The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines3-5, we identify CR8-a cyclin-dependent kinase (CDK) inhibitor6-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues

African food system and biodiversity mainly affected by urbanization via dietary shifts

The rapid urbanization in Africa profoundly affects local food and ecological systems. According to earlier research, urbanization may cause food production and biodiversity losses as agricultural or natural lands are absorbed by expanding cities. Land-use displacement effects may buffer agricultural production losses or may lead to additional biodiversity losses but are often overlooked. Moreover, impacts of dietary changes associated with urbanization are rarely considered. To address this, we combined spatially explicit projections of African urban area expansion with observed rice consumption shifts to inform a partial equilibrium model (the Global Biosphere Management Model). We demonstrate the importance of displacement effects to identify potential food production or biodiversity issues until 2050 and argue for their integration in land-use planning and policymaking across spatial scales. We identify that because of agricultural displacement, the impact of urban area expansion on food production losses is probably limited (<1%)—at the cost of additional losses of natural lands by 2050 (up to 2 Mt). We also show that considering dietary shifts associated with urbanization increases rice consumption, production (+8.0%), trade (up to +2 Mt of required import) and agricultural methane emissions (up to +12 MtCO2-equivalent yr–1), thereby underscoring the need for a systems approach in future sustainability studies

Feeding climate and biodiversity goals with novel plant-based meat and milk alternatives

Plant-based animal product alternatives are increasingly promoted to achieve more sustainable diets. Here, we use a global economic land use model to assess the food system-wide impacts of a global dietary shift towards these alternatives. We find a substantial reduction in the global environmental impacts by 2050 if globally 50% of the main animal products (pork, chicken, beef and milk) are substituted—net reduction of forest and natural land is almost fully halted and agriculture and land use GHG emissions decline by 31% in 2050 compared to 2020. If spared agricultural land within forest ecosystems is restored to forest, climate benefits could double, reaching 92% of the previously estimated land sector mitigation potential. Furthermore, the restored area could contribute to 13-25% of the estimated global land restoration needs under target 2 from the Kunming Montreal Global Biodiversity Framework by 2030, and future declines in ecosystem integrity by 2050 would be more than halved. The distribution of these impacts varies across regions—the main impacts on agricultural input use are in China and on environmental outcomes in Sub-Saharan Africa and South America. While beef replacement provides the largest impacts, substituting multiple products is synergistic

Cross-scale trade-off analysis for sustainable development: linking future demand for animal source foods and ecosystem services provision to the SDGs

Dietary transition towards higher consumption of animal source foods (ASF) associated with higher incomes across low and middle-income countries could have negative impacts on environmental systems and their potential in the long run to provide services necessary for achieving multiple Sustainable Development Goals (SDGs). In this article, we integrate economic, land use allocation, and biophysical models to investigate trade-offs between the five ecosystem services and their contributions to various SDGs associated with agricultural expansion to meet future demand for ASF, using Tanzania as a case study. Our results show that under the scenario of sustainable socio-economic development, between 2010 and 2030 in Tanzania, per capita income grows by 169% and the share of population at risk of hunger declines from 34.8% to 23%. These changes can be associated on a macro-level with positive contributions to achievement of SDG 1 (No Poverty) and SDG 2 (Zero Hunger). To satisfy feed demand for increased livestock production domestically, an increase by 21.4% of biomass production as compared to 2010 is needed. Analysis of alternative scenarios for meeting this new demand shows potential threats on a landscape level to achieving numerous SDGs and more generally to attaining sustainable food systems. Ecosystem-based contributions primarily decline to SDGs: SDG 3 (Health), SDG 6 (Clean Water), SDG 11 (Sustainable Cities), SDG 13 (Climate) and SDG 15 (Terrestrial Life). We find that higher crop productivity and redesign of agro-ecosystems to increase on-farm tree cover could significantly limit these losses. Alternatively, the growing demand for ASF could be satisfied with imports, which would allow for reducing the trade-offs locally. However, this would result in at least partially only displacing ecosystem service losses to the exporting countries

