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

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

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

Assessing the Impact of 10 years of FTA Research: a synthesis of the 5 integrated impact studies

In 2021, the CGIAR Research Program on Forests, Trees and Agroforestry (FTA) completed a set of studies, under the guidance and oversight of its Independent Steering Committee (ISC), to document its progress in addressing five key global challenges. These studies had the following purposes: (i) to design a workable approach and operational method to assess impacts at scale at the level of the FTA program, since 2011; (ii) to deploy the method effectively on a set of five identified development challenges addressed by FTA; (iii) to learn lessons from the exercise for FTA post 2021. This document provides a synthesis of the five studies and draws lessons and recommendations for research for development programs