A History of the Molecular Initiating Event

The adverse outcome pathway (AOP) framework provides an alternative to traditional $\textit{in vivo}$ experiments for the risk assessment of chemicals. AOPs consist of a number of key events (KEs) linked by key event relationships across a range of biological organization backed by scientific evidence. The first KE in the pathway is the molecular initiating event (MIE)-the initial chemical trigger that starts an AOP. Over the past 3 years the AOP conceptual framework has gained a large amount of momentum in toxicology as an alternative to animal methods, and so the MIE has come into the spotlight. What is an MIE? How can MIEs be measured or predicted? What research is currently contributing to our understanding of MIEs? In this Perspective we outline answers to these key questions.The authors acknowledge financial support from Unilever

Using Molecular Initiating Events To Generate 2D Structure-Activity Relationships for Toxicity Screening

Molecular initiating events (MIEs) can be boiled down to chemical interactions. Chemicals that interact must have intrinsic properties that allow them to exhibit this behavior, be these properties stereochemical, electronic, or otherwise. In an attempt to discover some of these chemical characteristics, we have constructed structural alert-style structure-activity relationships (SARs) to computationally predict MIEs. This work utilizes chemical informatics approaches, searching the ChEMBL database for molecules that bind to a number of pharmacologically important human toxicology targets, including G-protein coupled receptors, enzymes, ion channels, nuclear receptors, and transporters. By screening these compounds to find common 2D fragments and combining this approach with a good understanding of the literature, bespoke 2D structural alerts have been written. These SARs form the beginning of a tool for screening novel chemicals to establish the kind of interactions that they may be able to make in humans. These SARs have been run through an internal validation to test their quality, and the results of this are also discussed. MIEs have proven to be difficult to find and characterize, but we believe we have taken a key first step with this work.Unileve

3-(3-Bromo-4-methoxy­phen­yl)-1,5-diphenyl­pentane-1,5-dione

In the title compound, C24H21BrO3, the central bromo­methoxy­benzene ring forms dihedral angles of 63.6 (1) and 60.3 (1)° with the terminal phenyl rings, while the angle between the two phenyl rings is 25.8 (1)°. The crystal structure is stabilized by weak C—H⋯Br and C—H⋯O hydrogen bonds, and C—H⋯π and π–π stacking [centroid–centroid distance = 3.910 (3) Å] inter­actions

Existing evidence on the use of participatory scenarios in ecological restoration: a systematic map

Background and context The scale of land degradation worldwide has led to nearly one billion hectares committed to restoration globally. However, achieving such restoration targets will necessitate complex trade-offs against limited time, competing knowledge, costs, resources and varying stakeholder and societal preferences. Participatory scenarios allow a way to identify collaborative solutions for restoration planning and implementation best suited for the local cultures and societies they are tied to. They can be used to navigate uncertainties surrounding future trajectories of restored areas by evaluating trade-offs in outcomes. This research aims to systematically map the evidence on the use of participatory scenarios in restoration planning. We use the following research question: What evidence exists on the use of participatory scenarios in ecological restoration? This is answered by examining the characteristics of the evidence base, types of study design, types of outcomes, trade-offs in outcomes, and the role of participants. Methods A comprehensive and reproducible search strategy was followed using bibliographic databases, webbased searches, and targeted searching. Search results underwent a two-step screening process according to eligibility criteria. Metadata on key areas of interest were extracted from included texts and were narratively synthesised alongside data visualisations to answer the research questions. Review findings 18,612 records were initially identified, and 106 articles were included in the final map. Most studies were conducted in Europe and North America, focusing on restoring agricultural land or forests. Most texts used mixed methods and explored multiple outcome types, but environmental outcomes were the most assessed. Within environmental outcomes, indicators for ecological function were assessed more frequently than structural or compositional indicators. The most common reason for choosing outcomes and indicators was stakeholder interest. Tradeoffs in social, ecological, and economic outcomes were mainly examined across space using mapping techniques, while far fewer studies looked at trade-offs across stakeholders and time. Participants were mostly included in the scenario creation step and were usually chosen purposefully by the research team. Conclusions It is difficult to understand how useful scenarios are for restoration planning because few texts reported how scenarios fed into the process. Despite this, the range of outcomes used and different method types adopted suggests participatory scenarios allow for integrating different knowledge and approaches, alongside facilitating the use of qualitative or semi-quantitative data when this is more appropriate or quantitative data is not widely available. To better use participatory scenarios as a tool for ecological restoration planning, decision-makers can push for greater levels and definitions of participation from the offset of restoration projects with specified, regular, and structured communication and participation channels. We also recommend more systematic methods of participant selection, such as stakeholder analysis. Further research is needed to understand the effectiveness of participatory scenarios in restoration planning and whether the participation of stakeholders was successful in meeting objectives. To improve the evidence base, future studies should clearly evaluate their effectiveness in the restoration planning process and their success in meeting their participatory objectives. Evidence synthesis, Stakeholder engagement, Collaboration, Alternative futures, Socioecological systems, Co-productionpublishedVersio

