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The SCN2A gene encodes the Nav1.2 protein, a voltage-gated sodium channel crucial for initiating and transmitting action potentials in neurons. Dysfunction in Nav1.2, often stemming from genetic mutations in the SCN2A gene, leads to SCN2A-related disorders. Individuals harboring pathogenic SCN2A variants present with severe neurodevelopmental disorders such as epilepsy, autism spectrum disorders, movement disorders, cortical visual impairment, and intellectual disabilities. The FamilieSCN2A Foundation, a 501(c)(3) patient advocacy organization, is dedicated to enhancing the lives of those affected by SCN2A-related disorders. Fueled by a vision of a world with effective treatments and cures for all patients with SCN2A-related disorders, FamilieSCN2A Foundation has charted the course to a cure based on their core values of urgency, integrity, collaboration, and inclusion. Their strategic plan centers on building a comprehensive research-readiness infrastructure that maximizes the probability of bringing curative therapies to SCN2A patients. Appreciating that statistically most drug development initiatives will fail, creating an infrastructure that maximizes the number of drugs in development for SCN2A-related disorders in turn maximizes the net probability of success that FamilieSCN2A Foundation will achieving their vision. Through dynamic initiatives and notable achievements, including raising ~$6 million USD, funding 26 research grants totaling ~$4.7 million USD, and forging strategic partnerships across the SCN2A-related disorder ecosystem the foundation is actively executing its strategic plan. With SCN2A research advancing rapidly and a thriving ecosystem of diverse, engaged stakeholders, FamilieSCN2A Foundation believes the outlook for SCN2A-related disorders is bright., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Climate mitigation policies have broad environmental and socioeconomic impacts and thus underpin progress towards the United Nations Sustainable Development Goals (SDGs). Through national-scale integrated modeling, we explore the spillover effects of China's long-term climate mitigation pathways (CMPs) on achieving all 17 SDGs, and then identify a cost-effective CMP for China with co-benefits for sustainability. Our analysis indicates that the 9 original CMPs and 180 bundled CMPs can both substantially boost the SDGs, resulting in an increase of 6.33-8.86 and 5.90-9.33 points in overall SDG score (0=no progress, 100=full achievement) by 2060, compared to the Reference pathway of 70.75 points, respectively. The identified cost-effective CMP deals with the trade-offs among sustainability, CO 2 emissions and mitigation cost, and maximizes the synergies between them. This CMP can inform future directions for China's policy-makers to maximize the potential synergies between carbon neutrality and long-term sustainable development., (© 2024. The Author(s).)

We developed a high-resolution machine learning based surrogate model to identify a robust land-use future for Australia which meets multiple UN Sustainable Development Goals. We compared machine learning models with different architectures to pick the best performing model considering the data type, accuracy metrics, ability to handle uncertainty and computational overhead requirement. The surrogate model, called ML-LUTO Spatial, was trained on the Land-Use Trade-Offs (version 1.0) model of Australian agricultural land system sustainability. Using the surrogate model, we generated projections of land-use futures at 1.1 km resolution with 95% classification accuracy, and which far surpassed the computational benchmarks of the original model. This efficiency enabled the generation of numerous SDG-compliant (SDGs 2, 6, 7, 13, 15) future land-use maps on a standard laptop, a task previously dependent upon high-performance computing clusters. Combining these projections, we derived a single, robust land-use future and quantified the uncertainty. Our findings indicate that while agricultural land-use remains dominant in all Australian regions, extensive carbon plantings were identified in Queensland and environmental plantings played a role across the study area, reflecting a growing urgency for offsetting greenhouse gas emissions and the restoration of ecosystems to support biodiversity across Australia to meet the 2050 Sustainable Development Goals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

China's long-term sustainability faces socioeconomic and environmental uncertainties. We identify five key systemic risk drivers, called disruptors, which could push China into a polycrisis: pandemic disease, ageing and shrinking population, deglobalization, climate change, and biodiversity loss. Using an integrated simulation model, we quantify the effects of these disruptors on the country's long-term sustainability framed by 17 Sustainable Development Goals (SDGs). Here we show that ageing and shrinking population, and climate change would be the two most influential disruptors on China's long-term sustainability. The compound effects of all disruptors could result in up to 2.1 and 7.0 points decline in the China's SDG score by 2030 and 2050, compared to the baseline with no disruptors and no additional sustainability policies. However, an integrated policy portfolio involving investment in education, healthcare, energy transition, water-use efficiency, ecological conservation and restoration could promote resilience against the compound effects and significantly improve China's long-term sustainability., (© 2024. The Author(s).)

