C C Glembotski

San Diego State University, San Diego, California, United States

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Publications (111)681.75 Total impact

  • Christopher C Glembotski
    Circulation Research 08/2014; 115(6):546-8. · 11.86 Impact Factor
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    ABSTRACT: Diabetes is a multi-organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic-related diseases.
    EMBO Molecular Medicine 01/2014; 6(1):57-65. · 7.80 Impact Factor
  • Christopher C. Glembotski
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    ABSTRACT: The hypertrophic growth of cardiac myocytes is a highly dynamic process that underlies physiological and pathological adaptation of the heart. Accordingly, a better understanding of the molecular underpinnings of cardiac myocyte hypertrophy is required in order to fully appreciate the causes and functional consequences of the changes in the size of the healthy and diseased heart. Hypertrophy is driven by increases in cardiac myocyte protein, which must be balanced by cellular ability to maintain protein quality in order to avoid maladaptive accumulation of toxic misfolded proteins. Recent studies have shown that the endoplasmic reticulum (ER), which, in cardiac myocytes, comprises the sarco/endoplasmic reticulum (SR/ER), is the site of most protein synthesis. Thus, the protein quality control machinery located at the SR/ER is likely to be an important determinant of whether the heart responds adaptively to hypertrophic growth stimuli. The SR/ER-transmembrane protein, ATF6, serves a critical protein quality control function as a first responder to the accumulation of potentially toxic, misfolded proteins. Misfolded proteins transform ATF6 into a transcription factor that regulates a gene program that is partly responsible for enhancing protein quality control. Two ATF6-inducible genes that have been studied in the heart and shown to be adaptive are RCAN1 and Derl3, which encode proteins that decrease protein-folding demand, and enhance degradation of misfolded proteins, respectively. Thus, the ATF6-regulated SR/ER protein quality control system is important for maintaining protein quality during growth, making ATF6, and other components of the system, potentially attractive targets for the therapeutic management pathological cardiac hypertrophy. This article is part of a Special Issue entitled “Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy”.
    Journal of Molecular and Cellular Cardiology 01/2014; 71:11–15. · 5.15 Impact Factor
  • Christopher C Glembotski
    Circulation Research 10/2013; 113(10):1112-6. · 11.86 Impact Factor
  • Christopher C Glembotski
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    ABSTRACT: The hypertrophic growth of cardiac myocytes is a highly dynamic process that underlies physiological and pathological adaptation of the heart. Accordingly, a better understanding of the molecular underpinnings of cardiac myocyte hypertrophy is required in order to fully appreciate the causes and functional consequences of the changes in the size of the healthy and diseased heart. Hypertrophy is driven by increases in cardiac myocyte protein, which must be balanced by cellular ability to maintain protein quality in order to avoid maladaptive accumulation of toxic misfolded proteins. Recent studies have shown that the endoplasmic reticulum (ER), which, in cardiac myocytes, comprises the sarco/endoplasmic reticulum (SR/ER), is the site of most protein synthesis. Thus, the protein quality control machinery located at the SR/ER is likely to be an important determinant of whether the heart responds adaptively to hypertrophic growth stimuli. The SR/ER-transmembrane protein, ATF6, serves a critical protein quality control function as a first responder to the accumulation of potentially toxic, misfolded proteins. Misfolded proteins transform ATF6 into a transcription factor that regulates a gene program that is partly responsible for enhancing protein quality control. Two ATF6-inducible genes that have been studied in the heart and shown to be adaptive are RCAN1 and Derl3, which encode proteins that decrease protein-folding demand, and enhance degradation of misfolded proteins, respectively. Thus, the ATF6-regulated SR/ER protein quality control system is important for maintaining protein quality during growth, making ATF6, and other components of the system, potentially attractive targets for the therapeutic management pathological cardiac hypertrophy. This article is part of a Special Issue entitled Cardiac Protein Quality Control.
