The cell of origin dictates the temporal course of neurofibromatosis-1 (Nf1) low-grade glioma formation.

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma. Similar to the GFAP-Cre transgenic strain previously employed to generate Nf1 optic gliomas, Olig2+ cells also give rise to astrocytes in the murine optic nerve in vivo. However, in contrast to the GFAP-Cre strain where somatic Nf1 inactivation in embryonic neural progenitor/stem cells (Nf1flox/mut; GFAP-Cre mice) results in optic gliomas by 3 months of age in vivo, mice with Nf1 gene inactivation in Olig2+ OPCs (Nf1flox/mut; Olig2-Cre mice) do not form optic gliomas until 6 months of age. These distinct patterns of glioma latency do not reflect differences in the timing or brain location of somatic Nf1 loss. Instead, they most likely reflect the cell of origin, as somatic Nf1 loss in CD133+ neural progenitor/stem cells during late embryogenesis results in optic gliomas at 3 months of age. Collectively, these data demonstrate that the cell of origin dictates the time to tumorigenesis in murine optic glioma

Role of spatial anisotropy in design storm generation: Experiment and interpretation

Rainfall accumulation depths over a given area are strongly dependent on the shape of the storm together with its direction of advection. A method to produce design storms exhibiting anisotropic spatial scaling is presented by combining a state-of-the-art stochastic rainfall generator STEPS with the linear generalized scale invariance (GSI) notation. The enhanced model is used to create ensembles of design storms based on an extreme storm with a distinct rainband shape observed in Melbourne, Australia. Design storms are generated both with and without accounting for anisotropy. Effect of anisotropy on precipitation characteristics is studied using the entire region covered by the radar (radar scale) and at a significantly smaller catchment scale. A rainfall-runoff model is applied to route the rainfall through the catchment into streamflow. Accounting for anisotropy allows for a more realistic description of precipitation features at the radar scale. At the catchment scale, anisotropy increases the probability of high rainfall accumulations, which translates into greater flood volumes. No discernible difference was observed in streamflow characteristics after controlling for the accumulation over the catchment. This could be explained by a lower importance of anisotropy relative to other factors affecting streamflow generation, and by the difficulties in creating representative rainfall temporal properties at the catchment scale when the radar scale is used for model calibration. The proposed method provides a tool to create ensembles of design storms when the anisotropic shape of the fields is of importance.Peer reviewe

Hydrology modelling R packages: a unified analysis of models and practicalities from a user perspective

Following the rise of R as a scientific programming language, the increasing requirement for more transferable research, and the growth of data availability in hydrology, R packages containing hydrological models are becoming more and more available to hydrologists. Corresponding to the core of the hydrological studies workflow, their value is increasingly meaningful regarding the reliability of methods and results. Despite package and model distinctiveness, no study has ever 5 provided a comparison of R packages for conceptual rainfall-runoff modelling from a user perspective, contrasting their philosophy, model characteristics and ease of use. We have selected eight packages based on our ability to consistently run their models on simple hydrology modelling examples. We have uniformly analysed the exact structure of seven of the hydrological models integrated in these R packages in terms of conceptual storages and fluxes, spatial discretisation, data requirements and output provided. The analysis showed that very different modelling choices are associated with these packages, which emphasises various hydrological concepts. These specificities are not always sufficiently well explained by the package documentation. Therefore a synthesis of the package functionalities was performed from a user perspective. This synthesis helps inform selection of what packages could/should be used depending on the problem at hand. In this regard, technical features, documentation, R implementations and computational times were investigated. Moreover, by providing a framework for package comparison, this study is a step forward towards supporting more transferable and reusable methods and results for hydrological modelling in R

Can there be water scarcity with abundance of water? : Analyzing water stress during a severe drought in Finland

Severe droughts can affect water security even in countries with ample water resources. In addition, droughts are estimated to become more frequent in several regions due to changing climate. Drought affects many socio-economic sectors (e.g., agriculture, water supply, and industry), as it did in 2018 in Finland. Understanding the basin-wide picture is crucial in drought management planning. To identify vulnerable and water stressed areas in Finland, a water use-to-availability analysis was executed with a reference drought. Water stress was analyzed with the Water Depletion Index WDI. The analysis was executed using national water permits and databases. To represent a severe but realistic drought event, we modelled discharges and runoffs from the worst drought of the last century in Finland (1939–1942). The potential for performing similar analyses in data scarce contexts was also tested using estimates from global models as a screening tool. The results show that the South and Southwest of Finland would have problems with water availability during a severe drought. The most vulnerable areas would benefit from drought mitigation measures and management plans. These measures could be incorporated into the EU River Basin Management Plans