The United Nations' Sustainable Development Goal (SDG) 3.9 calls for a substantial reduction in deaths attributable to PM 2.5 pollution (DAPP). However, DAPP projections vary greatly and the likelihood of meeting SDG3.9 depends on complex interactions among environmental, socio-economic, and healthcare parameters. We project potential future trends in global DAPP considering the joint effects of each driver (PM 2.5 concentration, death rate of diseases, population size, and age structure) and assess the likelihood of achieving SDG3.9 under the Shared Socioeconomic Pathways (SSPs) as quantified by the Scenario Model Intercomparison Project (ScenarioMIP) framework with simulated PM 2.5 concentrations from 11 models. We find that a substantial reduction in DAPP would not be achieved under all but the most optimistic scenario settings. Even the development aligned with the Sustainability scenario (SSP1-2.6), in which DAPP was reduced by 19%, still falls just short of achieving a substantial (≥20%) reduction by 2030. Meeting SDG3.9 calls for additional efforts in air pollution control and healthcare to more aggressively reduce DAPP., (© 2024. The Author(s).)

Concurrently implemented green initiatives to combat global environmental crises may be curtailed or even sacrificed given the ongoing global economic contraction. We collected empirical data and information about green initiatives from 15 sites or countries worldwide. We systematically explored how specific policy, intended behaviors, and gains of given green initiative may interact with those of other green initiatives concurrently implemented in the same geographic area or involving the same recipients. Surprisingly, we found that spillover effects were very divergent: one initiative could reduce the gain of another by 22 % ∼ 100 %, representing alarming losses, while in other instances, substantial co-benefits could arise as one initiative can increase the gain of another by 9 % ∼ 310 %. Leveraging these effects will help countries keep green initiatives with significant co-benefits but stop initiatives with substantial spillover losses in the face of widespread budget cuts, better meeting the United Nations' sustainable development goals., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests that could inappropriately influence (bias) their work., (Copyright © 2024. Published by Elsevier B.V.)

Accelerating efforts for the Sustainable Development Goals requires understanding their synergies and trade-offs at the national and sub-national levels, which will help identify the key hurdles and opportunities to prioritize them in an indivisible manner for a country. Here, we present the importance of the 17 goals through synergy and trade-off networks. Our results reveal that 19 provinces show the highest trade-offs in SDG13 (Combating Climate Change) or SDG5 (Gender Equality) consistent with the national level, with other 12 provinces varying. 24 provinces show the highest synergies in SDG1 (No Poverty) or SDG6 (Clean Water and Sanitation) consistent with the national level, with the remaining 7 provinces varying. These common but differentiated SDG priorities reflect that to ensure a coordinated national response, China should pay more attention to the provincial situation, so that provincial governments can formulate more targeted policies in line with their own priorities towards accelerating sustainable development., (© 2024. The Author(s).)

Background: Spatial information about the location and suitability of areas for native plant and animal species under different climate futures is an important input to land use and conservation planning and management. Australia, renowned for its abundant species diversity and endemism, often relies on modeled data to assess species distributions due to the country's vast size and the challenges associated with conducting on-ground surveys on such a large scale. The objective of this article is to develop habitat suitability maps for Australian flora and fauna under different climate futures., Results: Using MaxEnt, we produced Australia-wide habitat suitability maps under RCP2.6-SSP1, RCP4.5-SSP2, RCP7.0-SSP3, and RCP8.5-SSP5 climate futures for 1,382 terrestrial vertebrates and 9,251 vascular plants vascular plants at 5 km2 for open access. This represents 60% of all Australian mammal species, 77% of amphibian species, 50% of reptile species, 71% of bird species, and 44% of vascular plant species. We also include tabular data, which include summaries of total quality-weighted habitat area of species under different climate scenarios and time periods., Conclusions: The spatial data supplied can help identify important and sensitive locations for species under various climate futures. Additionally, the supplied tabular data can provide insights into the impacts of climate change on biodiversity in Australia. These habitat suitability maps can be used as input data for landscape and conservation planning or species management, particularly under different climate change scenarios in Australia., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)

State-of-the-art cloud computing platforms such as Google Earth Engine (GEE) enable regional-to-global land cover and land cover change mapping with machine learning algorithms. However, collection of high-quality training data, which is necessary for accurate land cover mapping, remains costly and labor-intensive. To address this need, we created a global database of nearly 2 million training units spanning the period from 1984 to 2020 for seven primary and nine secondary land cover classes. Our training data collection approach leveraged GEE and machine learning algorithms to ensure data quality and biogeographic representation. We sampled the spectral-temporal feature space from Landsat imagery to efficiently allocate training data across global ecoregions and incorporated publicly available and collaborator-provided datasets to our database. To reflect the underlying regional class distribution and post-disturbance landscapes, we strategically augmented the database. We used a machine learning-based cross-validation procedure to remove potentially mis-labeled training units. Our training database is relevant for a wide array of studies such as land cover change, agriculture, forestry, hydrology, urban development, among many others., (© 2023. The Author(s).)