Targeting 1.5 degrees with the global carbon footprint of the Australian Capital Territory

In 2019 the Australian Capital Territory (ACT) government stated an ambition to prioritise reduction of Scope 3 greenhouse gas emissions, the size of which had not been fully quantified previously. This study calculated the total carbon footprint of the ACT in 2018, including Scope 1, 2 and 3 emissions and modelled scenarios to reduce all emissions in line with a 1.5 °C target approach. This is the first time a multi-scale analysis of local, sub-national and international supply chains has been undertaken for a city, using a nested and trade-adjusted global multi-region input-output model. This allowed for the quantification of global origins and destinations of emissions, which showed that the 2018 carbon footprint for the ACT was approximately 34.7 t CO2-eq/cap, with 83% attributed to Scope 3. Main contributions came from transport, electricity, manufacturing and public administration and safety, with emissions generated primarily in Australian States and Territories. Modelling in accordance with a 1.5 °C warming scenario showed a plausible reduction to 5.2 t CO2-eq/cap by 2045 (excluding offsets or carbon dioxide removal technologies), with remaining emissions predominantly embodied in international supply chains. This study demonstrates the radical changes required by a wealthy Australian city to achieve 1.5 °C compliance and identifies sectors and supply chains for prioritising policies to best achieve this outcome

(2E)-1-(2-Bromo­phen­yl)-3-(4-chloro­phen­yl)prop-2-en-1-one

In the title compound, C15H10BrClO, the dihedral angle between the mean planes of the benzene rings in the ortho-bromo- and para-chloro-substituted rings is 70.5 (6)°. The dihedral angles between the mean plane of the prop-2-en-1-one group and the mean planes of the benzene rings in the 4-chloro­phenyl and 2-bromo­phenyl rings are 14.9 (3) and 63.3 (8)°, respectively. In the crystal, inversion dimers linked by pairs of weak C—H⋯O interactions are observed as well as aromatic π–π stacking inter­actions

Existing evidence on the use of participatory scenarios in ecological restoration: a systematic map

Background and context: The scale of land degradation worldwide has led to nearly one billion hectares committed to restoration globally. However, achieving such restoration targets will necessitate complex trade-offs against limited time, competing knowledge, costs, resources and varying stakeholder and societal preferences. Participatory scenarios allow a way to identify collaborative solutions for restoration planning and implementation best suited for the local cultures and societies they are tied to. They can be used to navigate uncertainties surrounding future trajectories of restored areas by evaluating trade-offs in outcomes. This research aims to systematically map the evidence on the use of participatory scenarios in restoration planning. We use the following research question: What evidence exists on the use of participatory scenarios in ecological restoration? This is answered by examining the characteristics of the evidence base, types of study design, types of outcomes, trade-offs in outcomes, and the role of participants. Methods: A comprehensive and reproducible search strategy was followed using bibliographic databases, web-based searches, and targeted searching. Search results underwent a two-step screening process according to eligibility criteria. Metadata on key areas of interest were extracted from included texts and were narratively synthesised alongside data visualisations to answer the research questions. Review findings:18,612 records were initially identified, and 106 articles were included in the final map. Most studies were conducted in Europe and North America, focusing on restoring agricultural land or forests. Most texts used mixed methods and explored multiple outcome types, but environmental outcomes were the most assessed. Within environmental outcomes, indicators for ecological function were assessed more frequently than structural or compositional indicators. The most common reason for choosing outcomes and indicators was stakeholder interest. Trade-offs in social, ecological, and economic outcomes were mainly examined across space using mapping techniques, while far fewer studies looked at trade-offs across stakeholders and time. Participants were mostly included in the scenario creation step and were usually chosen purposefully by the research team. Conclusions: It is difficult to understand how useful scenarios are for restoration planning because few texts reported how scenarios fed into the process. Despite this, the range of outcomes used and different method types adopted suggests participatory scenarios allow for integrating different knowledge and approaches, alongside facilitating the use of qualitative or semi-quantitative data when this is more appropriate or quantitative data is not widely available. To better use participatory scenarios as a tool for ecological restoration planning, decision-makers can push for greater levels and definitions of participation from the offset of restoration projects with specified, regular, and structured communication and participation channels. We also recommend more systematic methods of participant selection, such as stakeholder analysis. Further research is needed to understand the effectiveness of participatory scenarios in restoration planning and whether the participation of stakeholders was successful in meeting objectives. To improve the evidence base, future studies should clearly evaluate their effectiveness in the restoration planning process and their success in meeting their participatory objectives

