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The term \"environmental flows\" describes the quantities, quality, and patterns of water flows required to sustain freshwater and estuarine ecosystems and the ecosystem services they provide. Environmental flows may be achieved in a number of different ways, most of which are based on either (1) limiting alterations from the natural flow baseline to maintain biodiversity and ecological integrity or (2) designing flow regimes to achieve specific ecological and ecosystem service outcomes. We argue that the former practice is more applicable to natural and semi-natural rivers where the primary objective and opportunity is ecological conservation. The latter \"designer\" approach is better suited to modified and managed rivers where return to natural conditions is no longer feasible and the objective is to maximize natural capital as well as support economic growth, recreation, or cultural history. This permits elements of ecosystem design and adaptation to environmental change. In a future characterized by altered climates and intensive regulation, where hybrid and novel aquatic ecosystems predominate, the designer approach may be the only feasible option. This conclusion stems from a lack of natural ecosystems from which to draw analogs and the need to support broader socioeconomic benefits and valuable configurations of natural and social capital.

Adaptation services are the ecosystem processes and services that benefit people by increasing their ability to adapt to change. Benefits may accrue from existing but newly used services where ecosystems persist or from novel services supplied following ecosystem transformation. Ecosystem properties that enable persistence or transformation are important adaptation services because they support future options. The adaptation services approach can be applied to decisions on trade‐offs between currently valued services and benefits from maintaining future options. For example, ecosystem functions and services of floodplains depend on river flows. In those regions of the world where climate change projections are for hotter, drier conditions, floods will be less frequent and floodplains will either persist, though with modified structure and function, or transform to terrestrial (flood‐independent) ecosystems. Many currently valued ecosystem services will reduce in supply or become unavailable, but new options are provided by adaptation services. We present a case study from the Murray–Darling Basin, Australia, for operationalizing the adaptation services concept for floodplains and wetlands. We found large changes in flow and flood regimes are likely under a scenario of +1.6°C by 2030, even with additional water restored to rivers under the proposed Murray–Darling Basin Plan. We predict major changes to floodplain ecosystems, including contraction of riparian forests and woodlands and expansion of terrestrial, drought‐tolerant vegetation communities. Examples of adaptation services under this scenario include substitution of irrigated agriculture with dryland cropping and floodplain grazing; mitigation of damage from rarer, extreme floods; and increased tourism, recreational, and cultural values derived from fewer, smaller wetlands that can be maintained with environmental flows. Management for adaptation services will require decisions on where intervention can enable ecosystem persistence and where transformation is inevitable. New ways of managing water that include consideration of the increasing importance of adaptation services requires major changes to decision‐making that better account for landscape heterogeneity and large‐scale change rather than attempting to maintain ecosystems in fixed states.

Transcriptomic personalisation of radiation therapy has gained considerable interest in recent years. However, independent model testing on in vitro data has shown poor performance. In this work, we assess the reproducibility in clinical applications of radiosensitivity signatures. Agreement between radiosensitivity predictions from published signatures using different microarray normalization methods was assessed. Control signatures developed from resampled in vitro data were benchmarked in clinical cohorts. Survival analysis was performed using each gene in the clinical transcriptomic data, and gene set enrichment analysis was used to determine pathways related to model performance in predicting survival and recurrence. The normalisation approach impacted calculated radiosensitivity index (RSI) values. Indeed, the limits of agreement exceeded 20% with different normalisation approaches. No published signature significantly improved on the resampled controls for prediction of clinical outcomes. Functional annotation of gene models suggested that many overlapping biological processes are associated with cancer outcomes in RT treated and non-RT treated patients, including proliferation and immune responses. In summary, different normalisation methods should not be used interchangeably. The utility of published signatures remains unclear given the large proportion of genes relating to cancer outcome. Biological processes influencing outcome overlapped for patients treated with or without radiation suggest that existing signatures may lack specificity.

Mankind’s quest for a manned mission to Mars is placing increased emphasis on the development of innovative radio-protective countermeasures for long-term space travel. Hibernation confers radio-protective effects in hibernating animals, and this has led to the investigation of synthetic torpor to mitigate the deleterious effects of chronic low-dose-rate radiation exposure. Here we describe an induced torpor model we developed using the zebrafish. We explored the effects of radiation exposure on this model with a focus on the liver. Transcriptomic and behavioural analyses were performed. Radiation exposure resulted in transcriptomic perturbations in lipid metabolism and absorption, wound healing, immune response, and fibrogenic pathways. Induced torpor reduced metabolism and increased pro-survival, anti-apoptotic, and DNA repair pathways. Coupled with radiation exposure, induced torpor led to a stress response but also revealed maintenance of DNA repair mechanisms, pro-survival and anti-apoptotic signals. To further characterise our model of induced torpor, the zebrafish model was compared with hepatic transcriptomic data from hibernating grizzly bears ( Ursus arctos horribilis ) and active controls revealing conserved responses in gene expression associated with anti-apoptotic processes, DNA damage repair, cell survival, proliferation, and antioxidant response. Similarly, the radiation group was compared with space-flown mice revealing shared changes in lipid metabolism.