Wastewater treatment plants (WWTPs) in China must be upgraded to meet new discharge standards, but this incurs both economic and environmental costs and benefits. To select the optimal upgrade pathway, we developed ten upgrade paths based on two common decision-making scenarios for WWTP upgrade in developing countries. Using model simulation, life-cycle assessment, life-cycle cost, and multiple-attribute decision-making, we incorporated the full costs and benefits associated with the construction and operation into the decision-making process. We used a weighting scheme of attributes for the three regions and ranked the upgrade paths using the technique for order preference by similarity to an ideal solution (TOPSIS). The results showed that constructed wetlands and sand filtration were advantageous in terms of lower economic costs and environmental impacts, while the denitrification filter pathways required less land. Optimal pathways differed by region, highlighting the importance of a detailed and integrated assessment of the costs and benefits of WWTP upgrade options over the full life cycle. Our findings can inform decision-making on upgrading China's WWTPs to meet stringent discharge standards and protect inland water and coastal environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Estimating the health burden of air pollution against the background of population aging is of great significance for achieving the Sustainable Development Goal 3.9 which aims to substantially reduce the deaths and illnesses from air pollution. Here, we estimated spatiotemporal changes in deaths attributable to PM 2.5 air pollution in China from 2000 to 2035 and examined the drivers. The results show that from 2019 to 2035, deaths were projected to decease 15.4% (6.6%-20.7%, 95% CI) and 8.4% (0.6%-13.5%) under the SSP1-2.6 and SSP5-8.5 scenario, respectively, but increase 10.4% (5.1%-20.5%) and 18.1% (13.0%-28.3%) under SSP2-4.5 and SSP3-7.0 scenarios. Population aging will be the leading contributor to increased deaths attributable to PM 2.5 air pollution, which will counter the positive gains achieved by improvements in air pollution and healthcare. Region-specific measures are required to mitigate the health burden of air pollution and this requires long-term efforts and mutual cooperation among regions in China., (© 2023. Springer Nature Limited.)

Since the early 2000s, China has carried out extensive "grain-for-green" and grazing exclusion practices to combat desertification in the desertification-prone region (DPR). However, the environmental and socioeconomic impacts of these practices remain unclear. We quantify and compare the changes in fractional vegetation cover (FVC) with economic and population data in the DPR before and after the implementation of these environmental programmes. Here we show that climatic change and CO 2 fertilization are relatively strong drivers of vegetation rehabilitation from 2001-2020 in the DPR, and the declines in the direct incomes of farmers and herders caused by ecological practices exceed the subsidies provided by governments. To minimize economic hardship, enhance food security, and improve the returns on policy investments in the DPR, China needs to adapt its environmental programmes to address the potential impacts of future climate change and create positive synergies to combat desertification and improve the economy in this region., (© 2023. The Author(s).)

The development of detailed national pathways towards sustainable food and land systems aims to provide stakeholders with clarity on how long-term goals could be achieved and to reduce roadblocks in the way to making commitments. However, the inability to perfectly capture the relationships between all variables in a system and the unknown probability of future values (deep uncertainty) makes it very difficult to design scenarios that account for the full breadth of system uncertainty. Here we use scenario discovery to systematically explore the effect of different parameter ranges on model outputs, and design resilient pathways to sustainability in which multiple target achievement requires a broad portfolio of solutions. We use a model of the Australian food and land system, the FABLE (Food, Agriculture, Biodiversity, Land-use, Energy) Calculator, to investigate conditions for achieving a sustainable Australian food and land system under scenarios based on the Shared Socioeconomic Pathways (SSP) 1, 2, and 3 narratives. Here we link the FABLE Calculator with a Monte Carlo simulation tool to explore hundreds of thousands of scenarios. This allows us to identify the ranges of systemic drivers that achieve multiple sustainability targets around diets, net forest growth, agricultural water consumption, greenhouse gas emissions, biodiversity conservation, and exports by 2050. Our results show that livestock productivity and density, afforestation, and dietary change are powerful influencers for sustainability target achievement. Around 10% of the SSP1 scenarios could achieve all modelled sustainability targets. However, practically none of the scenarios based on SSP2 and SSP3 narratives could achieve such targets. The results suggest that there are options to achieve a more sustainable and resilient Australian food and land-use system with better socio-economic and environmental outcomes than under current trends. However, its achievement requires significant structural changes and coordinated interventions in several components of the domestic food and land system to increase its resilience and environmental and socio-economic performance. Understanding the bounds within which this system needs to change and operate to achieve sustainability targets will enable greater clarity and flexibility during discussions between decision-makers and stakeholders., Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-022-01202-2., (© Crown 2022.)

