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

Hidden dynamics of soccer leagues: the predictive ‘power’ of partial standings

Objectives Soccer leagues reflect the partial standings of the teams involved after each round of competition. However, the ability of partial league standings to predict end-of-season position has largely been ignored. Here we analyze historical partial standings from English soccer to understand the mathematics underpinning league performance and evaluate the predictive ‘power’ of partial standings. Methods Match data (1995-2017) from the four senior English leagues was analyzed, together with random match scores generated for hypothetical leagues of equivalent size. For each season the partial standings were computed and Kendall’s normalized tau-distance and Spearman r-values determined. Best-fit power-law and logarithmic functions were applied to the respective tau-distance and Spearman curves, with the ‘goodness-of-fit’ assessed using the R2 value. The predictive ability of the partial standings was evaluated by computing the transition probabilities between the standings at rounds 10, 20 and 30 and the final end-of-season standings for the 22 seasons. The impact of reordering match fixtures was also evaluated. Results All four English leagues behaved similarly, irrespective of the teams involved, with the tau-distance conforming closely to a power law (R2>0.80) and the Spearman r-value obeying a logarithmic function (R2>0.87). The randomized leagues also conformed to a power-law, but had a different shape. In the English leagues, team position relative to end-of-season standing became ‘fixed’ much earlier in the season than was the case with the randomized leagues. In the Premier League, 76.9% of the variance in the final standings was explained by round-10, 87.0% by round-20, and 93.9% by round-30. Reordering of match fixtures appeared to alter the shape of the tau-distance curves. Conclusions All soccer leagues appear to conform to mathematical laws, which constrain the league standings as the season progresses. This means that partial standings can be used to predict end-of-season league position with reasonable accuracy

Estimating the burden of selected non-communicable diseases in Africa: a systematic review of the evidence

Background The burden of non-communicable diseases (NCDs) is rapidly increasing globally, and particularly in Africa, where the health focus, until recently, has been on infectious diseases. The response to this growing burden of NCDs in Africa has been affected owing to a poor understanding of the burden of NCDs, and the relative lack of data and low level of research on NCDs in the continent. Recent estimates on the burden of NCDs in Africa have been mostly derived from modelling based on data from other countries imputed into African countries, and not usually based on data originating from Africa itself. In instances where few data were available, estimates have been characterized by extrapolation and over-modelling of the scarce data. It is therefore believed that underestimation of NCDs burden in many parts of Africa cannot be unexpected. With a gradual increase in average life expectancy across Africa, the region now experiencing the fastest rate of urbanization globally, and an increase adoption of unhealthy lifestyles, the burden of NCDs is expected to rise. This thesis will, therefore, be focussing on understanding the prevalence, and/or where there are available data, the incidence, of four major NCDs in Africa, which have contributed highly to the burden of NCDs, not only in Africa, but also globally. Methods I conducted a systematic search of the literature on three main databases (Medline, EMBASE and Global Health) for epidemiological studies on NCDs conducted in Africa. I retained and extracted data from original population-based (cohort or cross sectional), and/or health service records (hospital or registry-based studies) on prevalence and/or incidence rates of four major NCDs in Africa. These include: cardiovascular diseases (hypertension and stroke), diabetes, major cancer types (cervical, breast, prostate, ovary, oesophagus, bladder, Kaposi, liver, stomach, colorectal, lung and non-Hodgkin lymphoma), and chronic respiratory diseases (chronic obstructive pulmonary disease (COPD) and asthma). From extracted crude prevalence and incidence rates, a random effect meta-analysis was conducted and reported for each NCD. An epidemiological model was applied on all extracted data points. The fitted curve explaining the largest proportion of variance (best fit) from the model was further applied. The equation generated from the fitted curve was used to determine the prevalence and cases of the specific NCD in Africa at midpoints of the United Nations (UN) population 5-year age-group population estimates for Africa. Results From the literature search, studies on hypertension had the highest publication output at 7680, 92 of which were selected, spreading across 31 African countries. Cancer had 9762 publications and 39 were selected across 20 countries; diabetes had 3701 publications and 48 were selected across 28 countries; stroke had 1227 publications and 19 were selected across 10 countries; asthma had 790 publications and 45 were selected across 24 countries; and COPD had the lowest output with 243 publications and 13 were selected across 8 countries. From studies reporting prevalence rates, hypertension, with a total sample size of 197734, accounted for 130.2 million cases and a prevalence of 25.9% (23.5, 34.0) in Africa in 2010. This is followed by asthma, with a sample size of 187904, accounting for 58.2 million cases and a prevalence of 6.6% (2.4, 7.9); COPD, with a sample size of 24747, accounting for 26.3 million cases and a prevalence of 13.4% (9.4, 22.1); diabetes, with a sample size of 102517, accounting for 24.5 million cases and a prevalence of 4.0% (2.7, 6.4); and stroke, with a sample size of about 6.3 million, accounting for 1.94 million cases and a prevalence of 317.3 per 100000 population (314.0, 748.2). From studies reporting incidence rates, stroke accounted for 496 thousand new cases in Africa in 2010, with a prevalence of 81.3 per 100000 person years (13.2, 94.9). For the 12 cancer types reviewed, a total of 775 thousand new cases were estimated in Africa in 2010 from registry-based data covering a total population of about 33 million. Among women, cervical cancer and breast cancer had 129 thousand and 81 thousand new cases, with incidence rates of 28.2 (22.1, 34.3) and 17.7 (13.0, 22.4) per 100000 person years, respectively. Among men, prostate cancer and Kaposi sarcoma closely follows with 75 thousand and 74 thousand new cases, with incidence rates of 14.5 (10.9, 18.0) and 14.3 (11.9, 16.7) per 100000 person years, respectively. Conclusion This study suggests the prevalence rates of the four major NCDs reviewed (cardiovascular diseases (hypertension and stroke), diabetes, major cancer types, and chronic respiratory diseases (COPD and asthma) in Africa are high relative to global estimates. Due to the lack of data on many NCDs across the continent, there are still doubts on the true prevalence of these diseases relative to the current African population. There is need for improvement in health information system and overall data management, especially at country level in Africa. Governments of African nations, international organizations, experts and other stakeholders need to invest more on NCDs research, particularly mortality, risk factors, and health determinants to have evidenced-based facts on the drivers of this epidemic in the continent, and prompt better, effective and overall public health response to NCDs in Africa