The utilisation of synthetic torpor for interplanetary travel once seemed farfetched. However, mounting evidence points to torpor-induced protective benefits from the main hazards of space travel, namely, exposure to radiation and microgravity. To determine the radio-protective effects of an induced torpor-like state we exploited the ectothermic nature of the Danio rerio (zebrafish) in reducing their body temperatures to replicate the hypothermic states seen during natural torpor. We also administered melatonin as a sedative to reduce physical activity. Zebrafish were then exposed to low-dose radiation (0.3 Gy) to simulate radiation exposure on long-term space missions. Transcriptomic analysis found that radiation exposure led to an upregulation of inflammatory and immune signatures and a differentiation and regeneration phenotype driven by STAT3 and MYOD1 transcription factors. In addition, DNA repair processes were downregulated in the muscle two days’ post-irradiation. The effects of hypothermia led to an increase in mitochondrial translation including genes involved in oxidative phosphorylation and a downregulation of extracellular matrix and developmental genes. Upon radiation exposure, increases in endoplasmic reticulum stress genes were observed in a torpor+radiation group with downregulation of immune-related and ECM genes. Exposing hypothermic zebrafish to radiation also resulted in a downregulation of ECM and developmental genes however, immune/inflammatory related pathways were downregulated in contrast to that observed in the radiation only group. A cross-species comparison was performed with the muscle of hibernating Ursus arctos horribilis (brown bear) to define shared mechanisms of cold tolerance. Shared responses show an upregulation of protein translation and metabolism of amino acids, as well as a hypoxia response with the shared downregulation of glycolysis, ECM, and developmental genes.

Water resources and water-related ecosystem services are vital to social–ecological systems, yet in many parts of the world water as a finite resource is revealed by its unsustainable and inequitable use. Increased threats to water security and supply of ecosystem services arise due to increasing and contested demand and declining supply due to climate change and other stressors. Trade-off decisions need to be made between competing sectors of food production, hydropower generation and environmental needs: the water–food–energy–environment nexus. New approaches are needed to address how water resources and ecosystem service benefits are shared among competing interests. One approach involves changes to decision contexts, shaped by the values, rules and knowledge which decision makers draw upon when considering options. By changing decision contexts, new opportunities become available. Here, we describe Nexus Webs; a knowledge framework designed to promote collaborative exploration of synergies and trade-offs and enable changes in decision contexts for water use. As part of the process of shifting this framework from concept to operation, we apply Nexus Webs to contrasting water use scenarios in the Pangani Basin (Tanzania and Kenya), where water is over-allocated and highly contested. Under each scenario, we detail linkages between different water uses and their effects on assets (ecosystems, biodiversity and built infrastructure), the effects on assets for the supply of ecosystem services and how these affect livelihoods and wellbeing. We outline how Nexus Webs can be developed and used to change the decision context to consider options for more socially inclusive and equitable use of water resources.

Loss PTEN function is one of the most common events driving aggressive prostate cancers and biochemically, PTEN is a lipid phosphatase which opposes the activation of the oncogenic PI3K-AKT signalling network. However, PTEN also has additional potential mechanisms of action, including protein phosphatase activity. Using a mutant enzyme, PTEN Y138L, which selectively lacks protein phosphatase activity, we characterised genetically modified mice lacking either the full function of PTEN in the prostate gland or only lacking protein phosphatase activity. The phenotypes of mice carrying a single allele of either wild-type Pten or PtenY138L in the prostate were similar, with common prostatic intraepithelial neoplasia (PIN) and similar gene expression profiles. However, the latter group, lacking PTEN protein phosphatase activity additionally showed lymphocyte infiltration around PIN and an increased immune cell gene expression signature. Prostate adenocarcinoma, elevated proliferation and AKT activation were only frequently observed when PTEN was fully deleted. We also identify a common gene expression signature of PTEN loss conserved in other studies (including Nkx3.1, Tnf and Cd44). We provide further insight into tumour development in the prostate driven by loss of PTEN function and show that PTEN protein phosphatase activity is not required for tumour suppression.