    Journal of Molecular and Cellular Cardiology 10/2013; · 5.15 Impact Factor
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) is comprised of two structurally distinct multiprotein complexes, mTOR complexes 1 and 2 (mTORC1 and 2). Deregulation of mTOR signaling occurs during and contributes to the severity of myocardial damage from ischemic heart disease. However, the relative roles of mTORC1 versus mTORC2 in the pathogenesis of ischemic damage are unknown. Combined pharmacological and molecular approaches were used to alter the balance of mTORC1 and mTORC2 signaling in cultured cardiac myocytes and in mouse hearts subjected to conditions that mimic ischemic heart disease. The importance of mTOR signaling in cardiac protection was demonstrated by pharmacological inhibition of both mTORC1 and mTORC2 with Torin1, which led to increased cardiomyocyte apoptosis and tissue damage after myocardial infarction (MI). Predominant mTORC1 signaling mediated by suppression of mTORC2 with Rictor similarly increased cardiomyocyte apoptosis and tissue damage after MI. In comparison, preferentially shifting toward mTORC2 signaling by inhibition of mTORC1 with PRAS40 led to decreased cardiomyocyte apoptosis and tissue damage after MI. These results suggest that selectively increasing mTORC2 while concurrently inhibting of mTORC1 signaling is a novel therapeutic approach for the treatment of ischemic heart disease.
    Circulation 09/2013; · 15.20 Impact Factor
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    ABSTRACT: Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition of mTORC1 activation. Among mTORC1 regulatory binding partners, the role of Proline Rich AKT Substrate of 40 kDa (PRAS40) in controlling mTORC1 activity and cellular growth in response to pathological and physiological stress in the heart has never been addressed. This report shows PRAS40 is regulated by AKT in cardiomyocytes and that AKT-driven phosphorylation relieves the inhibitory function of PRAS40. PRAS40 overexpression in vitro blocks mTORC1 in cardiomyocytes and decreases pathological growth. Cardiomyocyte-specific overexpression in vivo blunts pathological remodeling after pressure overload and preserves cardiac function. Inhibition of mTORC1 by PRAS40 preferentially promotes protective mTORC2 signaling in chronic diseased myocardium. In contrast, strong PRAS40 phosphorylation by AKT allows for physiological hypertrophy both in vitro and in vivo, whereas cardiomyocyte-specific overexpression of a PRAS40 mutant lacking capacity for AKT-phosphorylation inhibits physiological growth in vivo, demonstrating that AKT-mediated PRAS40 phosphorylation is necessary for induction of physiological hypertrophy. Therefore, PRAS40 phosphorylation acts as a molecular switch allowing mTORC1 activation during physiological growth, opening up unique possibilities for therapeutic regulation of the mTORC1 complex to mitigate pathologic myocardial hypertrophy by PRAS40.
    Proceedings of the National Academy of Sciences 07/2013; · 9.81 Impact Factor
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    ABSTRACT: Rationale: Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based upon the phosphorylation status of involved signaling molecules. While numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the non-myocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown. Objective: To establish the role of Pin1 in the heart. Methods and Results: Here we show that either genetic deletion or cardiac over-expression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, MEK and Raf-1 in cultured cardiomyocytes following hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, while over-expression of Pin1 increases Raf-1 phosphorylation on the auto-inhibitory site Ser259 leading to reduced MEK activation. Conclusions: Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of two major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.
    Circulation Research 03/2013; · 11.86 Impact Factor
  • Shirin Doroudgar, Christopher C Glembotski
    Circulation Research 01/2013; 112(1):9-12. · 11.86 Impact Factor
  • Christopher C Glembotski
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    ABSTRACT: Although the function of the sarcoplasmic/endoplasmic reticulum (SR/ER) in cardiac contractile calcium handling is well established, its roles in protein synthesis, folding, and quality control in cardiac myocytes are not as clear. This review explores evidence suggesting that, in cardiac myocytes, protein synthesis and contractile calcium handling may be physically and functionally integrated.
    Physiology 12/2012; 27(6):343-350. · 6.75 Impact Factor
  • Shirin Doroudgar, Christopher C Glembotski
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    ABSTRACT: Secreted and transmembrane proteins play critical roles in myocardial health and disease. Studies in non-myocytes have shown that the peri-nuclear ER is the site for synthesis, folding and quality control of most secreted and transmembrane proteins, as well as a nexus of a signal transduction system, the ER stress response, that informs the cell about the status of ER protein folding. Moreover, the dynamic physical and functional association of the ER with mitochondria has emerged as a key site of integrating ER function with mitochondrial metabolism, but is only just beginning to be understood in the myocardium. Although a great deal is known about roles played by the sarcoplasmic reticulum (SR) in contractile calcium handling in the heart, little is known about the relative locations and functions of the peri-nuclear ER and the SR in terms of secreted and membrane protein synthesis and folding. In this review we will explore the current state of knowledge of the location of secreted and membrane protein synthesis, folding, and quality control machinery in cardiac myocytes, as well as our understanding of the functional consequences of ER stress and the unfolded protein response in the heart in terms of protein synthesis, cell growth, and metabolic regulation.
