Contributors: Adriaenssens, AE, Gribble, Fiona, Reimann, Frank
ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response
Contributors: Carroll, Jason, Nagarajan, Sankari, Rao, Shalini V, Sutton, Joseph, Cheeseman, Danya, Dunn, Shanade, Papachristou, Evangelia, Gonzalez Prada, Jose-Enrique, Couturier, Dominique-Laurent, Kumar, Sanjeev
... Using genome-wide CRISPR screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the most critical factors required for response to two classes of Estrogen Receptor-alpha (ER) antagonists as these SWI/SNF-specific gene knockouts lead to drug resistance. Unexpectedly, ARID1A was also the top candidate for response to the BET inhibitor JQ1, but in the opposite direction, where loss of ARID1A sensitised breast cancer cells to BET inhibition. We show that ARID1A is a repressor which binds chromatin at ER cis-regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but FOXA1-dependent and active ER-independent manner. Deletion of ARID1A resulted in loss of Histone Deacetylase 1 (HDAC1) binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease and our findings provide mechanistic insight into this process whilst revealing rational treatment strategies for these patients. Key words: ARID1A, Breast cancer, Treatment resistance, CRISPR screens
The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart.
Contributors: Tate, Mitchel, Higgins, Gavin C, De Blasio, Miles J, Lindblom, Runa, Prakoso, Darnel, Deo, Minh, Kiriazis, Helen, Park, Min, Baeza-Garza, Carlos D, Caldwell, Stuart T
... PURPOSE: Methylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy. METHODS: Male 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks. Several morphological and systemic parameters were assessed, as well as cardiac function by echocardiography. RESULTS: Akita mice were smaller in size than wild type counterparts in terms of body weight and tibial length. Akita mice exhibited elevated blood glucose and glycated haemoglobin. Total heart and individual ventricles were all smaller in Akita mice. None of the aforementioned parameters was impacted by MitoGamide treatment. Echocardiographic analysis confirmed that cardiac dimensions were smaller in Akita hearts. Diastolic dysfunction was evident in Akita mice, and notably, MitoGamide treatment preferentially improved several of these markers, including e'/a' ratio and E/e' ratio. CONCLUSIONS: Our findings suggest that MitoGamide, a novel mitochondria-targeted approach, offers cardioprotection in experimental diabetes and therefore may offer therapeutic potential for the treatment of cardiomyopathy in patients with diabetes.
Contributors: Fowden, Abigail, Giussani, Dino, Forhead, Alison
... In many species, the pattern of growth and physiological development in utero has an important role in determining not only neonatal viability but also adult phenotype and disease susceptibility. Changes in fetal development induced by a range of environmental factors including maternal nutrition, disease, placental insufficiency and social stresses have all been shown to induce adult cardiovascular and metabolic dysfunction that often lead to ill health in later life. Compared to other precocious animals, much less is known about the physiological development of the fetal horse or the longer term impacts on its phenotype of altered development in early life because of its inaccessibility in utero, large size and long lifespan. This review summaries the available data on the normal metabolic, cardiovascular and endocrine development of the fetal horse during the second half of gestation. It also examines the responsiveness of these physiological systems to stresses such as hypoglycaemia and hypotension during late gestation. Particular emphasis is placed on the role of the equine placenta and fetal endocrine glands in mediating the changes in fetal development seen towards term and in response to nutritional and other environmental cues. The final part of the review presents the evidence that the early life environment of the horse can alter its subsequent metabolic, cardiovascular and endocrine phenotype as well as its postnatal growth and bone development. It also highlights the immediate neonatal environment as a key window of susceptibility for programming of equine phenotype. Although further studies are needed to identify the cellular and molecular mechanisms involved, developmental programming of physiological phenotype is likely to have important implications for the health and potential athletic performance of horses, particularly if born with abnormal body weight, premature or dysmature characteristics or produced by assisted reproductive technologies, indicative of an altered early life environment.
