1,720,996 research outputs found
Recommended from our members
Cardiac Stretch-Induced Transcriptomic Changes are Axis-Dependent
Full text linkCardiac myocytes are striated muscle cells with myofilaments running along their length and Z-discs in a transverse direction. These cells contain structures that are sensitive to mechanical stretch and transduce this signal into a biochemical response. By altering the major axis of biaxial, mechanical stretch, I hypothesized that different signaling pathways and transcription regulators would be activated and lead to divergent gene expression profiles in cardiac myocytes.To investigate the effect of stretch axis, cardiac myocytes were cultured on a micropatterned substrate, and the primary stretch axis was applied either parallel or transverse to the myofibril direction. RNA sequencing (RNA-Seq) was conducted to study whole genomic expression changes after acute cardiac myocyte stretch. After 30 minutes of stretch, 53 and 168 genes were considered differentially expressed (DE) from transverse and longitudinal stretch, respectively. After 4 hours, the number of DE genes increased to 795 in longitudinal stretch while it decreased to 35 in transverse stretch. Gene ontology (GO) term analysis indicated enrichment of transcription factor (TF) activity and protein kinase activity by both stretch axes; whereas longitudinal but not transverse stretch induced expression of genes involved in sarcomere organization and cytoskeletal protein binding.Although researchers have identified sensors, pathways, and TFs involved in cardiac mechanotransduction, I, for the first time, integrated this information into a logic-based network model of cardiac myocyte stretch signaling. This model was validated against independent data and correctly predicted the effect of stretch or effect of inhibitors on stretch response in 54 of 61 experiments.This network model was used in conjunction with the RNA-Seq data to identify the mechanisms regulating gene expression changes due to longitudinal and transverse stretch. Analysis of this network identified serum response factor (SRF) and myocyte enhancer factor-2 (MEF2) as critical TFs in regulating longitudinal stretch-induced gene changes whose activity is modulated by protein kinase C (PKC). In addition, cyclic adenosine monophosphate response element-binding protein (CREB) was found to be activated by both longitudinal and transverse stretch. The network model provides evidence that cardiac myocytes engage different transcriptional regulators in response to different principal orientations of biaxial stretch
Recommended from our members
Mechanical Effects of Regional Structural Remodeling in the Left Ventricle
Full text linkCardiovascular disease is the primary cause of death in the United States and presents a significant challenge for researchers and clinicians due to the complexity and non-uniformity of structure-function relationships in the heart. The largest of the four heart chambers, the left ventricle, must pump efficiently and adapt to changes in demand or blood flow, which the normal heart does remarkably well. However, in disease states, the compensatory response of the myocardium and persistent overloading can cause remodeling to become counter-productive.Two of the major diseases contributing to overall cardiac morbidity and mortality are hypertension and myocardial infarction. While much is understood about the forms of remodeling and the associated dysfunction that occur in these disease states, they are usually measured at the scale of the entire organ (e.g. ejection fraction), or only in a select region of tissue. Many studies have shown regional variations in structural properties in the normal heart, but a comprehensive understanding of regional remodeling and the resultant functional consequences in disease states is lacking. Thus, the primary aims of this dissertation are to:1. Determine the effect of pressure overload on regional distributions of electrophysiological and calcium handling proteins in the rat left ventricle.2. Test the hypothesis that regional gradients in structural properties such as myocyte geometry are diminished in pressure overload.a. Determine whether regional variations in these structural features could be comprehensively and non-invasively quantified using DT-MRI.3. Compare the measured size of a scar after myocardial infarction using traditional methods to the size of the corresponding region of dysfunction using a novel 3D MRI-based approach.A better understanding of regional variations in normal and diseased ventricles will be valuable in identifying potential targets for therapeutic intervention to slow, prevent, or reverse adverse remodeling in patients with cardiac diseases such as hypertension or infarction, and provide insight as to the mechanisms by which regional variations contribute to overall pump function
Recommended from our members
Patient-specific Modeling of Cardiac Biomechanics in Repaired Tetralogy of Fallot