Sustainable food systems require malnutrition and climate change to be addressed in parallel. Here, we estimate the non-CO 2 greenhouse gas emissions resulting from closing the world's dietary nutrient gap-that between country-level nutrient supply and population requirements-for energy, protein, iron, zinc, vitamin A, vitamin B12 and folate under five climate-friendly intervention scenarios in 2030. We show that improving crop and livestock productivity and halving food loss and waste can close the nutrient gap with up to 42% lower emissions (3.03 Gt CO 2 eq yr -1 ) compared with business-as-usual supply patterns with a persistent nutrient gap (5.48 Gt CO 2 eq yr -1 ). Increased production and trade of vegetables, eggs, and roots and tubers can close the nutrient gap with the lowest emissions in most countries-with ≤23% increase in total caloric production required for 2030 relative to 2015. We conclude that the world's nutrient gap could be closed without exceeding global climate targets and without drastic changes to national food baskets., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Lakes are important natural resources and carbon gas emitters and are undergoing rapid changes worldwide in response to climate change and human activities. A detailed global characterization of lakes and their long-term dynamics does not exist, which is however crucial for evaluating the associated impacts on water availability and carbon emissions. Here, we map 3.4 million lakes on a global scale, including their explicit maximum extents and probability-weighted area changes over the past four decades. From the beginning period (1984-1999) to the end (2010-2019), the lake area increased across all six continents analyzed, with a net change of +46,278 km 2 , and 56% of the expansion was attributed to reservoirs. Interestingly, although small lakes (<1 km 2 ) accounted for just 15% of the global lake area, they dominated the variability in total lake size in half of the global inland lake regions. The identified lake area increase over time led to higher lacustrine carbon emissions, mostly attributed to small lakes. Our findings illustrate the emerging roles of small lakes in regulating not only local inland water variability, but also the global trends of surface water extent and carbon emissions., (© 2022. The Author(s).)

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal messenger RNAs (mRNAs). The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by real-time quantitative reverse transcription PCR (qRT-PCR), while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups ("healthy", "osteosarcoma", "other bone tumor", or "non-neoplastic disease"). Pre-treatment samples from osteosarcoma cases were used as the training set, and a validation set from post-treatment samples was used for testing, classifying as "osteosarcoma detected" or "osteosarcoma-NOT detected". Dogs in a validation set whose post-treatment samples were classified as "osteosarcoma-NOT detected" had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof of concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response., (© 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Non-timber forest products (NTFPs) contribute to the well-being of mountain communities in many ways but their availability is being impacted by climate change. Policy and programs to enhance adaptation can alleviate these impacts, but to be effective they require an understanding of mountain community perceptions of climate change impacts on NTFPs and the perceived barriers to climate change adaptation. Here, we explored mountain communities' adaptation responses to the perceived impacts of climate change on NTFPs and people's barriers to adaptation using a structured questionnaire delivered as a field-based survey of 278 forest-dependent households from the Upper Madi Watershed of Nepal. We present a quantitative graphical exploration of the results to provide a simple overview of climate change impacts of NTFPs and local adaptation. The most common adaptation practices adopted by the mountain communities in the study area include the self-regulation of over-collection of NTFPs, alternative income generating activities, improved stoves, agroforestry, and sourcing alternative tools and materials. However, adaptation options to deal with increased invasive plant species and pest insect outbreaks appear to be challenging despite having the highest perceived impact on NTFPs. Adaptation practices are constrained by several factors such as the lack of predictability of extreme events and climate-related hazards, lack of technical knowledge, fatalistic beliefs and perceived lack of agency, and limited government support. Our results can inform policies and programs required for addressing the impacts of climate change on mountain communities in Nepal and other developing nations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The dataset presents the raw data collected through household surveys of smallholder farmers on adaptation to climatic variabilities and change in Sudurpaschim Pradesh (Far Western Province), Nepal. The dataset comprises farmers' responses on the likely determinants of adaptation decisions, actual uptake of adaptation measures, and the barriers to adaptation. We collected the data by conducting face-to-face interviews of 327 farmers using structured questionnaires in all nine districts representing the Mountain, Hill, and Terai agroecosystems in the province. We employed a stratified random sampling technique to recruit participants and interviewed them during December 2019 and March 2020. The interview methodology was approved by the Human Ethics Review Committee at Deakin University, Australia. The dataset is important for understanding the drivers of climate change adaptation and the barriers to adaptation to enhance the resilience of smallholder agriculture in far-western Nepal and can inform climate change adaptation strategies for the region and for the smallholder agroecosystems more broadly. The data are provided with this article., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2021 The Authors. Published by Elsevier Inc.)