The Evolution of Manor Courts in Medieval England, c.1250-1350: the Evidence of the Personal Actions
Contributors: Briggs, Christopher, Schofield, Phillipp R
... Manor courts held by landlords for their tenants and other local people existed in their thousands across medieval England. These courts played a significant role in the everyday lives of villagers, formed a major site for the preservation of law and order, and have been studied by generations of historians. Yet room for debate remains concerning the character of these institutions in the later thirteenth and early fourteenth centuries, and the influences that proved most important for their evolution. This article uses a new database concerning hundreds of manorial personal actions – lawsuits which treated areas roughly equivalent to modern tort and contract law – to explore the procedures and practices of the manor courts, and to reconstruct their development over the first century for which detailed records of their proceedings survive. It is argued that although significant local variation among manor courts persisted, especially in the west of England, overall there was a broad process of ‘convergence’. Yet this was not simply a top-down process involving the transmission of practices from the king’s courts of common law, or the communication of external rules by legal professionals or landlords. Instead, the suitors, litigants and jurors of the manor courts played a decisive role in this process. The manorial personal actions thus provide an important instance of the fundamental role of experienced laypeople in simultaneously shaping and exploiting key institutions of medieval governance and law.
Contributors: McEniery, Carmel, Araghi, Marzieh, Shipley, Martin, Wilkinson, Ian, Valencia-Hernández, Carlos, Kivimaki, Mika, Sabia, Severine, Singh-Manoux, Archana, Brunner, Eric
... Aortic stiffness is associated with an increased risk of cardio- and cerebrovascular disease and mortality and may increase risk of dementia. The aim of the present study is to examine the association between arterial stiffness and cognitive decline in a large prospective cohort study with three repeated cognitive assessment over 7 years of follow-up. Aortic pulse wave velocity (PWV) was measured among 4,300 participants (mean±standard deviation age 65.1±5.2 years) in 2007-09 and categorized based on the tertiles: (lowest third: 8.91 m/s). A battery of cognitive tests was administered to assess cognitive function in 2007-09, 2012-13, and 2015-16. Standardized global cognitive score (mean=0, SD=1) in highest third versus lowest third of PWV category was lower at baseline (-0.12, 95% CI -0.18, -0.06). Accelerated 7-year cognitive decline was observed among individuals with the highest PWV [difference in 7-year cognitive change for highest third vs. lowest third PWV: -0.06, 95% CI -0.11, -0.01, P <0.01]. Higher aortic stiffness was associated with faster cognitive decline. Clinicians may be able to use arterial stiffness severity as an indicator to administer prompt treatments to prevent or delay the onset of cognitive decline or dementia. Future studies need to determine whether early intervention of vascular stiffness is effective in delaying these outcomes.
Contributors: Rubinsztein, David
... An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled “Aging Research and Drug Discovery (ARDD)” held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.
Relationship between measures of cerebrovascular reactivity and intracranial lesion progression in acute TBI patients: an exploratory analysis
Contributors: Mathieu, François, Zeiler, Frederisk A, Whitehouse, Daniel P, Das, Tilak, Ercole, Ari, Smielewski, Peter, Hutchinson, Peter J, Czosnyka, Marek, Newcombe, Virginia, Menon, David K
... Background: Failure of cerebral autoregulation and progression of intracranial lesion have both been shown to contribute to poor outcome in patients with acute traumatic brain injury (TBI), but the interplay between the two phenomena has not been investigated. Preliminary evidence leads us to hypothesize that brain tissue adjacent to primary injury foci may be more vulnerable to large fluctuations in blood flow in the absence of intact autoregulatory mechanisms. The goal of this study was therefore to assess the influence of cerebrovascular reactivity measures on radiological lesion expansion in a cohort of patient with acute TBI. Methods: We conducted a retrospective cohort analysis on 50 TBI patients who had undergone high-frequency multimodal intracranial monitoring and for which at least two brain computed tomography (CT) scans had been performed the acute phase of injury. We first performed univariate analyses on the full cohort to identify non-neurophysiological factors (i.e. initial lesion volume, timing of scan, coagulopathy) associated with traumatic lesion growth in this population. In a subset analysis of 23 patients who had intracranial recording data covering the period between the initial and repeat CT scan, we then correlated changes in serial volumetric lesion measurements with cerebrovascular reactivity metrics derived from the pressure-reactivity index (PRx), pulse amplitude index (PAx), and RAC (correlation coefficient between the pulse amplitude of intracranial pressure and cerebral perfusion pressure). Using multivariate methods, these results were subsequently adjusted for the non-neurophysiological confounders identified in the univariate analyses. Results: We observed significant positive linear associations between the degree of cerebrovascular reactivity impairment and progression of pericontusional edema. The strongest correlations were observed between edema progression and the following indices of cerebrovascular reactivity between sequential scans: % time PRx >0.25 (r=0.69, p =0.002); and % time PAx >0.25 (r=0.64, p =0.006). These associations remained significant after adjusting for initial lesion volume and mean cerebral perfusion pressure. In contrast, progression of the hemorrhagic core and extra-axial hemorrhage volume did not appear to be strongly influenced by autoregulatory status. Conclusions: Our preliminary findings suggest a possible link between autoregulatory failure and traumatic edema progression, which warrant re-evaluation in larger scale prospective studies.
