Publications by authors named "Rachel Lopez"

7 Publications

  • Page 1 of 1

Quantitative analysis of mitochondrial ATP synthesis.

Math Biosci 2021 Jun 17:108646. Epub 2021 Jun 17.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, 48109, MI, USA. Electronic address:

We present a computational framework for analyzing and simulating mitochondrial ATP synthesis using basic thermodynamic and kinetic principles. The framework invokes detailed descriptions of the thermodynamic driving forces associated with the processes of the electron transport chain, mitochondrial ATP synthetase, and phosphate and adenine nucleotide transporters. Assembling models of these discrete processes into an integrated model of mitochondrial ATP synthesis, we illustrate how to analyze and simulate in vitro respirometry experiments and how models identified from in vitro experimental data effectively explain cardiac respiratory control in vivo. Computer codes for these analyses are embedded as Python scripts in a Jupyter Book to facilitate easy adoption and modification of the concepts developed here. This accessible framework may also prove useful in supporting educational applications. All source codes are available on at https://beards-lab.github.io/QAMAS_book/.
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http://dx.doi.org/10.1016/j.mbs.2021.108646DOI Listing
June 2021

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts.

Function (Oxf) 2020 22;1(2):zqaa018. Epub 2020 Sep 22.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical-free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multiscale computational model of cardiac mechanoenergetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.
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http://dx.doi.org/10.1093/function/zqaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552914PMC
September 2020

Testing three explanations for stigmatization of people of Asian descent during COVID-19: maladaptive coping, biased media use, or racial prejudice?

Ethn Health 2021 01 15;26(1):94-109. Epub 2020 Oct 15.

Division of Biostatistics, The Ohio State University, Columbus, OH, USA.

Objective: To investigate factors associated with the stigmatization of people of Asian descent during COVID-19 in the United States and factors that can mitigate or prevent stigmatization.

Design: A national sample survey of adults ( = 842) was conducted online between May 11 and May 19, 2020. Outcome variables were two dimensions of stigmatization, responsibility and persons as risk. Hierarchical regression analyses were performed.

Results: Racial prejudice, maladaptive coping, and biased media use each explained stigmatization. Racial prejudice, comprising stereotypical beliefs and emotion toward Asian Americans, was a stronger predictor of stigmatization than maladaptive coping or biased media use. Fear concerning the ongoing COVID-19 situation and the use of social media and partisan cable TV also predicted stigmatization. Low self-efficacy in dealing with COVID-19, when associated with high estimated harm of COVID-19, increased stigmatization. High perceived institutional efficacy in the handling of COVID-19 increased stigmatization when linked to high estimated harm of COVID-19. On the other hand, high perceived collective efficacy in coping with COVID-19 was associated with low stigmatization. More indirect contacts with Asians via the media predicted less stigmatization.

Conclusions: Efforts to reduce stigmatization should address racial stereotypes and emotions, maladaptive coping, and biased media use by providing education and resources to the public. Fostering collective efficacy and media-based contacts with Asian Americans can facilitate these efforts.
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http://dx.doi.org/10.1080/13557858.2020.1830035DOI Listing
January 2021

Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.

Physiol Genomics 2016 08 10;48(8):601-15. Epub 2016 Jun 10.

Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medicine/Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California

Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.
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http://dx.doi.org/10.1152/physiolgenomics.00035.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005461PMC
August 2016

Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf: IMPLICATIONS FOR TRANSCRIPTIONAL REGULATION.

J Biol Chem 2016 07 16;291(30):15428-46. Epub 2016 May 16.

From the Departments of Anesthesiology, Medicine, Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 and

Transcriptome remodeling in heart disease occurs through the coordinated actions of transcription factors, histone modifications, and other chromatin features at pathology-associated genes. The extent to which genome-wide chromatin reorganization also contributes to the resultant changes in gene expression remains unknown. We examined the roles of two chromatin structural proteins, Ctcf (CCCTC-binding factor) and Hmgb2 (high mobility group protein B2), in regulating pathologic transcription and chromatin remodeling. Our data demonstrate a reciprocal relationship between Hmgb2 and Ctcf in controlling aspects of chromatin structure and gene expression. Both proteins regulate each others' expression as well as transcription in cardiac myocytes; however, only Hmgb2 does so in a manner that involves global reprogramming of chromatin accessibility. We demonstrate that the actions of Hmgb2 on local chromatin accessibility are conserved across genomic loci, whereas the effects on transcription are loci-dependent and emerge in concert with histone modification and other chromatin features. Finally, although both proteins share gene targets, Hmgb2 and Ctcf, neither binds these genes simultaneously nor do they physically colocalize in myocyte nuclei. Our study uncovers a previously unknown relationship between these two ubiquitous chromatin proteins and provides a mechanistic explanation for how Hmgb2 regulates gene expression and cellular phenotype. Furthermore, we provide direct evidence for structural remodeling of chromatin on a genome-wide scale in the setting of cardiac disease.
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http://dx.doi.org/10.1074/jbc.M116.719633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957031PMC
July 2016

Structure and Reactivity of X-ray Amorphous Uranyl Peroxide, U2O7.

Inorg Chem 2016 Apr 14;55(7):3541-6. Epub 2016 Mar 14.

Department of Civil and Environmental Engineering and Earth Sciences, University of Notre Dame , Notre Dame, Indiana 46556, United States.

Recent accidents resulting in worker injury and radioactive contamination occurred due to pressurization of uranium yellowcake drums produced in the western U.S.A. The drums contained an X-ray amorphous reactive form of uranium oxide that may have contributed to the pressurization. Heating hydrated uranyl peroxides produced during in situ mining can produce an amorphous compound, as shown by X-ray powder diffraction of material from impacted drums. Subsequently, studtite, [(UO2)(O2)(H2O)2](H2O)2, was heated in the laboratory. Its thermal decomposition produced a hygroscopic anhydrous uranyl peroxide that reacts with water to release O2 gas and form metaschoepite, a uranyl-oxide hydrate. Quantum chemical calculations indicate that the most stable U2O7 conformer consists of two bent (UO2)(2+) uranyl ions bridged by a peroxide group bidentate and parallel to each uranyl ion, and a μ2-O atom, resulting in charge neutrality. A pair distribution function from neutron total scattering supports this structural model, as do (1)H- and (17)O-nuclear magnetic resonance spectra. The reactivity of U2O7 in water and with water in air is higher than that of other uranium oxides, and this can be both hazardous and potentially advantageous in the nuclear fuel cycle.
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http://dx.doi.org/10.1021/acs.inorgchem.6b00017DOI Listing
April 2016

Not low hanging but still sweet: Metabolic proteomes in cardiovascular disease.

J Mol Cell Cardiol 2016 Jan 22;90:70-3. Epub 2015 Nov 22.

Department of Anesthesiology, David Geffen School of Medicine, UCLA, United States; Department of Medicine/Cardiology, David Geffen School of Medicine, UCLA, United States. Electronic address:

The application of proteomics in biology and medicine has reached a moment of truth. The demand of biologists for transformative insights into how cells work, plus the mandate of basic science research to ultimately impact clinical medicine, crystallize as a test on the rigor and reproducibility of any 'omics measurement. Studies like that by Boylston et al. indicate that proteomics can pass that test.
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http://dx.doi.org/10.1016/j.yjmcc.2015.11.022DOI Listing
January 2016
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