Interdependence of Angiogenesis and Arteriogenesis in Development and Disease

The structure of arterial networks is optimized to allow efficient flow delivery to metabolically active tissues. Optimization of flow delivery is a continuous process involving synchronization of the structure and function of the microcirculation with the upstream arterial network. Risk factors for ischemic cardiovascular diseases, such as diabetes mellitus and hyperlipidemia, adversely affect endothelial function, induce capillary regression, and disrupt the micro- to macrocirculation cross-talk. We provide evidence showing that this loss of synchronization reduces arterial collateral network recruitment upon arterial stenosis, and the long-term clinical outcome of current revascularization strategies in these patient cohorts. We describe mechanisms and signals contributing to synchronized growth of micro- and macrocirculation in development and upon ischemic challenges in the adult organism and identify potential therapeutic targets. We conclude that a long-term successful revascularization strategy should aim at both removing obstructions in the proximal part of the arterial tree and restoring “bottom-up” vascular communication

Predicting gene expression in the human malaria parasite Plasmodium falciparum using histone modification, nucleosome positioning, and 3D localization features.

Empirical evidence suggests that the malaria parasite Plasmodium falciparum employs a broad range of mechanisms to regulate gene transcription throughout the organism's complex life cycle. To better understand this regulatory machinery, we assembled a rich collection of genomic and epigenomic data sets, including information about transcription factor (TF) binding motifs, patterns of covalent histone modifications, nucleosome occupancy, GC content, and global 3D genome architecture. We used these data to train machine learning models to discriminate between high-expression and low-expression genes, focusing on three distinct stages of the red blood cell phase of the Plasmodium life cycle. Our results highlight the importance of histone modifications and 3D chromatin architecture in Plasmodium transcriptional regulation and suggest that AP2 transcription factors may play a limited regulatory role, perhaps operating in conjunction with epigenetic factors

Dynamics of vascular branching morphogenesis: the effect of blood and tissue flow

Vascularization of embryonic organs or tumors starts from a primitive lattice of capillaries. Upon perfusion, this lattice is remodeled into branched arteries and veins. Adaptation to mechanical forces is implied to play a major role in arterial patterning. However, numerical simulations of vessel adaptation to haemodynamics has so far failed to predict any realistic vascular pattern. We present in this article a theoretical modeling of vascular development in the yolk sac based on three features of vascular morphogenesis: the disconnection of side branches from main branches, the reconnection of dangling sprouts ('dead ends'), and the plastic extension of interstitial tissue, which we have observed in vascular morphogenesis. We show that the effect of Poiseuille flow in the vessels can be modeled by aggregation of random walkers. Solid tissue expansion can be modeled by a Poiseuille (parabolic) deformation, hence by deformation under hits of random walkers. Incorporation of these features, which are of a mechanical nature, leads to realistic modeling of vessels, with important biological consequences. The model also predicts the outcome of simple mechanical actions, such as clamping of vessels or deformation of tissue by the presence of obstacles. This study offers an explanation for flow-driven control of vascular branching morphogenesis

Participation in Solvolysis: A Look Back

From the beginning, the »carbonium ion controversy« of yesteiyear was characterized and skewed by a series of assumptions, definitions and antecedents the significance of which was not fully realized at the time by many principals involved in it. An attempt is made here to illuminate these aspects in the light of new developments in our laboratory and elsewhere

When, why and how tumour clonal diversity predicts survival

The utility of intratumour heterogeneity as a prognostic biomarker is the subject of ongoing clinical investigation. However, the relationship between this marker and its clinical impact is mediated by an evolutionary process that is not well understood. Here, we employ a spatial computational model of tumour evolution to assess when, why and how intratumour heterogeneity can be used to forecast tumour growth rate and progression‐free survival. We identify three conditions that can lead to a positive correlation between clonal diversity and subsequent growth rate: diversity is measured early in tumour development; selective sweeps are rare; and/or tumours vary in the rate at which they acquire driver mutations. Opposite conditions typically lead to negative correlation. In cohorts of tumours with diverse evolutionary parameters, we find that clonal diversity is a reliable predictor of both growth rate and progression‐free survival. We thus offer explanations—grounded in evolutionary theory—for empirical findings in various cancers, including survival analyses reported in the recent TRACERx Renal study of clear‐cell renal cell carcinoma. Our work informs the search for new prognostic biomarkers and contributes to the development of predictive oncology

Analysis of refractive endpoint differences between directional and non-directional projection screens

Analysis of refractive endpoint differences between directional and non-directional projection screen

Micro-RNA 92a as a Therapeutic Target for Cardiac Microvascular Dysfunction in Diabetes

Microvascular dysfunction is a pathological hallmark of diabetes, and is central to the ethology of diabetes-associated cardiac events. Herein, previous studies have highlighted the role of the vasoactive micro-RNA 92a (miR-92a) in small, as well as large, animal models. In this study, we explore the effects of miR-92a on mouse and human cardiac microvascular endothelial cells (MCMEC, HCMEC), and its underlying molecular mechanisms. Diabetic HCMEC displayed impaired angiogenesis and a pronounced inflammatory phenotype. Quantitative PCR (qPCR) showed an upregulation of miR-92a in primary diabetic HCMEC. Downregulation of miR-92a by antagomir transfection in diabetic HCMEC rescued angiogenesis and ameliorated diabetic endothelial bed inflammation. Furthermore, additional analysis of potential in silico-identified miR-92a targets in diabetic HCMEC revealed the miR-92a dependent downregulation of an essential metalloprotease, ADAM10. Accordingly, downregulation of ADAM10 impaired angiogenesis and wound healing in MCMEC. In myocardial tissue slices from diabetic pigs, ADAM10 dysregulation in micro- and macro-vasculature could be shown. Altogether, our data demonstrate the role of miR-92a in cardiac microvascular dysfunction and inflammation in diabetes. Moreover, we describe for the first time the metalloprotease ADAM10 as a novel miR-92a target, mediating its anti-angiogenic effect

Exploratory analysis of genomic segmentations with Segtools

<p>Abstract</p> <p>Background</p> <p>As genome-wide experiments and annotations become more prevalent, researchers increasingly require tools to help interpret data at this scale. Many functional genomics experiments involve partitioning the genome into labeled segments, such that segments sharing the same label exhibit one or more biochemical or functional traits. For example, a collection of ChlP-seq experiments yields a compendium of peaks, each labeled with one or more associated DNA-binding proteins. Similarly, manually or automatically generated annotations of functional genomic elements, including <it>cis</it>-regulatory modules and protein-coding or RNA genes, can also be summarized as genomic segmentations.</p> <p>Results</p> <p>We present a software toolkit called <it>Segtools </it>that simplifies and automates the exploration of genomic segmentations. The software operates as a series of interacting tools, each of which provides one mode of summarization. These various tools can be pipelined and summarized in a single HTML page. We describe the Segtools toolkit and demonstrate its use in interpreting a collection of human histone modification data sets and <it>Plasmodium falciparum </it>local chromatin structure data sets.</p> <p>Conclusions</p> <p>Segtools provides a convenient, powerful means of interpreting a genomic segmentation.</p