Whole-Genome Sequences of Five Strains of Kocuria rosea, NCTC2676, NCTC7514, NCTC7512, NCTC7528, and NCTC7511.
Contributors: Turnbull, Jake D, Russell, Julie E, Fazal, Mohammed-Abbas, Grayson, Nicholas E, Deheer-Graham, Ana, Oliver, Karen, Holroyd, Nancy, Parkhill, Julian, Alexander, Sarah
... Kocuria rosea is a Gram-positive coccus found in the environment and within normal human skin microbiota, and more recently, it has been potentially implicated as an opportunistic pathogen. Here, we describe the genome sequences of five strains of K. rosea (NCTC2676, NCTC7514, NCTC7512, NCTC7528, and NCTC7511).
Immune Responses to Gametocyte Antigens in a Malaria Endemic Population—The African falciparum Context: A Systematic Review and Meta-Analysis
Contributors: Muthui, Michelle K, Kamau, Alice, Bousema, Teun, Blagborough, Andrew Michael, Bejon, Philip, Kapulu, Melissa C
... Background: Malaria elimination remains a priority research agenda with the need for interventions that reduce and/or block malaria transmission from humans to mosquitoes. Transmission-blocking vaccines (TBVs) are in development, most of which target the transmission stage (i.e., gametocyte) antigens Pfs230 and Pfs48/45. For these interventions to be implemented, there is a need to understand the naturally acquired immunity to gametocytes. Several studies have measured the prevalence of immune responses to Pfs230 and Pfs48/45 in populations in malaria-endemic areas. Methods: We conducted a systematic review of studies carried out in African populations that measured the prevalence of immune responses to the gametocyte antigens Pfs230 and Pfs48/45. We assessed seroprevalence of antibody responses to the two antigens and investigated the effects of covariates such as age, transmission intensity/endemicity, season, and parasite prevalence on the prevalence of these antibody responses by meta-regression. Results: We identified 12 studies covering 23 sites for inclusion in the analysis. We found that the range of reported seroprevalence to Pfs230 and Pfs48/45 varied widely across studies, from 0 to 64% for Pfs48/45 and from 6 to 72% for Pfs230. We also found a modest association between increased age and increased seroprevalence to Pfs230: adults were associated with higher seroprevalence estimates in comparison to children (β coefficient 0.21, 95% CI: 0.05–0.38, p = 0.042). Methodological factors were the most significant contributors to heterogeneity between studies which prevented calculation of pooled prevalence estimates. Conclusions: Naturally acquired sexual stage immunity, as detected by antibodies to Pfs230 and Pfs48/45, was present in most studies analyzed. Significant between-study heterogeneity was seen, and methodological factors were a major contributor to this, and prevented further analysis of epidemiological and biological factors. This demonstrates a need for standardized protocols for conducting and reporting seroepidemiological analyses.