4,5,7,8,17-Penta­hydr­oxy-14,18-dimethyl-6-methyl­ene-3,10-dioxapenta­cyclo­[9.8.0.01,7.04,19.013,18]nona­dec-14-ene-9,16-dione methanol solvate dihydrate

The title quassinoid compound, C20H24O9·CH3OH·2H2O, is a natural eurycomanone isolated from the roots of Eurycoma longifolia. The mol­ecules contain a fused five-ring system, with one tetra­hydro­furan ring adopting an envelope conformation, one tetra­hydro­pyran-2-one ring in a screw boat conformation, one cyclo­hexenone ring in a half-chair conformation and two cyclo­hexane rings in chair conformations. Intra­molecular C—H⋯O inter­actions generate S(5) ring motifs and an O—H⋯O inter­action generates an S(7) ring motif. In the crystal, mol­ecules are linked via inter­molecular O—H⋯O inter­actions along the b axis and further stacked along a axis. The absolute configuration of the title compound was inferred from previously solved structures of its analogues

A second polymorph of (2E)-1-(4-fluoro­phen­yl)-3-(3,4,5-trimethoxy­phen­yl)prop-2-en-1-one

The crystal structure of the title compound, C18H17FO4, reported here is a polymorph of the structure first reported by Patil et al. [Mol. Cryst. Liq. Cryst. Sci. Technol. Sect. A (2007), 461, 123–130]. It is a chalcone analog and consists of substituted phenyl rings bonded at the opposite ends of a propenone group, the biologically active region. The dihedral angle between the mean planes of the aromatic rings within the 4-fluoro­phenyl and trimethoxy­phenyl groups is 28.7 (1)° compared to 20.8 (6)° in the published structure. The angles between the mean plane of the prop-2-ene-1-one group and the mean plane of aromatic rings within the 4-fluoro­phenyl and trimethoxy­phenyl groups are 30.3 (4) and 7.4 (7)°, respectively, in contast to 10.7 (3) and 12.36° for the polymorph. While the two 3-meth­oxy groups are in the plane of the trimeth­oxy-substituted ring, the 4-meth­oxy group is in a synclinical [−sc = −78.1 (2)°] or anti­clinical [+ac = 104.0 (4)°] position, compared to a +sc [53.0 (4)°] or −ac [−132.4 (7)°] position. While no classical hydrogen bonds are present, weak inter­molecular C—H⋯π-ring inter­actions are observed which contribute to the stability of the crystal packing. The two polymorphs crystallize in the same space group, P21/c, but have different cell parameters for the a, b and c axes and the β angle. A comparison of the mol­ecular geometries of both polymorphs to a geometry optimized density functional theory (DFT) calculation at the B3-LYP/6–311+G(d,p) level for each structure provides additional support to these observations

rac-[3-Hydroxy-6,9-dimethyl-6-(4-methylpent-3-en-1-yl)-6a,7,8,9,10,10a-hexahydro-6H-1,9-epoxybenzo[c]chromen-4-yl](phenyl)methanone

The title compound congestiflorone, C28H32O4, which was isolated from the stem bark of Mesua congestiflora, consists of a benzophenone skeleton with two attached pyran rings to which a cyclo­hexane ring and a C6 side chain are bonded. The benzene ring is significantly distorted from planarity (r.m.s. deviation = 0.0007 Å) due to the constraints imposed by junctions with the two pyran rings. The cyclo­hexane ring is in a chair conformation, one pyran ring is in a boat conformation, while the other is a distorted chair. The phenyl and benzene rings make a dihedral angle of 55.85 (9)°. An intra­molecular O—H⋯O hydrogen bond is observed. In the crystal, mol­ecules are linked via C—H⋯O inter­actions