SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome

Reperfusion of patients after myocardial infarction (heart attack) triggers cardiac inflammation that leads to infarct expansion and heart failure (HF). We previously showed that the circadian mechanism is a critical regulator of reperfusion injury. However, whether pharmacological targeting using circadian medicine limits reperfusion injury and protects against HF is unknown. Here, we show that short-term targeting of the circadian driver REV-ERB with SR9009 benefits long-term cardiac repair post-myocardial ischemia reperfusion in mice. Gain and loss of function studies demonstrate specificity of targeting REV-ERB in mice. Treatment for just one day abates the cardiac NLRP3 inflammasome, decreasing immunocyte recruitment, and thereby allowing the vulnerable infarct to heal. Therapy is given in vivo, after reperfusion, and promotes efficient repair. This study presents downregulation of the cardiac inflammasome in fibroblasts as a cellular target of SR9009, inviting more targeted therapeutic investigations in the future

An International Expert Delphi Consensus to Develop Dedicated Geriatric Radiation Oncology Curriculum Learning Outcomes.

PURPOSE: The management of older adults with cancer is rapidly becoming a significant challenge in radiation oncology (RO) practice. The education of future radiation oncologists in geriatric oncology is fundamental to ensuring that older adults receive high-quality care. Currently RO trainees receive little training and education in geriatric oncology. The objective of this study was to define core geriatric RO curriculum learning outcomes relevant to RO trainees worldwide. METHODS AND MATERIALS: A 2-stage modified Delphi consensus was conducted. Stage 1 involved the formation of an expert reference panel (ERP) of multiprofessional experts in geriatric oncology and/or RO and the compilation of a potential geriatric RO learning outcomes set. Stage 2 involved 3 iterative rounds: round 1 and round 2 (both online surveys), and an intervening ERP round. These aimed at identifying and refining ideal geriatric RO learning outcomes. Invited participants for round 1 and 2 included oncology health care professionals with expertise across RO, geriatric oncology, and/or education and consumers. Predefined Delphi consensus definitions were applied to the results of rounds 1 and 2. RESULTS: An ERP of 11 experts in geriatric oncology and/or RO was formed. Seventy potential knowledge- and skill-based learning outcomes were identified. In round 1, 103 of 179 invited eligible Delphi participants completed the survey (58% response rate). The ERP round was conducted, resulting in the exclusion of 28 learning outcomes. In round 2, 54 of 103 completed the survey (52% response rate). This identified a final total of 33 geriatric RO learning outcomes. CONCLUSIONS: The geriatric RO learning outcomes described in this study form an international consensus that can inform RO training bodies worldwide. This represents the first fundamental step in developing a global educational framework aimed at improving RO trainee knowledge and skills in geriatric oncology

Quantification of Extracellular DNA Network Abundance and Architecture within Streptococcus gordonii Biofilms Reveals Modulatory Factors

Extracellular DNA (eDNA) is an important component of biofilm matrix that serves to maintain biofilm structural integrity, promotes genetic exchange within the biofilm, and provides protection against antimicrobial compounds. Advances in microscopy techniques have provided evidence of the cobweb- or lattice-like structures of eDNA within biofilms from a range of environmental niches. However, methods to reliably assess the abundance and architecture of eDNA remain lacking. This study aimed to address this gap by development of a novel, high-throughput image acquisition and analysis platform for assessment of eDNA networks in situ within biofilms. Utilizing Streptococcus gordonii as the model, the capacity for this imaging system to reliably detect eDNA networks and monitor changes in abundance and architecture (e.g., strand length and branch number) was verified. Evidence was provided of a synergy between glucans and eDNA matrices, while it was revealed that surface-bound nuclease SsnA could modify these eDNA structures under conditions permissive for enzymatic activity. Moreover, cross talk between the competence and hexaheptapeptide permease systems was shown to regulate eDNA release by S. gordonii. This novel imaging system can be applied across the wider field of biofilm research, with potential to significantly advance interrogation of the mechanisms by which the eDNA network architecture develops, how it can influence biofilm properties, and how it may be targeted for therapeutic benefit. IMPORTANCE Extracellular DNA (eDNA) is critical for maintaining the structural integrity of many microbial biofilms, making it an attractive target for the management of biofilms. However, our knowledge and targeting of eDNA are currently hindered by a lack of tools for the quantitative assessment of eDNA networks within biofilms. Here, we demonstrate use of a novel image acquisition and analysis platform with the capacity to reliably monitor the abundance and architecture of eDNA networks. Application of this tool to Streptococcus gordonii biofilms has provided new insights into how eDNA networks are stabilized within the biofilm and the pathways that can regulate eDNA release. This highlights how exploitation of this novel imaging system across the wider field of biofilm research has potential to significantly advance interrogation of the mechanisms by which the eDNA network architecture develops, how it can influence biofilm properties, and how it may be targeted for therapeutic benefit

Liquid racism and the Danish Prophet Muhammad cartoons

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 The Author.This article examines reactions to the October 2005 publication of the Prophet Muhammad cartoons in the Danish newspaper Jyllands-Posten. It does so by using the concept of ‘liquid racism’. While the controversy arose because it is considered blasphemous by many Muslims to create images of the Prophet Muhammad, the article argues that the meaning of the cartoons is multidimensional, that their analysis is significantly more complex than most commentators acknowledge, and that this complexity can best be addressed via the concept of liquid racism. The article examines the liquidity of the cartoons in relation to four readings. These see the cartoons as: (1) a criticism of Islamic fundamentalism; (2) blasphemous images; (3) Islamophobic and racist; and (4) satire and a defence of freedom of speech. Finally, the relationship between postmodernity and the rise of fundamentalism is discussed because the cartoons, reactions to them, and Islamic fundamentalism, all contain an important postmodern dimension.ESR