The therapeutic activation of antitumour immunity by immune checkpoint inhibitors (ICIs) is a significant advance in cancer medicine, not least due to the prospect of long-term remission. However, many patients are unresponsive to ICI therapy and may experience serious side effects; companion biomarkers are urgently needed to help inform ICI prescribing decisions. We present the IMMUNETS networks of gene coregulation in five key immune cell types and their application to interrogate control of nivolumab response in advanced melanoma cohorts. The results evidence a role for each of the IMMUNETS cell types in ICI response and in driving tumour clearance with independent cohorts from TCGA. As expected, ‘immune hot’ status, including T cell proliferation, correlates with response to first-line ICI therapy. Genes regulated in NK, dendritic, and B cells are the most prominent discriminators of nivolumab response in patients that had previously progressed on another ICI. Multivariate analysis controlling for tumour stage and age highlights CIITA and IKZF3 as candidate prognostic biomarkers. IMMUNETS provide a resource for network biology, enabling context-specific analysis of immune components in orthogonal datasets. Overall, our results illuminate the relationship between the tumour microenvironment and clinical trajectories, with potential implications for precision medicine.

Background Metastatic clear cell renal cell cancer (mccRCC) portends a poor prognosis and urgently requires better clinical tools for prognostication as well as for prediction of response to treatment. Considerable investment in molecular risk stratification has sought to overcome the performance ceiling encountered by methods restricted to traditional clinical parameters. However, replication of results has proven challenging, and intratumoural heterogeneity (ITH) may confound attempts at tissue-based stratification. Methods We investigated the influence of confounding ITH on the performance of a novel molecular prognostic model, enabled by pathologist-guided multiregion sampling ( n  = 183) of geographically separated mccRCC cohorts from the SuMR trial (development, n  = 22) and the SCOTRRCC study (validation, n  = 22). Tumour protein levels quantified by reverse phase protein array (RPPA) were investigated alongside clinical variables. Regularised wrapper selection identified features for Cox multivariate analysis with overall survival as the primary endpoint. Results The optimal subset of variables in the final stratification model consisted of N-cadherin, EPCAM, Age, mTOR (NEAT). Risk groups from NEAT had a markedly different prognosis in the validation cohort (log-rank p  = 7.62 × 10 −7 ; hazard ratio (HR) 37.9, 95% confidence interval 4.1–353.8) and 2-year survival rates (accuracy = 82%, Matthews correlation coefficient = 0.62). Comparisons with established clinico-pathological scores suggest favourable performance for NEAT (Net reclassification improvement 7.1% vs International Metastatic Database Consortium score, 25.4% vs Memorial Sloan Kettering Cancer Center score). Limitations include the relatively small cohorts and associated wide confidence intervals on predictive performance. Our multiregion sampling approach enabled investigation of NEAT validation when limiting the number of samples analysed per tumour, which significantly degraded performance. Indeed, sample selection could change risk group assignment for 64% of patients, and prognostication with one sample per patient performed only slightly better than random expectation (median logHR = 0.109). Low grade tissue was associated with 3.5-fold greater variation in predicted risk than high grade ( p  = 0.044). Conclusions This case study in mccRCC quantitatively demonstrates the critical importance of tumour sampling for the success of molecular biomarker studies research where ITH is a factor. The NEAT model shows promise for mccRCC prognostication and warrants follow-up in larger cohorts. Our work evidences actionable parameters to guide sample collection (tumour coverage, size, grade) to inform the development of reproducible molecular risk stratification methods.

Cell identity is governed by gene expression, regulated by transcription factor (TF) binding at cis-regulatory modules. Decoding the relationship between TF binding patterns and gene regulation is nontrivial, remaining a fundamental limitation in understanding cell decision-making. We developed the NetNC software to predict functionally active regulation of TF targets; demonstrated on nine datasets for the TFs Snail, Twist, and modENCODE Highly Occupied Target (HOT) regions. Snail and Twist are canonical drivers of epithelial to mesenchymal transition (EMT), a cell programme important in development, tumour progression and fibrosis. Predicted “neutral” (non-functional) TF binding always accounted for the majority (50% to 95%) of candidate target genes from statistically significant peaks and HOT regions had higher functional binding than most of the Snail and Twist datasets examined. Our results illuminated conserved gene networks that control epithelial plasticity in development and disease. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington’s epigenetic landscape during epithelial remodelling. Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology, with implications for precision medicine. Predicted invasion roles were validated using a tractable cell model, supporting our approach.