Michael Simons - Academia.edu (original) (raw)

Papers by Michael Simons

Assessment of arterial circulation development and function in mice is a frequent experimental ch... more Assessment of arterial circulation development and function in mice is a frequent experimental challenge. A number of techniques including micro-CT angiography, fluorescent angiography, laser-Doppler perfusion imaging electron pramagnetic resonance and nuclear magnetic resonance can be used to assess the anatomic extent and functional state of an arterial circulation in a given organ. The chapter discusses the application of these tools in adult mice.

Integrative Physiological and Behavioral Science, 1994

Healthy systems in physiology and medicine are remarkable for their structural variability and dy... more Healthy systems in physiology and medicine are remarkable for their structural variability and dynamical complexity. The concept of fractal growth and form offers novel approaches to understanding morpbogenesis and function from the level of the gene to the organism. For example, scale-invariance and long-range power-law correlations are features of non-coding DNA sequences as well as of healthy heartbeat dynamics. For cardiac regulation, perturbation of the control mechanisms by disease or aging may lead to a breakdown of these long-range correlations that normally extend over thousands of heartbeats. Quantification of such long-range scaling alterations are providing new approaches to problems ranging from molecular evolution to monitoring patients at high risk of sudden death.

Chaos, Solitons & Fractals, 1995

Our purpose is to describe some recent progress in applying fractal concepts to systems of releva... more Our purpose is to describe some recent progress in applying fractal concepts to systems of relevance to biology and medicine. We review several biological systems characterized by fractal geometry, with a particular focus on the long-range power-law correlations found recently in DNA sequences containing noncoding material, Furthermore, we discuss the finding that the exponent a quantifying these long-range correlations ("fractal complexity") is smaller for coding than for noncoding sequences. We also discuss the application of fractal scaling analysis to the dynamics of heartbeat regulation, and report the recent finding that the normal heart is characterized by long-range "anticorrelations" which are absent in the diseased heart.

Biophysical Journal, 1993

Mapping nucleotide sequences onto a "DNA walk" produces a novel representation of DNA that can th... more Mapping nucleotide sequences onto a "DNA walk" produces a novel representation of DNA that can then be studied quantitatively using techniques derived from fractal landscape analysis. We used this method to analyze 11 complete genomic and cDNA myosin heavy chain (MHC) sequences belonging to 8 different species. Our analysis suggests an increase in fractal complexity for MHC genes with evolution with vertebrate > invertebrate > yeast. The increase in complexity is measured by the presence of long-range power-law correlations, which are quantified by the scaling exponent a. We develop a simple iterative model, based on known properties of polymeric sequences, that generates long-range nucleotide correlations from an initially noncorrelated coding region. This new model-as well as the DNA walk analysis-both support the intron-late theory of gene evolution.

Biophysical Journal, 1994

Recently, it was observed that noncoding regions of DNA sequences possess long-range power-law co... more Recently, it was observed that noncoding regions of DNA sequences possess long-range power-law correlations, whereas coding regions typically display only short-range correlations. We develop an algorithm based on this finding that enables investigators to perform a statistical analysis on long DNA sequences to locate possible coding regions. The algorithm is particularly successful in predicting the location of lengthy coding regions. For example, for the complete genome of yeast chromosome III (315,344 nucleotides), at least 82% of the predictions correspond to putative coding regions; the algorithm correctly identified all coding regions larger than 3000 nucleotides, 92% of coding regions between 2000 and 3000 nucleotides long, and 79% of coding regions between 1000 and 2000 nucleotides. The predictive ability of this new algorithm supports the claim that there is a fundamental difference in the correlation property between coding and noncoding sequences. This algorithm, which is not species-dependent, can be implemented with other techniques for rapidly and accurately locating relatively long coding regions in genomic sequences.

Protein Engineering, 1995

Journal of Molecular Biology, 2008

PR39, a naturally occurring and cell-permeable proline-and arginine-rich peptide, blocks the degr... more PR39, a naturally occurring and cell-permeable proline-and arginine-rich peptide, blocks the degradation of IκBα hereby attenuating inflammation. It is a non-competitive and reversible inhibitor of 20S proteasome. To identify its basis of action, we used solution NMR spectroscopy and mutational analyses of the active fragment, PR11, which identified amino acids required for human 20S proteasome inhibiting activity. We then examined PR11 mediated changes in the expression of NF-κB-dependent genes in situ. The results provide prerequisites for proteasome inhibition by PR-peptides providing a powerful new tool to investigate inflammatory processes. These findings offer new leads in developing drugs to treat heart diseases or stroke.