Engaging with History after Macpherson

The Race Relations Amendment Act (2000) identifies a key role for education, and more specifically history, in promoting ‘race equality’ in Britain. In this article Ian Grosvenor and Kevin Myers consider the extent of young people’s current engagement with the history of ‘diversity, change and immigration’ which underpins the commitment to ‘race equality’. Finding that in many of Britain’s schools and universities a singular and exclusionary version of history continues to dominate the curriculum, they go on to consider the reasons for the neglect of multiculturalism. The authors identify the development of an aggressive national identity that depends on the past for its legitimacy and argue that this sense of the past is an important obstacle to future progress

Narratives of ethnic identity among practitioners in community settings in the northeast of England

The increasing ethnic diversity of the UK has been mirrored by growing public awareness of multicultural issues, alongside developments in academic and government thinking. This paper explores the contested meanings around ethnic identity/ies in community settings, drawing on semi-structured interviews with staff from Children’s Centres and allied agencies conducted for a research project that examined the relationship between identity and the participation of parents/carers in services in northeast England. The research found that respondents were unclear about, especially, white ethnic identities, and commonly referred to other social categorizations, such as age, nationality, and circumstances such as mobility, when discussing service users. While in some cases this may have reflected legitimate attempts to resist overethnicizing non-ethnic phenomena, such constructions coexisted with assumptions about ethnic difference and how it might translate into service needs. These findings raise important considerations for policy and practice

Morphology, adipocyte size, and fatty acid analysis of dairy cattle digital cushions, and the effect of body condition score and age

The digital cushion is an essential part of maintaining a healthy foot, working to dissipate foot strike and body weight forces and lameness from claw horn disruption lesions. Despite the importance of the digital cushion, little is known about the basic anatomy, adipocyte morphology, and fatty acid composition in relation to age, limb position, and body condition score. In total, 60 claws (from 17 cows) were selected and collected from a herd, ensuring that body condition score data and computed micro-tomography were known for each animal. Digital cushion tissue underwent histological staining combined with stereology, systematic random sampling, and cell morphology analysis, in addition to lipid extraction followed by fatty acid analysis. The results describe digital cushion architecture and adipocyte sizes. Adipocyte size was similar across all 4 claws (distal left lateral and medial and distal right lateral and medial) and across the ages (aged 2–7 yr); however, animals with body condition score of 3.00 or more at slaughter had a significantly increased cell size in comparison to those with a score of less than 2.50. Of 37 fatty acid methyl esters identified, 5 differed between either the body condition score or different age groups. C10:0 capric acid, C14:0 myristic acid, C15:0 pentadecanoic acid, and C20:0 arachidic acid percentages were all lesser in lower body condition score cows, whereas C22:1n-9 erucic acid measurements were lesser in younger cows. Saturated fatty acid, monounsaturated fatty acid, and polyunsaturated fatty acid percentages were not altered in the different claws, ages, or body condition score groups. Triglyceride quantities did not differ for claw position or age but had decreased quantities in lower body condition score animals. Digital cushion anatomy, cellular morphology, and fatty acid composition have been described in general and also in animals with differing ages, body condition scores, and in the differing claws. Understanding fat deposition, mobilization, and composition are essential in not only understanding the roles that the digital cushion plays but also in preventing disorders and maintaining cattle health and welfare

A fully-automated low-cost cardiac monolayer optical mapping robot.

Scalable and high-throughput electrophysiological measurement systems are necessary to accelerate the elucidation of cardiac diseases in drug development. Optical mapping is the primary method of simultaneously measuring several key electrophysiological parameters, such as action potentials, intracellular free calcium and conduction velocity, at high spatiotemporal resolution. This tool has been applied to isolated whole-hearts, whole-hearts in-vivo, tissue-slices and cardiac monolayers/tissue-constructs. Although optical mapping of all of these substrates have contributed to our understanding of ion-channels and fibrillation dynamics, cardiac monolayers/tissue-constructs are scalable macroscopic substrates that are particularly amenable to high-throughput interrogation. Here, we describe and validate a scalable and fully-automated monolayer optical mapping robot that requires no human intervention and with reasonable costs. As a proof-of-principle demonstration, we performed parallelized macroscopic optical mapping of calcium dynamics in the well-established neonatal-rat-ventricular-myocyte monolayer plated on standard 35 mm dishes. Given the advancements in regenerative and personalized medicine, we also performed parallelized macroscopic optical mapping of voltage dynamics in human pluripotent stem cell-derived cardiomyocyte monolayers using a genetically encoded voltage indictor and a commonly-used voltage sensitive dye to demonstrate the versatility of our system.The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). The study was supported by the Ministry of Science and Innovation (MCIN) (PID2019-109329RB-I00), the Fundación Interhospitalaria para la Investigación Cardiovascular, the McEwen Stem Cell Institute, the Canada Research Chairs Program, the Stem Cell Network, the University of Toronto’s Medicine by Design/Canada First Research Excellence Fund initiative, and Ted Rogers Centre for Heart Research Education Fund.S

Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study

Background & AimsIn acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure.MethodsPigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure.ResultsThe Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen.ConclusionsThe survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients