Feature visualisation of classification of diabetic retinopathy using a convolutional neural network

Convolutional Neural Networks (CNNs) have been demonstrated to achieve state-of-the-art results on complex computer vision tasks, including medical image diagnosis of Diabetic Retinopathy (DR). CNNs are powerful because they determine relevant image features automatically. However, the current inability to demonstrate what these features are has led to CNNs being considered to be 'black box' methods whose results should not be trusted. This paper presents a method for identifying the learned features of a CNN and applies it in the context of the diagnosis of DR in fundus images using the well-known DenseNet. We train the CNN to diagnose and determine the severity of DR and then successfully extract feature maps from the CNN which identify the regions and features of the images which have led most strongly to the CNN prediction. This feature extraction process has great potential, particularly for encouraging confidence in CNN approaches from users and clinicians, and can aid in the further development of CNN methods. There is also potential for determining previously unidentified features which may contribute to a classification

Inhibition of Phosphodiesterase 3A by Cilostazol Dampens Proinflammatory Platelet Functions

Objective: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 inhibitors have demonstrated efficacy in secondary prevention of arterial thrombosis, partially mediated by their antiplatelet action. Yet it is unclear whether such inhibitors also affect platelets’ inflammatory functions. Here, we aimed to examine the effect of the PDE3A inhibitor cilostazol and the PDE5 inhibitor tadalafil on platelet function in various aspects of thromboinflammation. Approach and results: cilostazol, but not tadalafil, delayed ex vivo platelet-dependent fibrin formation under whole blood flow over type I collagen at 1000 s−1. Similar results were obtained with blood from Pde3a deficient mice, indicating that cilostazol effects are mediated via PDE3A. Interestingly, cilostazol specifically reduced the release of phosphatidylserine-positive extracellular vesicles (EVs) from human platelets while not affecting total EV release. Both cilostazol and tadalafil reduced the interaction of human platelets with inflamed endothelium under arterial flow and the release of the chemokines CCL5 and CXCL4 from platelets. Moreover, cilostazol, but not tadalafil, reduced monocyte recruitment and platelet-monocyte interaction in vitro. Conclusions: this study demonstrated yet unrecognised roles for platelet PDE3A and platelet PDE5 in platelet procoagulant and proinflammatory responses

Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

Polymorphisms in the Mitochondrial Ribosome Recycling Factor EF-G2mt/MEF2 Compromise Cell Respiratory Function and Increase Atorvastatin Toxicity

Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans

Serotonin synthesis, release and reuptake in terminals: a mathematical model

<p>Abstract</p> <p>Background</p> <p>Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system.</p> <p>Methods</p> <p>We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data.</p> <p>Results</p> <p>We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct <it>in silico </it>experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine.</p> <p>Conclusions</p> <p>Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.</p

Uma visão da produção científica internacional sobre a classificação internacional para a prática de enfermagem

A Classificação Internacional para a Prática de Enfermagem (CIPE®) é um sistema classificatório que visa padronizaruma linguagem universal para Enfermagem. Este artigo propõe identificar os estudos desenvolvidos noâmbito mundial abordando a CIPE®, categorizando-os segundo suas finalidades. Trata-se de uma revisão de literatura,em base de dados da Biblioteca Virtual em Saúde, pelo o termo “ICNP”, com abrangência até 2009. Foramencontrados 124 artigos; 65 analisados, cujo conteúdo foi agrupado em nove categorias: abordagens gerais;aplicabilidade à prática; avaliação de classificações; experiências com recursos computacionais; desenvolvimento einclusão de termos; abordagem sobre sistemas classificatórios; uso para ancorar a construção de declarações deenfermagem; traduções; e outros. Verificou-se que poucos trabalhos apresentam projetos ou avaliam resultados deaplicações práticas da CIPE®; a maioria aborda aspectos conceituais ou realiza comparações com outras classificações.Diversos trabalhos concluem sobre a adequação e relevância da CIPE®, mas apontam a necessidade de aperfeiçoamento

The relationship between canopy cover and colony size of the wood ant Formica lugubris : implications for the thermal effects on a keystone ant species

Climate change may affect ecosystems and biodiversity through the impacts of rising temperature on species' body size. In terms of physiology and genetics, the colony is the unit of selection for ants so colony size can be considered the body size of a colony. For polydomous ant species, a colony is spread across several nests. This study aims to clarify how climate change may influence an ecologically significant ant species group by investigating thermal effects on wood ant colony size. The strong link between canopy cover and the local temperatures of wood ant's nesting location provides a feasible approach for our study. Our results showed that nests were larger in shadier areas where the thermal environment was colder and more stable compared to open areas. Colonies (sum of nests in a polydomous colony) also tended to be larger in shadier areas than in open areas. In addition to temperature, our results supported that food resource availability may be an additional factor mediating the relationship between canopy cover and nest size. The effects of canopy cover on total colony size may act at the nest level because of the positive relationship between total colony size and mean nest size, rather than at the colony level due to lack of link between canopy cover and number of nests per colony. Causal relationships between the environment and the life-history characteristics may suggest possible future impacts of climate change on these species