Doxorubicin In Vivo Rapidly Alters Expression and Translation of Myocardial Electron Transport Chain Genes, Leads to ATP Loss and Caspase 3 Activation

BackgroundDoxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.Methodology/principal findingsMice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted.Conclusions/significanceThese data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage

Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.

BACKGROUND: Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear. RESULTS: Here, we report that hepatic respiratory capacity is enhanced following short-term exposure to hypoxia (2 days, 10% O2) and is associated with increased abundance of the respiratory chain supercomplex III2+IV and increased cardiolipin levels. Suppression of this enhanced respiratory capacity, achieved via mild inhibition of mitochondrial complex III, disrupted metabolic homeostasis. Hypoxic exposure for 2 days led to accumulation of plasma and hepatic long chain acyl-carnitines. This was observed alongside depletion of hepatic triacylglycerol species with total chain lengths of 39-53 carbons, containing palmitic, palmitoleic, stearic, and oleic acids, which are associated with de novo lipogenesis. The changes to hepatic respiratory capacity and lipid metabolism following 2 days hypoxic exposure were transient, becoming resolved after 14 days in line with systemic acclimation to hypoxia and elevated circulating haemoglobin concentrations. CONCLUSIONS: The liver maintains metabolic homeostasis in response to shorter term hypoxic exposure through transient enhancement of respiratory chain capacity and alterations to lipid metabolism. These findings may have implications in understanding and treating hepatic pathologies associated with hypoxia.GlaxoSmithKlin

A simple sequent calculus for nominal logic

The front end of the human auditory system, the cochlea, converts sound signals from the outside world into neural impulses transmitted along the auditory pathway for further processing. The cochlea senses and separates sound in a nonlinear active fashion, exhibiting remarkable sensitivity and frequency discrimination. Although several electronic models of the cochlea have been proposed and implemented, none of these are able to reproduce all the characteristics of the cochlea, including large dynamic range, large gain and sharp tuning at low sound levels, and low gain and broad tuning at intense sound levels. Here, we implement the 'Cascade of Asymmetric Resonators' (CAR) model of the cochlea on an FPGA. CAR represents the basilar membrane filter in the 'Cascade of Asymmetric Resonators with Fast-Acting Compression' (CAR-FAC) cochlear model. CAR-FAC is a neuromorphic model of hearing based on a pole-zero filter cascade model of auditory filtering. It uses simple nonlinear extensions of conventional digital filter stages that are well suited to FPGA implementations, so that we are able to implement up to 1224 cochlear sections on Virtex-6 FPGA to process sound data in real time. The FPGA implementation of the electronic cochlea described here may be used as a front-end sound analyser for various machine-hearing applications

Air pollution and health impacts of oil & gas production in the United States

Oil and gas production is one of the largest emitters of methane, a potent greenhouse gas and a significant contributor of air pollution emissions. While research on methane emissions from oil and gas production has grown rapidly, there is comparatively limited information on the distribution of impacts of this sector on air quality and associated health impacts. Understanding the contribution of air quality and health impacts of oil and gas can be useful for designing mitigation strategies. Here we assess air quality and human health impacts associated with ozone, fine particulate matter, and nitrogen dioxide from the oil and gas sector in the US in 2016, and compare this impact with that of the associated methane emissions. We find that air pollution in 2016 from the oil and gas sector in the US resulted in 410 000 asthma exacerbations, 2200 new cases of childhood asthma and 7500 excess deaths, with $77 billion in total health impacts. NO2 was the highest contributor to health impacts (37%) followed by ozone (35%), and then PM2.5 (28%). When monetized, these air quality health impacts of oil and gas production exceeded estimated climate impact costs from methane leakage by a factor of 3. These impacts add to the total life cycle impacts of oil and gas, and represent potential additional health benefits of strategies that reduce consumption of oil and gas. Policies to reduce oil and gas production emissions will lead to additional and significant health benefits from co-pollutant reductions that are not currently quantified or monetized

ACMG clinical laboratory standards for next-generation sequencing

Next-generation sequencing technologies have been and continue to be deployed in clinical laboratories, enabling rapid transformations in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude, and continuous advances are being made. It is now feasible to analyze an individual's near-complete exome or genome to assist in the diagnosis of a wide array of clinical scenarios. Next-generation sequencing technologies are also facilitating further advances in therapeutic decision making and disease prediction for at-risk patients. However, with rapid advances come additional challenges involving the clinical validation and use of these constantly evolving technologies and platforms in clinical laboratories. To assist clinical laboratories with the validation of next-generation sequencing methods and platforms, the ongoing monitoring of next-generation sequencing testing to ensure quality results, and the interpretation and reporting of variants found using these technologies, the American College of Medical Genetics and Genomics has developed the following professional standards and guidelines

