Bridging the gap between climate scenarios and law - a roadmap for mutual contributions

To bridge the knowledge gap between climate scenarios and law, this presentation is aimed to demonstrate currently demanded mutual contributions by legal professionals and integrated assessment modellers on 1) how legal knowledge can be integrated into climate scenarios and 2) how scientific evidence generated from climate scenarios can better guide climate litigation cases. We expect that this could support judges in making trade-offs in climate-related court cases and could contribute to the acceptance of decisions by judges in such cases. Given the emissions gap and the measures that must be taken to comply with the Paris Agreement, the latter is likely becoming more relevant. Regarding the first part, the results are based on an empirical research project on Improving the Integration of Legal Knowledge and Scholars in Climate Scenario Assessments (https://www.uu.nl/en/research/sustainability/improving-the-integration-of-legal-knowledge-and-scholars-in-climate-scenario-assessments) and a workshop (https://www.uu.nl/en/research/sustainability/workshop-report-promoting-the-mutual-understanding-between-legal-and-governance-scholars-and-climate) resulted from this project held in May 2023. Via interviews and focus-group discussions with 24 experts in climate modelling, climate law and politics, and ethics, our research highlights four legal aspects for integration, which are: 1) implementation end enforcement of climate targets, 2) key normative principles, 3) legal uncertainties, and 4) the applicability of scenarios in regional and local legal contexts. Considering the challenges of integration due to epistemic distinctions between disciplines, experts held different opinions on the feasibility of integrating those four aspects. Regarding actionable steps for the short term, revising narratives and a ‘legal reality check’ are the most agreed ones. The former refers to adding legal obligations that safeguard justice, fairness and fundamental human rights - traceable to various treaties - to narratives of the global futures. The latter refers to scrutinising the ‘shared feasibility space’ between law on the one hand and modelled scenarios and emission reduction pathways on the other: it can be the compatibility of legal principles with modelled scenarios based on different assessment criteria (e.g. fair share of burdens), or to compare scenarios with and without regulatory boundary conditions in a specific jurisdiction on a specific mitigation solution (e.g. BECCS scenarios). Regarding the second part, the currently ongoing research focuses on the adoption of authoritative scientific evidence from climate scenarios - typically the projections referred to in the IPCC reports - in climate litigation cases. First, inspired by the Daubert Criteria, this research explores the possibility of developing guidelines for judges to deal with scientific uncertainties contained in multiple projected futures and determining admissibility of scientific evidence. Second, seeing the increasing reference to ‘open norms’ (e.g. due diligence, fair share) and fundamental human rights (to private life or a healthy environment) in court cases, modelled scenarios could provide information for guiding judges in their interpretation of key concepts such as carbon budgets, fair share, emission gap, appropriate emission reduction obligations, and climate-induced harm and loss and damage. We expect that this could be beneficial to the supportability of judges' decisions in climate cases

Numerical Modeling of a Granular Collapse Immersed in a Viscous Fluid

The three-dimensional unsteady collapse of the granular column in a viscous fluid has been investigated with an IBM/DEM approach. Present numerical simulations allow one to confirm quantitatively several experimental observations of Rondon et al. regarding morphology, characteristic sizes of granular deposits and the basal pressure below the column. In the presented simulations, the collapse dynamics is controlled by the viscous time Tv. To our knowledge, a numerical approach, e.g. the IBM/DEM method, is able for the first time to capture the pore pressure feedback phenomenon in flowing fluid-grains mixture. The effect of the initial packing fraction has a great influence of the dynamics of granular collapse in the simulation results as in the experiments of Rondon et al. Furthermore, the IBM/DEM permits to investigate the inner state of the granular column during the collapse, in particular, the evolution of the pressure field inside the granular column can be analyzed which is difficult to do in experiments. Simulations of the collapse of a granular column immersed in a fluid can be performed in the inertial and free-fall regimes as well varying the nature of the fluid and/or the particles

Perimenstrual symptoms and it's management - Assessment with Menstrual Distress Questionnaire -

月経周期の変化に伴う多様で複雑な月経周辺期の症状を,出来るだけ単純で基本的に共通した変化として捉え,症状に適した対応を検討することを目的として本研究を行った｡月経を有する22～45歳の女性34名に対し,Menstrual Distress Questionnaireの即時的回答法を用いて月経周辺期を[痛み],[集中力],[行動変化],[自律神経反応],[水分貯留],[負の感情]から構成された35症状6領域で縦断的に追究し,以下の結果を得た｡ 1.月経周辺期の症状を縦断的に比較検討した結果,Moosのデータと近似した日本人のデータを示した｡ 2.月経周辺期における領域の推移では,身体的症状で構成される[痛み領域],[水分貯留領域]の2領域が精神的症状で構成される他の領域に比べ,常に上位を占めていた｡以上の事より,月経周辺期の生理的変化に伴う精神的愁訴は,身体的変化によって誘発されている可能性が示唆された｡Each of 34 women rated their experience of 46 symptoms on a six-point scale separately for the premenstrual, menstrual, and intermenstrual phases of her most recent menstrual cycle. The 46 symptoms were intercorrelated and factor analyzed separately for each phase. These symptoms were divided into six clusters of symptoms, such as pain, concentration, behavioral change, autonomic reaction, water retention, and negative affect. Pain and water retention were composed of physical symptoms, were always at higher position than three clusters of menstrual symptoms in perimenstrual change. Thus, mental symptoms in perimenstrual physiological changes were might be induced by physical changes

Lowe Syndrome Protein OCRL1 Supports Maturation of Polarized Epithelial Cells

Mutations in the inositol polyphosphate 5-phosphatase OCRL1 cause Lowe Syndrome, leading to cataracts, mental retardation and renal failure. We noted that cell types affected in Lowe Syndrome are highly polarized, and therefore we studied OCRL1 in epithelial cells as they mature from isolated individual cells into polarized sheets and cysts with extensive communication between neighbouring cells. We show that a proportion of OCRL1 targets intercellular junctions at the early stages of their formation, co-localizing both with adherens junctional components and with tight junctional components. Correlating with this distribution, OCRL1 forms complexes with junctional components α-catenin and zonula occludens (ZO)-1/2/3. Depletion of OCRL1 in epithelial cells growing as a sheet inhibits maturation; cells remain flat, fail to polarize apical markers and also show reduced proliferation. The effect on shape is reverted by re-expressed OCRL1 and requires the 5′-phosphatase domain, indicating that down-regulation of 5-phosphorylated inositides is necessary for epithelial development. The effect of OCRL1 in epithelial maturation is seen more strongly in 3-dimensional cultures, where epithelial cells lacking OCRL1 not only fail to form a central lumen, but also do not have the correct intracellular distribution of ZO-1, suggesting that OCRL1 functions early in the maturation of intercellular junctions when cells grow as cysts. A role of OCRL1 in junctions of polarized cells may explain the pattern of organs affected in Lowe Syndrome

Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice

The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by therapeutic monoclonal antibodies, emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East Respiratory Syndrome CoV (MERS-CoV). The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral which has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19

Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity is observed in Vero E6 cells (EC50 = 1.65 μM) because of their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase of SARS-CoV-2. In mice infected with the chimeric virus, therapeutic RDV administration diminishes lung viral load and improves pulmonary function compared with vehicle-treated animals. These data demonstrate that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19