Urbanization and climate change are together exacerbating water scarcity-where water demand exceeds availability-for the world's cities. We quantify global urban water scarcity in 2016 and 2050 under four socioeconomic and climate change scenarios, and explored potential solutions. Here we show the global urban population facing water scarcity is projected to increase from 933 million (one third of global urban population) in 2016 to 1.693-2.373 billion people (one third to nearly half of global urban population) in 2050, with India projected to be most severely affected in terms of growth in water-scarce urban population (increase of 153-422 million people). The number of large cities exposed to water scarcity is projected to increase from 193 to 193-284, including 10-20 megacities. More than two thirds of water-scarce cities can relieve water scarcity by infrastructure investment, but the potentially significant environmental trade-offs associated with large-scale water scarcity solutions must be guarded against., (© 2021. The Author(s).)

Land-use change alters the dynamics of freshwater ecosystem services flows by affecting both service supply (by influencing hydrological processes and runoff) and demand (via changes in human water use). However, few studies have considered the wide range of effects of land-use change on freshwater ecosystem services' flows. In this study, we distinguished the impacts of changing water supply and demand in the Aojiang River watershed, Fujian Province, China, an important water resource for more than seven million people. Rapid urbanization between 1991 and 2015 led to a minor increase of 2.5% in the supply of freshwater ecosystem services. However, demand increased by 96.3%, leading to a 25.7% overall decrease in freshwater ecosystem services flows. Downstream demand for freshwater increased substantially due to large shifts in agricultural, urban, and industrial activities. Our analysis provides detailed information on freshwater ecosystem services flows from supply to beneficiaries within a watershed, thus facilitating integrated watershed management and decision making. This study demonstrates how land-use change and ecosystem services' flows can be integrated both at local and regional scales for land-use management, water reallocation, and ecological compensation, thus promoting the sustainability of freshwater ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Angiosarcoma is a rare cancer of blood vessel-forming cells with a high patient mortality and few treatment options. Although chemotherapy often produces initial clinical responses, outcomes remain poor, largely due to the development of drug resistance. We previously identified a subset of doxorubicin-resistant cells in human angiosarcoma and canine hemangiosarcoma cell lines that exhibit high lysosomal accumulation of doxorubicin. Hydrophobic, weak base chemotherapeutics, like doxorubicin, are known to sequester within lysosomes, promoting resistance by limiting drug accessibility to cellular targets. Drug synergy between the beta adrenergic receptor (β-AR) antagonist, propranolol, and multiple chemotherapeutics has been documented in vitro , and clinical data have corroborated the increased therapeutic potential of propranolol with chemotherapy in angiosarcoma patients. Because propranolol is also a weak base and accumulates in lysosomes, we sought to determine whether propranolol enhanced doxorubicin cytotoxicity via antagonism of β-ARs or by preventing the lysosomal accumulation of doxorubicin. β-AR-like immunoreactivities were confirmed in primary tumor tissues and cell lines; receptor function was verified by monitoring downstream signaling pathways of β-ARs in response to receptor agonists and antagonists. Mechanistically, propranolol increased cytoplasmic doxorubicin concentrations in sarcoma cells by decreasing the lysosomal accumulation and cellular efflux of this chemotherapeutic agent. Equivalent concentrations of the receptor-active S-(-) and -inactive R-(+) enantiomers of propranolol produced similar effects, supporting a β-AR-independent mechanism. Long-term exposure of hemangiosarcoma cells to propranolol expanded both lysosomal size and number, yet cells remained sensitive to doxorubicin in the presence of propranolol. In contrast, removal of propranolol increased cellular resistance to doxorubicin, underscoring lysosomal doxorubicin sequestration as a key mechanism of resistance. Our results support the repurposing of the R-(+) enantiomer of propranolol with weak base chemotherapeutics to increase cytotoxicity and reduce the development of drug-resistant cell populations without the cardiovascular and other side effects associated with antagonism of β-ARs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Saha, Kim, Amaya, Witcher, Khammanivong, Korpela, Brown, Taylor, Bryan and Dickerson.)

While the need to reduce the impacts of pesticide use on the environment is increasingly acknowledged, the existing data on the use of agricultural chemicals are hardly adequate to support this goal. This study presents a novel, spatially explicit, national-scale baseline analysis of pesticide toxicity hazard (the potential for chemicals to do harm). The results show an uneven contribution of land uses and growing regions toward the national aggregate toxicity hazard. A hectare of horticultural crops generates on average ten times more aquatic ecotoxicity hazard and five times more human toxicity hazard than a hectare of broadacre crops, but the higher yields and incomes in horticulture mean that both sectors are similar in terms of environmental efficiency. Livestock is the sector with the least contribution to overall hazard, even when the indirect hazard associated with feed is considered. Metrics such as pesticide use (kg/ha) or spray frequency (sprays/ha), commonly reported in highly aggregated forms, are not linearly related to toxicity hazard and are therefore less informative in driving reductions in impact. We propose toxicity hazard as a more suitable indicator for real-world risk than quantity of pesticide used, especially because actual risk can often be difficult to quantify. Our results will help broaden the discussion around pathways toward sustainability in the land-use sector and identify targeted priorities for action.