A framework for characterising and evaluating the effectiveness of environmental modelling

Environmental modelling is transitioning from the traditional paradigm that focuses on the model and its quantitative performance to a more holistic paradigm that recognises successful model-based outcomes are closely tied to undertaking modelling as a social process, not just as a technical procedure. This paper redefines evaluation as a multi-dimensional and multi-perspective concept, and proposes a more complete framework for identifying and measuring the effectiveness of modelling that serves the new paradigm. Under this framework, evaluation considers a broader set of success criteria, and emphasises the importance of contextual factors in determining the relevance and outcome of the criteria. These evaluation criteria are grouped into eight categories: project efficiency, model accessibility, credibility, saliency, legitimacy, satisfaction, application, and impact. Evaluation should be part of an iterative and adaptive process that attempts to improve model-based outcomes and foster pathways to better futures

Study of Z boson production in pPb collisions at √sNN = 5.02 TeV

© 2016 The Author.The production of Z bosons in pPb collisions at sNN=5.02 TeV is studied by the CMS experiment via the electron and muon decay channels. The inclusive cross section is compared to pp collision predictions, and found to scale with the number of elementary nucleon-nucleon collisions. The differential cross sections as a function of the Z boson rapidity and transverse momentum are measured. Though they are found to be consistent within uncertainty with theoretical predictions both with and without nuclear effects, the forward-backward asymmetry suggests the presence of nuclear effects at large rapidities. These results provide new data for constraining nuclear parton distribution functions

COVID-19 pandemic and mortality in nursing homes across USA and Europe up to October 2021

Purpose We compared the prevalence of COVID-19 and related mortality in nursing homes (NHs) in 14 countries until October 2021. We explored the relationship between COVID-19 mortality in NHs with the average size of NHs and with the COVID-19 deaths at a population level. Methods The total number of COVID-19 cases and COVID-19-related deaths in all NHs as well as the total number of NHs and NH beds were provided by representatives of 14 countries. The population level respective figures in each country were provided up to October 2021. Results There was a wide variation in prevalence of COVID-19 cases and deaths between countries. We observed a significant correlation between COVID-19 deaths in NHs and that of the total population and between the mean size of NHs and COVID-19 deaths. Conclusion Side-by-side comparisons between countries allow international sharing of good practice to better enable future pandemic preparedness.Peer reviewe

COVID-19 pandemic and mortality in nursing homes across USA and Europe up to October 2021

Purpose We compared the prevalence of COVID-19 and related mortality in nursing homes (NHs) in 14 countries until October 2021. We explored the relationship between COVID-19 mortality in NHs with the average size of NHs and with the COVID-19 deaths at a population level. Methods The total number of COVID-19 cases and COVID-19-related deaths in all NHs as well as the total number of NHs and NH beds were provided by representatives of 14 countries. The population level respective figures in each country were provided up to October 2021. Results There was a wide variation in prevalence of COVID-19 cases and deaths between countries. We observed a significant correlation between COVID-19 deaths in NHs and that of the total population and between the mean size of NHs and COVID-19 deaths. Conclusion Side-by-side comparisons between countries allow international sharing of good practice to better enable future pandemic preparedness.Peer reviewe

An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. SIGNIFICANCE: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.This article is highlighted in the In This Issue feature, p. 275

Effective modeling for integrated water resource management: a guide to contextual practices by phases and steps and future opportunities

The effectiveness of Integrated Water Resource Management (IWRM) modeling hinges on the quality of practices employed through the process, starting from early problem definition all the way through to using the model in a way that serves its intended purpose. The adoption and implementation of effective modeling practices need to be guided by a practical understanding of the variety of decisions that modelers make, and the information considered in making these choices. There is still limited documented knowledge on the modeling workflow, and the role of contextual factors in determining this workflow and which practices to employ. This paper attempts to contribute to this knowledge gap by providing systematic guidance of the modeling practices through the phases (Planning, Development, Application, and Perpetuation) and steps that comprise the modeling process, positing questions that should be addressed. Practice-focused guidance helps explain the detailed process of conducting IWRM modeling, including the role of contextual factors in shaping practices. We draw on findings from literature and the authors’ collective experience to articulate what and how contextual factors play out in employing those practices. In order to accelerate our learning about how to improve IWRM modeling, the paper concludes with five key areas for future practice-related research: knowledge sharing, overcoming data limitations, informed stakeholder involvement, social equity and uncertainty management. © 2019 Elsevier Lt