Forecasting cocoa yields for 2050

Cocoa is a food-industrial crop that could play a more important role in poverty reduction for small producers in developing countries worldwide. Every year, the cocoa-chocolate value chain moves billions of dollars, providing important dividends for producing countries and for national and international companies around the world. The International Model for Policy Analysis of Agricultural Commodities and Trade (IMPACT) is a structural simulation model, which allows for future analysis of cocoa market globally. The model has been developed at International Food Policy Research Institute (IFPRI) to consider the long-term challenges facing policymakers in reducing hunger, and poverty in a sustainable fashion. IMPACT is the main quantitative tool used by the Global Futures & Strategic Foresight (GFSF) initiative, in which Bioversity International is involved as a partner. The aim of this study is to validate the performance and improve parameterization of IMPACT cocoa components. The main objective is to review and suggest changes to the Intrinsic Productivity Growth Rates (IPRs) for cocoa in order to improve the model’s baseline projections. It focuses on the ten largest cocoa producing countries in reviewing parameters related to yield growth rates until 2050. Based on historical cocoa yield time series, as reported by FAOStat, forecasts are made using an Autoregressive Integrated Moving Average (ARIMA). The forecasts, together with statistically estimated prediction intervals, supported by literature sources and expert knowledge are compared against respective yield trajectories embedded in IMPACT in order to make recommendations. For each country, we discuss the latest information about hindrances and opportunities to cocoa yield growth, including policies, planned investments and disease status. In almost all the cases, except Indonesia, we recommend adjustments of the IPRs. Alarmingly, none of the countries is projected under baseline scenario assumptions to exceed average yield level of 1 t/ha and half of them is expected to remain below 0.6 t/ha until 2050. This emphasizes the need for a change of the business as usual policies and investments in order to improve the livelihoods of the cocoa growing farmers around the world

The Min Min light and the Fata Morgana - An optical account of a mysterious Australian phenomenon.

Despite intense interest in this mysterious Australian phenomenon, the Min Min light has never been explained in a satisfactory way.An optical explanation of the Min Min light phenomenon is offered, based on a number of direct observations of the phenomenon, as well as a field demonstration, in the Channel Country of Western Queensland. This explanation is based on the inverted mirage or Fata Morgana, where light is refracted long distances over the horizon by the refractive index gradient that occurs in the layers of air during a temperature inversion. Both natural and man-made light sources can be involved, with the isolated light source making it difficult to recognise the features of the Fata Morgana that are obvious in daylight and with its unsuspected great distance contributing to the mystery of its origins.Many of the strange properties of the Min Min light are explicable in terms of the unusual optical conditions of the Fata Morgana, if account is also taken of the human factors that operate under these highly-reduced stimulus conditions involving a single isolated light source without reference landmarks

Linking ecosystem services provisioning with demand for animal-sourced food: an integrated modeling study for Tanzania

Standard tools that can quantitatively track the impacts of higher global demand for animal-sourced food to their local environmental effects in developing countries are largely missing. This paper presents a novel integrated assessment framework that links a model of the global agricultural and food system, a landscape-level environmental impact assessment model, and an ecosystem services simulation model. For Tanzania, this integrated assessment showed that a projected increase in the demand and production of foods of livestock origin with optimistic economic growth between 2010 and 2030 leads to an improvement in food security. However, resulting transitions in land use impact negatively on the future provisioning of ecosystem services, increasing phosphorus, nitrogen, and sediment in runoff and reducing water quality in areas downstream of the agricultural expansion. Losses in ecosystem services are lowest when diversified farming practices are adopted in areas of agricultural land expansion. The role of land management in the environmental impacts of expanded livestock production is highlighted, as is the need for a new generation of analytical tools to inform policy recommendations

Readout of histone methylation by Trim24 locally restricts chromatin opening by p53.

The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually diverse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as DNA methylation, do not influence the binding of p53 across the genome. Instead, the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated histone 3 lysine 4 (H3K4), thereby preferentially localizing to those p53 sites that reside in closed chromatin, whereas it is deterred from accessible chromatin by H3K4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to affect gene expression as a function of the local chromatin state. These findings link H3K4 methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors that locally modulate TF function.Luke Isbel, Murat Iskar, Sevi Durdu, Joscha Weiss, Ralph S. Grand, Eric Hietter-Pfeiffer, Zuzanna Kozicka, Alicia K. Michael, Lukas Burger, Nicolas H. Thomä, Dirk Schübele

Data for "Feeding climate and biodiversity goals with novel plant-based meat and milk alternatives"

Research data supporting the study "Feeding climate and biodiversity goals with novel plant-based meat and milk alternatives". It contains: 1) merged.gdx - data derived from the original scenario database 2) map.csv - mapping of food commodities to food groups used for analysis 3) manure.csv - results on nitrogen input to cropland and N crop fertilization from manure 4) AgMIP_regions.shp - shape file used to make maps 5) Paper_visuals_NCOM.R - R script to analyze and visualize the data. It reproduces the main figures in the paper and the appendix   last tested for R Studio 2022.12.0 Build 353, Release (7d165dcf, 2022-12-03) for Windows 10 Pro, 64-bit operating system Instructions: The R code, file 4, reads in files 1, 2 and 3 and generates figures, tables and maps. The directories (line 50 and 58) need to be updated to the location of the data (the current folder)