The Sustainable Development Goals (SDGs) recognise the importance of action across all scales to achieve a sustainable future. To contribute to overall national- and global-scale SDG achievement, local communities need to focus on a locally-relevant subset of goals and understand potential future pathways for key drivers which influence local sustainability. We developed a participatory method to co-create local socioeconomic pathways by downscaling the SDGs and driving forces of the shared socioeconomic pathways (SSPs) via a local case study in southern Australia through contextual analysis and community engagement. We linked the SSPs and SDGs by identifying driving forces and describing how they affect the achievement of local SDGs. We co-created six local socioeconomic pathways with the local community which track towards futures with different levels of fulfilment of the SDGs and each encompasses a narrative storyline incorporating locally-specific ideas from the community. We tested and validated the local pathways with the community. This method extends the SSPs in two dimensions-into the broader field of sustainability via the SDGs, and by recontextualizing them at the local scale. The local socioeconomic pathways can contribute to achieving local sustainability goals from the bottom up in alignment with global initiatives., Competing Interests: Conflict of interestThe authors have no conflicts of interest to declare that are relevant to the content of this article., (© The Author(s), under exclusive licence to Springer Japan KK part of Springer Nature 2021, corrected publication 2021.)

Food system innovations will be instrumental to achieving multiple Sustainable Development Goals (SDGs). However, major innovation breakthroughs can trigger profound and disruptive changes, leading to simultaneous and interlinked reconfigurations of multiple parts of the global food system. The emergence of new technologies or social solutions, therefore, have very different impact profiles, with favourable consequences for some SDGs and unintended adverse side-effects for others. Stand-alone innovations seldom achieve positive outcomes over multiple sustainability dimensions. Instead, they should be embedded as part of systemic changes that facilitate the implementation of the SDGs. Emerging trade-offs need to be intentionally addressed to achieve true sustainability, particularly those involving social aspects like inequality in its many forms, social justice, and strong institutions, which remain challenging. Trade-offs with undesirable consequences are manageable through the development of well planned transition pathways, careful monitoring of key indicators, and through the implementation of transparent science targets at the local level., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

This dataset presents data collected from household surveys from Upper Madi Watershed of Nepal describing the benefits of non-timber forest products (NTFPs) to people of mountain ecosystems, their perceptions of climate change, and perceived impacts of climate change on NTFPs ecosystem services. The data were collected from 278 households that were randomly selected from the four villages in the watershed during the period September to December 2019. The survey assessed socio-demographic information; collected and utilized NTFPs; perceptions of climate change, and; perceived impacts of climate change on NTFPs ecosystem services. These data are important in understanding the benefits of non-timber forest products in mountain ecosystems and the impacts of climate change as the benefits and impacts are currently not well understood. The data will be helpful in formulation and implementation of adaptation strategies to sustain the supply, protection, and management of NTFPs in mountain ecosystems., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 The Authors.)

Smallholder agriculture is a major contributor to global food production and is vital for ensuring food security in many developing countries. Smallholder agriculture is a typically complex and heterogeneous social-ecological system that is especially susceptible to climatic variability. Research has often focused on examining climate impacts on crops in smallholder agriculture. However, the resilience of smallholder agriculture in terms of maintaining yield remains largely unexplored. We empirically quantified the resilience of rice, wheat and maize to climatic variabilities for the Far Western Province of Nepal. We calculated resilience indices (RI) comparing the anomalies of actual yield in agricultural statistics to the expected yields generated by a process-based yield simulation model for nine districts across the Terai, Hill and Mountain regions of the province. Based on the sustainable livelihoods framework, we then assessed the degree to which indicator variables correlate with resilience. The results demonstrate the variability of resilience across regions and crops. Terai, Hill and Mountain regions were found to be resilient in wheat, rice and wheat, and maize, respectively. Each region has maintained resilience in at least one crop suggesting that smallholder farmers have prioritised food subsistence. While Nepal's current Agricultural Development Strategy is focused on boosting yields in the Terai, we found the region to be less resilient overall compared to the Hill and the Mountain regions. Theory-driven capital indicators exhibited a weak and often contradictory relationship with resilience. Such indicators, used in isolation, could therefore misguide the resilience assessment in the absence of complementary fine-scale exploratory social research necessary to explain the drivers of resilience in smallholder agriculture and infer policy decisions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Air pollution kills nearly 1 million people per year in China. In response, the Chinese government implemented the Air Pollution Prevention and Control Action Plan (APPCAP) from 2013 to 2017 which had a significant impact on reducing PM 2.5 concentration. However, the health benefits of the APPCAP are not well understood. Here we examine the spatiotemporal dynamics of annual deaths attributable to PM 2.5 pollution (DAPP) in China and the contribution from the APPCAP using decomposition analysis. Despite a 36.1% increase in DAPP from 2000 to 2017, The APPCAP-induced improvement in air quality achieved substantial health benefits, with the DAPP in 2017 reduced by 64 thousand (6.8%) compared to 2013. However, the policy is unlikely to result in further major reductions in DAPP and more ambitious policies are required to reduce the health impacts of air pollution by 2030 and meet the United Nation's Sustainable Development Goal 3.