Full text linkSurgical advancements in the management of Tetralogy of Fallot, the most common cyanotic congenital heart defect, have allowed individuals to survive into adulthood. However, most individuals develop pulmonary regurgitation, causing right ventricular volume overload, dilatation, and possible dysfunction. These patients require pulmonary valve replacement (PVR), but the timing and indications for the operation are still under investigation. One proposed clinical indicator for PVR is a right ventricular end-diastolic volume index (RVEDVI) greater than 150 mL/m2, though this threshold value is somewhat controversial. Because diastolic fiber strains have been found to correlate well with ventricular remodeling in response to volume overload, a correlation may also exist between diastolic fiber strain and reverse remodeling after alleviation of volume overload. In this thesis, biventricular image-based computational models were developed to test the hypothesis that RVEDVI correlates with post-PVR regional diastolic fiber strains in the right ventricle. Two computational models with RVEDVIs of 170 mL/m2 and 115 mL/m2 were developed, and each model underwent full-beat simulation before and after virtual PVR. Preliminary findings suggest that RVEDVI may in fact correlate negatively with post-PVR regional diastolic fiber strains of repaired ToF patients, particularly in regions of the right ventricular free wall adjacent to the septum
Recommended from our members
Atlas-Based Strategies for Identifying Novel Markers of Left Ventricular Remodeling in Repaired Tetralogy of Fallot
Full text linkTetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD), occurring in approximately 1 out of every 3,500 births. Innovative surgical strategies have significantly improved early survival, but patients with repaired TOF are at risk of late complications due to residual structural and electromechanical cardiac malformations. Chronic right-ventricular (RV) volume overload due to pulmonary valve incompetency is a common problem in repaired TOF, and pulmonary valve replacement can alleviate regurgitation and normalize RV volume and function. However, left-ventricular (LV) systolic dysfunction can develop in the long-term and its mechanisms are poorly understood. Traditional assessment of LV remodeling and dysfunction for prognostic purposes is limited due to the complex inter-patient variability of LV morphology and the compounding effects of RV dilatation and dysfunction.In this thesis, we seek to help address the challenges with clinical management of repaired TOF by elucidating patterns of LV remodeling that associate with systolic dysfunction and can provide an indication of further LV deterioration. To this purpose, we use statistical shape analysis to quantify inter- and intra-population variation of LV morphology and systolic function. The aims of this dissertation are to:1. Characterize the statistical variation of end-diastolic (ED) shape and systolic function in a large cohort of patients with repaired TOF using routinely acquired cardiac magnetic resonance image data;2. identify novel features of ED morphology that associate with systolic dysfunction using computational models of LV mechanics informed by patterns discovered in patient data;3. test the hypothesis that novel atlas-based features of remodeling are predictive of functional deterioration of the LV.Here we demonstrated the first derivation and use of an atlas of LV shape of a large cohort of repaired TOF from multi-center cardiac magnetic resonance image data. Abnormal shape features from an asymptomatic reference population associated with global systolic function in our TOF cohort, but were inadequate for assessment of LV functional deterioration; conversely, we found novel LV shape features from the repaired TOF atlas, rather than standard CMR measures or shape features from the reference atlas, to be associated with the change in global systolic function in a longitudinal study. Mechanistic models of systolic mechanics informed by statistical atlases were capable of systematically testing for shape determinants of LV dysfunction, and were used to generate hypotheses of disease mechanisms that would otherwise need to be measured invasively. A more comprehensive assessment of LV morphology in repaired TOF using statistical shape atlas techniques has the potential to discover hidden patterns of adverse remodeling that contain mechanistic insight and prove valuable for clinical decision-making
Evidence for mechanisms underlying the functional benefits of a myocardial matrix hydrogel for post-MI treatment
Full text linkBackground There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. Objectives This study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection. Methods Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague-Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways. Results Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. Conclusions These results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
