An overview of the collaborative partnership between Sheffield Hallam University and Tunku Abdul Rahman College

This paper provides an outline of the strategic partnership between Tunku Abdul Rahman College and Sheffield Hallam University's Built Environment Department. Within the paper curriculum design and key course developments, with supporting rationale are established. The different cultural aspects of teaching international students are explored, noting how student engagement and behaviour has changed and developed over a 13 year relationship. The paper concludes with the identification of future collaborative ventures

Paul D. Workman Photograph Collection- Accession 1109

The Paul D. Workman Photograph Collection consists of photographs taken by Rock Hill, SC resident and WWII veteran Major Paul D. Workman (1900-1968). Maj. Workman was the nephew of Winthrop founder and first president, David Bancroft Johnson (1856-1928) through Dr. Johnson’s half-sister Florence Nance Workman (1872-1940). The collection consists of 168 slides, 5 negatives, and 76 photograph prints. Most of the images are of Rock Hill, SC and are of spring scenes including Glencairn Gardens and other gardens, the Rock Hill Centennial Parade in 1952, local businesses, Sullivan Middle School (formerly Rock Hill High School, the Southern Rail Road, and the Elks Club of Rock Hill.https://digitalcommons.winthrop.edu/manuscriptcollection_findingaids/2285/thumbnail.jp

HSF1 in Translation

The master regulator of the classical cytoprotective “heat shock” response, heat shock factor 1 (HSF1), is increasingly implicated in cancer pathogenesis, but the mechanisms remain poorly understood. A recent study connects increased protein translation to activation of HSF1 in malignant cells and demonstrates the therapeutic benefit of targeting this link

Unveiling the Secrets of the Ancestral PI3 Kinase Vps34

Vps34 is the primordial member of the PI3 kinase family involved in vesicular trafficking, nutrient signaling, and autophagy. A report in Science unveils the Vps34 structure, providing new insights into the catalytic mechanism, explaining why Vsp34 is so difficult to inhibit, and facilitating design of chemical tools and potential drugs

Couple relationships in the context of heroin use

Background: Recent prevalence studies of opiate users within England estimate there to be over 250,000. Opiate users make up 53% of people in drug treatment services. Although retention in treatment improves treatment outcomes, dropout rates remain high. Intimate relationships may be an influential factor in opiate users’ treatment and recovery, however limited research has been conducted to understand the experiences of opiate using couples (relationships where both members use opiates). This project sought to examine how these relationships are experienced and how they may influence individuals’ attempts to reduce opiate use. Design: This portfolio reports a meta-ethnographic approach to the synthesis of the qualitative literature on the relationship experiences of opiate using couples; and an empirical study exploring the lived experience of individuals in treatment for opiate use whilst their opiate using partner is not in treatment. This study adopted an Interpretative Phenomenological Analysis method. Results: The systematic review synthesised findings from 27 studies, developing six high order themes; centrality of opiate use to the relationship, stabilising and destabilising features of the relationship, relationship and addiction reinforcers, negotiating treatment, and gendered power dynamics. The empirical paper produced themes of how opiate users in treatment rationalise but also re-evaluate their relationship, whilst conceptualising their recovery and experiencing a disruption to their sense of identity. Conclusion: The systematic review suggests that opiate use plays a complex and reciprocal role within couple relationships, and also demonstrates how individuals may negotiate treatment and recovery from within opiate using relationships. The empirical paper posits that individuals in treatment for opiate use undergo a number of challenges in optimising their treatment experience, and illuminate the dilemmas faced by individuals when remaining in their relationship whilst simultaneously reducing their opiate use

Co-crystalization and in vitro biological characterization of 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors

A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp9

A General Mechanistic Model for Admixture Histories of Hybrid Populations

Admixed populations have been used for inferring migrations, detecting natural selection, and finding disease genes. These applications often use a simple statistical model of admixture rather than a modeling perspective that incorporates a more realistic history of the admixture process. Here, we develop a general model of admixture that mechanistically accounts for complex historical admixture processes. We consider two source populations contributing to the ancestry of a hybrid population, potentially with variable contributions across generations. For a random individual in the hybrid population at a given point in time, we study the fraction of genetic admixture originating from a specific one of the source populations by computing its moments as functions of time and of introgression parameters. We show that very different admixture processes can produce identical mean admixture proportions, but that such processes produce different values for the variance of the admixture proportion. When introgression parameters from each source population are constant over time, the long-term limit of the expectation of the admixture proportion depends only on the ratio of the introgression parameters. The variance of admixture decreases quickly over time after the source populations stop contributing to the hybrid population, but remains substantial when the contributions are ongoing. Our approach will facilitate the understanding of admixture mechanisms, illustrating how the moments of the distribution of admixture proportions can be informative about the historical admixture processes contributing to the genetic diversity of hybrid populations

Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546)