An exploration of the views of paramedics regarding airway management

© 2016 Brandling et al. Background: Paramedics are a skilled group of clinicians with expertise in airway management. Our research group has completed a trial comparing supraglottic airway devices with tracheal intubation during out of hospital cardiac arrest. This is a contentious topic amongst paramedics in the United Kingdom (UK). We explored the customs and beliefs of UK paramedics in relation to airway management, and whether tracheal intubation contributes to and sustains paramedic professional identity. Methods: The study took place within South Western Ambulance Service NHS Foundation Trust. We used a qualitative approach, conducting interviews and focus groups with paramedics. The themes arising from interviews were discussed in focus groups, developing a deeper understanding and providing insight and recommendations for future research and policy. Purposive sampling accounted for differing training and for participation in the main trial. There were 17interviews and five focus groups with a further 17 participants. Data saturation was achieved. Results: Four domains were identified. Pride - The ability to use a life-saving skill in austere conditions. Utility - Different training routes and experience have led to different attitudes towards airway management. Inconsistent expectations - Paramedics felt that there were different perceptions of their abilities amongst hospital staff and the general public. Professionalization - Debate over airway management is not founded on good evidence. Conclusion: We have demonstrated that UK paramedics have a wide range of views regarding airway management, and that these are based on evidence and experience rather than dogma. Airway management contributes to paramedics' professional identity, but is not reliant on this

How Thermal Evolution and Mass Loss Sculpt Populations of Super-Earths and Sub-Neptunes: Application to the Kepler-11 System and Beyond

We use models of thermal evolution and XUV-driven mass loss to explore the composition and history of low-mass low-density transiting planets. We investigate the Kepler-11 system in detail and provide estimates of both the current and past planetary compositions. We find that a H/He atmosphere on Kepler-11b is highly vulnerable to mass loss. By comparing to formation models, we show that in situ formation of the system is unlikely. Instead we propose that it is a water-rich system of sub-Neptunes that migrated from beyond the snow line. For the broader population of observed planets, we show that there is a threshold in bulk planet density and incident flux above which no low-mass transiting planets have been observed. We suggest that this threshold is due to the instability of H/He atmospheres to XUV-driven mass loss. Importantly, we find that this flux-density threshold is well reproduced by our thermal evolution/contraction models that incorporate a standard mass loss prescription. Treating the planets' contraction history is essential because the planets have significantly larger radii during the early era of high XUV fluxes. Over time low mass planets with H/He envelopes can be transformed into water-dominated worlds with steam atmospheres or rocky super-Earths. Finally, we use this threshold to provide likely minimum masses and radial velocity amplitudes for the general population of Kepler candidates. Likewise, we use this threshold to provide constraints on the maximum radii of low-mass planets found by radial velocity surveys.Comment: 17 pages, 7 figures. Accepted for publication in ApJ. Compared to the submitted version we made modest modifications to our mass loss model including reducing our default mass loss efficiency. However, the central conclusions of the paper are unchange

The Bishopric of Bamberg in the Medieval World

Der Band „Das Bistum Bamberg in der Welt des Mittelalters“ bietet den um bibliographische Hinweise erweiterten Text der Vorträge, die im Rahmen der Ringvorlesung des Zentrums für Mittelalterstudien (ZEMAS) der Universität Bamberg im Jahr des tausendjährigen Bestehens der (Erz-)Diözese Bamberg gehalten wurden. Ausführlich behandelt wird die Gründung des Bistums 1007 und seine Entwicklung im weiteren Verlauf des Mittelalters. Neben den historischen kommen auch baugeschichtliche, kunsthistorische und literaturgeschichtliche Aspekte zur Sprache. Alle Vorträge sind vergleichend angelegt und zeigen auf, in welche größeren Prozesse Gründung und Entwicklung des Bistums Bamberg sich einfügen. Der Blick reicht daher von Bamberg und Oberfranken über Merseburg, Magdeburg, Prag, Regensburg, Kärnten, Konstanz und Eger bis nach Burgund, Istrien, Apulien und in die Werkstätten arabischer Elfenbeinschnitzer in Andalusien.The volume "The Diocese of Bamberg in the Medieval World" collects extended versions of papers presented in the Centre for Medieval Studies (ZEMAS) at the university of Bamberg lecture series commemorating the millenary anniversary of the (arch) diocese of Bamberg. The lectures address, in detail, the founding of the diocese in 1007 and its subsequent development over the course of the Middle Ages. Employing an interdisciplinary approach, the papers emphasize political history, architectural history, art history, and literary history. All the lectures are presented comparatively and demonstrate how the foundation and the development of the diocese of Bamberg are integrated in larger processes and developments. This perspective extends the scope of these papers from Bamberg and Upper Franconia to Merseburg, Magdeburg, Prague, Regensburg, Carinthia (Austria), Constance, and Cheb (Czech Republic) to Burgundy (France), Apulia (Italy), Istria (Croatia), and the workshops of Arab ivory carvers in Andalusia

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.</p