Uncertainty assessment techniques have been extensively applied as an estimate of accuracy to compensate for weaknesses with traditional approaches. Traditional approaches to mapping accuracy assessment have been based on a confusion matrix, and hence are not only dependent on the availability of test data but also incapable of capturing the spatial variation in classification error. Here, we apply and compare two uncertainty assessment techniques that do not rely on test data availability and enable the spatial characterisation of classification accuracy before the validation phase, promoting the assessment of error propagation within the classified imagery products. We compared the performance of emerging deep neural network (DNN) with the popular random forest (RF) technique. Uncertainty assessment was implemented by calculating the Shannon entropy of class probabilities predicted by DNN and RF for every pixel. The classification uncertainties of DNN and RF were quantified for two different hyperspectral image datasets-Salinas and Indian Pines. We then compared the uncertainty against the classification accuracy of the techniques represented by a modified root mean square error (RMSE). The results indicate that considering modified RMSE values for various sample sizes of both datasets, the derived entropy based on the DNN algorithm is a better estimate of classification accuracy and hence provides a superior uncertainty estimate at the pixel level.

Conservation targets perform beneficial auxiliary functions that are rarely acknowledged, including raising awareness, building partnerships, promoting investment, and developing new knowledge. Building on these auxiliary functions could enable more rapid progress towards current targets and inform the design of future targets., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Angiosarcoma is the most common malignant cardiac tumor. Cardiac angiosarcoma is a highly lethal neoplasm that is largely resistant to conventional anti-cancer therapy. Mean survival of patients with cardiac angiosarcoma is only 4 months, and almost all patients will succumb to the disease within 1 year. The beta blocker propranolol is an emerging therapy against angiosarcoma. When combined with conventional therapies, propranolol increases progression free and overall survival in patients with this tumor type. It is currently unknown if propranolol is capable of showing anti-cancer efficacy as a single agent therapy. We report a case of a 61 year old woman diagnosed with primary cardiac angiosarcoma and liver and lung metastases. This patient chose to decline conventional therapy, and instead was prescribed the beta blocker propranolol as a single agent treatment. After 12 months, the mediastinal mass substantially debulked and decreased in size, and the metastatic nodules stabilized or resolved with no evidence of hyper-metabolic activity on PET-CT. This is the first reported data showing long term efficacy of the beta blocker propranolol as a single agent therapy against angiosarcoma., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Experiences with nature through visits to protected areas provide important cultural ecosystem services that have the potential to strengthen pro-environmental attitudes and behavior. Understanding accessibility to protected areas and likely preferences for enjoying the benefits of nature visits are key factors in identifying ways to reduce inequality in access and inform the planning and management for future protected areas. We develop, at a regional scale, a novel social media database of visits to public protected areas in part of the Chilean biodiversity hotspot using geotagged photographs and assess the inequality of access using the home locations of the visitors and socio-economic data. We find that 20% of the population of the region make 87% of the visits to protected areas. The larger, more biodiverse protected areas were the most visited and provided most cultural ecosystem services. Wealthier people tend to travel further to visit protected areas while people with lower incomes tend to visit protected areas that are closer to home. By providing information on the current spatial flows of people to protected areas, we demonstrate the need to expand the protected area network, especially in lower income areas, to reduce inequality in access to the benefits from cultural ecosystem services provided by nature to people., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Symptoms of depression are present in over half of all cancer patients, and selective serotonin reuptake inhibitor (SSRI) anti-depressant medications are prescribed to nearly a quarter of these individuals in order to cope with their disease. Previous studies have provided evidence that elevated serotonin (5-HT) and serotonin receptor levels may contribute to oncogenic progression, yet little is known regarding the mechanism by which this occurs. The data demonstrated that serotonin receptor mRNAs and proteins are expressed across diverse cancer types, and that serotonin stimulation of tumor cells activates oncogenic signaling mediators including components of the AKT, CREB, GSK3, and MAPK pathways. Selective pharmacological inhibition of the seven known classes of 5-HT receptors in sarcoma and breast cancer cells resulted in dose dependent decreases in tumor cell viability, activation of the p53 DNA damage pathway, suppression of MAPK activity, and significantly reduced tumor volume in an in ovo model. Based on a retrospective clinical analysis of 419 patients diagnosed with breast cancer, we discovered that use of SSRIs was associated with a 2.3-fold increase in tumor proliferation rates for late stage patients based on their Ki-67 index (P=0.03). These data provide evidence that serotonin signaling pathways, which treating oncologists often pharmacologically target to assist cancer patients to psychologically cope with their illness, activate signaling pathways known to promote tumor growth and survival.