Cytoskeleton, 2015

In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutat... more In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutations also result in cardiomyopathies in humans. The current studies have utilized the Snell&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s waltzer (sv) mouse (a functional null mutation for Myo6) to determine if this mouse also exhibits cardiac defects and thus used to determine the cellular and molecular basis for Myo6-associated heart disease. Myo6 is expressed in mouse heart where it is predominantly expressed in vascular endothelial cells (VECs) based on co-localization with the VEC cell marker CD31. Sv/sv heart mass is significantly greater than that of sv/+ littermates, a result of left ventricle hypertrophy. The left ventricle of the sv/sv exhibits extensive fibrosis, both interstitial and perivascular, based on histologic staining, and immunolocalization of several markers for fibrosis including fibronectin, collagen IV, and the fibroblast marker vimentin. Myo6 is also expressed in lung VECs but not in VECs of intestine, kidney or liver. Sv/sv lungs exhibit increased peri-aveolar fibrosis and enlarged air sacs. Electron microscopy of sv/sv cardiac and lung VECs revealed abnormal ultrastructure, including luminal protrusions and increased numbers of cytoplasmic vesicles. Previous studies have shown that loss of function of either Myo6 or its adaptor binding partner synectin/GIPC results in impaired arterial development due to defects in VEGF signaling. However, examination of synectin/GIPC -/- heart revealed no fibrosis or significantly altered VEC ultrastructure, suggesting that the cardiac and lung defects observed in the sv/sv mouse are not due to Myo6 function in arterial development. This article is protected by copyright. All rights reserved.

PLoS biology, 2015

Blood vascular networks in vertebrates are essential to tissue survival. Establishment of a fully... more Blood vascular networks in vertebrates are essential to tissue survival. Establishment of a fully functional vasculature is complex and requires a number of steps including vasculogenesis and angiogenesis that are followed by differentiation into specialized vascular tissues (i.e., arteries, veins, and lymphatics) and organ-specific differentiation. However, an equally essential step in this process is the pruning of excessive blood vessels. Recent studies have shown that pruning is critical for the effective perfusion of blood into tissues. Despite its significance, vessel pruning is the least understood process in vascular differentiation and development. Two recently published PLOS Biology papers provide important new information about cellular dynamics of vascular regression.

Proceedings of the National Academy of Sciences of the United States of America, Jan 28, 2015

The contribution of endothelial-derived miR-17∼92 to ischemia-induced arteriogenesis has not been... more The contribution of endothelial-derived miR-17∼92 to ischemia-induced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemia-triggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery. Individual cluster components positively or negatively regulate endothelial cell (EC) functions in vitro, and, remarkably, ECs lacking the cluster spontaneously form cords in a manner rescued by miR-17a, -18a, and -19a. Using both in vitro and in vivo analyses, we identified FZD4 and LRP6 as targets of miR-19a/b. Both of these targets were up-regulated in 17∼92 KO ECs compared with control ECs, and both were shown to be targeted by miR-19 using luciferase assays. We demonstrate that miR-19a nega...

Tubular structures are a fundamental anatomic theme recurring in a wide range of animal species. ... more Tubular structures are a fundamental anatomic theme recurring in a wide range of animal species. In mammals, tubulogenesis underscores the development of several systems and organs, including the vascular system, the lungs, and the kidneys. All tubular systems are hierarchical, branching into segments of gradually diminishing diameter. There are only 2 cell types that form the lumen of tubular systems:

Circulation research, Jan 8, 2015

Formation of arterial vasculature, here termed arteriogenesis, is a central process in embryonic ... more Formation of arterial vasculature, here termed arteriogenesis, is a central process in embryonic vascular development as well as in adult tissues. Although the process of capillary formation, angiogenesis, is relatively well understood, much remains to be learned about arteriogenesis. Recent discoveries point to the key role played by vascular endothelial growth factor receptor 2 in control of this process and to newly identified control circuits that dramatically influence its activity. The latter can present particularly attractive targets for a new class of therapeutic agents capable of activation of this signaling cascade in a ligand-independent manner, thereby promoting arteriogenesis in diseased tissues.

Circulation research, Jan 27, 2015

Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying ... more Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg, vascular endothelial growth factor) and other signals (eg, Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or affects the me...

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1996

Research has demonstrated that myocardial perfusion imaging increases the sensitivity and specifi... more Research has demonstrated that myocardial perfusion imaging increases the sensitivity and specificity of stress electrocardiography. However, the additional effect of the perfusion component of a stress study on clinical management algorithms remains poorly defined. We prospectively assessed the decision-making process in 518 patients, from 191 clinicians, undergoing stress myocardial perfusion imaging in our departments. Each clinician was asked, by telephone interview, to define the probability of reversible myocardial ischemia and their management plan (i.e., no antianginal treatment, medical therapy or an invasive intervention) in three stages: pretest, after the stress data was made available and after completion of the perfusion study. The results of the stress data alone influenced the estimate of the probability of reversible ischemia in 149 of 518 patients, and management strategy in 50 of 518 patients. The data from the perfusion component in isolation changed probability ...

Seminars in Thoracic and Cardiovascular Surgery, 2003

The presence of endothelial progenitor cells has been demonstrated in the bone marrow and systemi... more The presence of endothelial progenitor cells has been demonstrated in the bone marrow and systemic circulation of adults, thus raising the possibility of a novel strategy to induce therapeutic angiogenesis for ischemic arterial disease. Successful incorporation into sites of actively occurring angiogenesis in numerous animal models has accelerated the enthusiasm for exploiting their therapeutic capacity in humans and has led to the recent use of putative endothelial precursor cells in phase I feasibility and safety studies. However, key biological issues remain ill defined. The relative contribution of these cells to postnatal physiological and pathological neovascularization has not been fully characterized. Furthermore, the molecular phenotype of the putative endothelial progenitor cell and the processes leading to their mobilization from the bone marrow and homing to sites of angiogenesis have yet to be elucidated. This review addresses these fundamental issues that warrant further basic investigation before the full therapeutic potential of these cells can be achieved within appropriate target patients.