Each listing unit was then assigned one of four vulnerability categories. Units ranked most vulnerable overall were Chinook (O. tshawytscha) in the California Central Valley, coho (O. kisutch) in California and southern Oregon, sockeye (O. nerka) in the Snake River Basin, and spring-run Chinook in the interior Columbia and Willamette River Basins. We identified units with similar vulnerability profiles using a hierarchical cluster analysis. Life history characteristics, especially freshwater and estuary residence times, interplayed with gradations in exposure from south to north and from coastal to interior regions to generate landscape-level patterns within each species. Nearly all listing units faced high exposures to projected increases in stream temperature, sea surface temperature, and ocean acidification, but other aspects of exposure peaked in particular regions. Anthropogenic factors, especially migration barriers, habitat degradation, and hatchery influence, have reduced the adaptive capacity of most steelhead and salmon populations. Enhancing adaptive capacity is essential to mitigate for the increasing threat of climate change. Collectively, these results provide a framework to support recovery planning that considers climate impacts on the majority of West Coast anadromous salmonids.

Combining population-dynamic and ecophysiological models to predict climate-induced insect range shifts.

Hundreds of species are shifting their ranges in response to recent climate warming. To predict how continued climate warming will affect the potential, or "bioclimatic range," of a skipper butterfly, we present a population­dynamic model of range shift in which population growth is a function of temperature. We estimate the parameters of this model using previously published data for Atalopedes campestris. Summer and winter temperatures affect population growth rate independently in this species and therefore interact as potential range­limiting factors. Our model predicts a two­phase response to climate change; one range­limiting factor gradually becomes dominant, even if warming occurs steadily along a thermally linear landscape. Whether the range shift accelerates or decelerates and whether the number of generations per year at the range edge increases or decreases depend on whether summer or winter warms faster. To estimate the uncertainty in our predictions of range shift, we use a parametric bootstrap of biological parameter values. Our results show that even modest amounts of data yield predictions with reasonably small confidence intervals, indicating that ecophysiological models can be useful in predicting range changes. Nevertheless, the confidence intervals are sensitive to regional differences in the underlying thermal landscape and the warming scenario.

Plastic and evolutionary responses to climate change in fish.

The physical and ecological 'fingerprints' of anthropogenic climate change over the past century are now well documented in many environments and taxa. We reviewed the evidence for phenotypic responses to recent climate change in fish. Changes in the timing of migration and reproduction, age at maturity, age at juvenile migration, growth, survival and fecundity were associated primarily with changes in temperature. Although these traits can evolve rapidly, only two studies attributed phenotypic changes formally to evolutionary mechanisms. The correlation-based methods most frequently employed point largely to 'fine-grained' population responses to environmental variability (i.e. rapid phenotypic changes relative to generation time), consistent with plastic mechanisms. Ultimately, many species will likely adapt to long-term warming trends overlaid on natural climate oscillations. Considering the strong plasticity in all traits studied, we recommend development and expanded use of methods capable of detecting evolutionary change, such as the long term study of selection coefficients and temporal shifts in reaction norms, and increased attention to forecasting adaptive change in response to the synergistic interactions of the multiple selection pressures likely to be associated with climate change.