China has responded to a national land-system sustainability emergency via an integrated portfolio of large-scale programmes. Here we review 16 sustainability programmes, which invested US$378.5 billion (in 2015 US$), covered 623.9 million hectares of land and involved over 500 million people, mostly since 1998. We find overwhelmingly that the interventions improved the sustainability of China's rural land systems, but the impacts are nuanced and adverse outcomes have occurred. We identify some key characteristics of programme success, potential risks to their durability, and future research needs. We suggest directions for China and other nations as they progress towards the Sustainable Development Goals of the United Nations' Agenda 2030.

Environmentally extended input-output analysis (EEIOA) supports environmental policy by quantifying how demand for goods and services leads to resource use and emissions across the economy. However, some types of resource use and emissions require spatially explicit impact assessment for meaningful interpretation, which is not possible in conventional EEIOA. For example, water use in locations of scarcity and of abundance are not environmentally equivalent. Opportunities for spatially explicit impact assessment in conventional EEIOA are limited because official input-output tables tend to be produced at the scale of political units, which are not usually well-aligned with environmentally relevant spatial units. In this study, spatially explicit water-scarcity factors and a spatially disaggregated Australian water-use account were used to develop water-scarcity extensions that were coupled with a multiregional input-output model (MRIO). The results link demand for agricultural commodities to the problem of water scarcity in Australia and globally. Important differences were observed between the water-use and water-scarcity footprint results as well as the relative importance of direct and indirect water use, with significant implications for sustainable production and consumption-related policies. The approach presented here is suggested as a feasible general approach for incorporating spatially explicit impact assessments in EEIOA.

The Convention on Biological Diversity and its Strategic Plan for Biodiversity 2011-2020 form the central pillar of the world's conservation commitment, with 196 signatory nations; yet its capacity to reign in catastrophic biodiversity loss has proved inadequate. Indicators suggest that few of the Convention on Biological Diversity's Aichi targets that aim to reduce biodiversity loss will be met by 2020. While the indicators have been criticized for only partially representing the targets, a bigger problem is that the indicators do not adequately draw attention to and measure all of the drivers of the biodiversity crisis. Here, we show that many key drivers of biodiversity loss are either poorly evaluated or entirely lacking indicators. We use a biodiversity-crisis hierarchy as a conceptual model linking drivers of change to biodiversity loss to evaluate the scope of current indicators. We find major gaps related to monitoring governments, human population size, corruption and threat-industries. We recommend the hierarchy is used to develop an expanded set of indicators that comprehensively monitor the human behaviour and institutions that drive biodiversity loss and that, so far, have impeded progress towards achieving global biodiversity targets.

Patients with metastatic angiosarcoma undergoing chemotherapy, radiation, and/or surgery experience a median progression free survival of less than 6 months and a median overall survival of less than 12 months. Given the aggressive nature of this cancer, angiosarcoma clinical responses to chemotherapy or targeted therapeutics are generally very poor. Inhibition of beta adrenergic receptor (β-AR) signaling has recently been shown to decrease angiosarcoma tumor cell viability, abrogate tumor growth in mouse models, and decrease proliferation rates in preclinical and clinical settings. In the current study we used cell and animal tumor models to show that β-AR antagonism abrogates mitogenic signaling and reduces angiosarcoma tumor cell viability, and these molecular alterations translated into patient tumors. We demonstrated that non-selective β-AR antagonists are superior to selective β-AR antagonists at inhibiting angiosarcoma cell viability. A prospective analysis of non- selective β-AR antagonists in a single arm clinical study of metastatic angiosarcoma patients revealed that incorporation of either propranolol or carvedilol into patients' treatment regimens leads to a median progression free and overall survival of 9 and 36 months, respectively. These data suggest that incorporation of non-selective β-AR antagonists into existing therapies against metastatic angiosarcoma can enhance clinical outcomes.