    Journal of Molecular and Cellular Cardiology 10/2012; · 5.15 Impact Factor
  • Christopher C Glembotski
    Circulation Research 08/2012; 111(5):509-12. · 11.86 Impact Factor
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    ABSTRACT: ER stress leads to upregulation of multiple folding and quality control components, known as the unfolded protein response (UPR). Glucose Regulated Proteins 78 and 94 (GRP78/BiP and GRP94) are often upregulated coordinately as part of this homeostatic response. Given that ER chaperones have distinct sets of clients, we asked how cells respond to ablation of individual chaperones. The cellular responses to silencing BiP, GRP94, HSP47, PDIA6 and OS-9, were distinct. When BiP was silenced, a widespread UPR was observed, but when GRP94 was either inhibited or depleted by RNAi, the expression of only some genes, notably BiP and protein disulfide isomerase A6 (PDIA6) was induced. Silencing of HSP47 or OS-9 did not lead to any compensatory induction of other genes. The selective response to GRP94 depletion was distinct from a typical ER stress response, both because other UPR target genes were not affected and because the canonical UPR signaling branches were not activated. The response to silencing of GRP94 did not preclude further UPR induction when chemical stress was imposed. Importantly, re-expression of wild-type GRP94 in the silenced cells prevented the up-regulation of BiP and PDIA6, while re-expression of an ATPase-deficient GRP94 mutant did not, indicating that cells monitor the state of activity of GRP94. These findings suggest that cells are able to distinguish among folding resources and generate distinct responses.
    Journal of Cell Science 08/2012; · 5.88 Impact Factor
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    ABSTRACT: The endoplasmic reticulum (ER) stress protein mesencephalic astrocyte-derived neurotrophic factor (MANF) has been reported to protect cells from stress-induced cell death before and after its secretion; however, the conditions under which it is secreted are not known. Accordingly, we examined the mechanism of MANF release from cultured ventricular myocytes and HeLa cells, both of which secrete proteins via the constitutive pathway. Although the secretion of proteins via the constitutive pathway is not known to increase upon changes in intracellular calcium, MANF secretion was increased within 30 min of treating cells with compounds that deplete sarcoplasmic reticulum (SR)/ER calcium. In contrast, secretion of atrial natriuretic factor from ventricular myocytes was not increased by SR/ER calcium depletion, suggesting that not all secreted proteins exhibit the same characteristics as MANF. We postulated that SR/ER calcium depletion triggered MANF secretion by decreasing its retention. Consistent with this were co-immunoprecipitation and live cell, zero distance, photo affinity cross-linking, demonstrating that, in part, MANF was retained in the SR/ER via its calcium-dependent interaction with the SR/ER-resident protein, GRP78 (glucose-regulated protein 78 kDa). This unusual mechanism of regulating secretion from the constitutive secretory pathway provides a potentially missing link in the mechanism by which extracellular MANF protects cells from stresses that deplete SR/ER calcium. Consistent with this was our finding that administration of recombinant MANF to mice decreased tissue damage in an in vivo model of myocardial infarction, a condition during which ER calcium is known to be dysregulated, and MANF expression is induced.
    Journal of Biological Chemistry 05/2012; 287(31):25893-904. · 4.65 Impact Factor
  • John A Vekich, Peter J Belmont, Donna J Thuerauf, Christopher C Glembotski
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    ABSTRACT: Proper folding of secreted and transmembrane proteins made in the rough endoplasmic reticulum (ER) requires oxygen for disulfide bond formation. Accordingly, ischemia can impair ER protein folding and initiate the ER stress response, which we previously showed is activated in the ischemic heart and in culture cardiac myocytes subjected to simulated ischemia. ER stress and ischemia activate the transcription factor, activating transcription factor 6 (ATF6), which induces numerous genes, many of which have not been identified, or examined in the heart. Using an ATF6 transgenic mouse model, we previously showed that ATF6 protected the heart from ischemic damage; however, the mechanism of this protection remains to be determined. In this study, we showed that, in the mouse heart, and in cultured cardiac myocytes, ATF6 induced the protein disulfide isomerase associated 6 (PDIA6) gene, which encodes an ER enzyme that catalyzes protein disulfide bond formation. Moreover, in cultured cardiac myocytes, ER stress-mediated PDIA6 promoter activation was ATF6-dependent, and required an ER stress response element (ERSE) and a nearby CCAAT box element. Electromobility shift assays and chromatin immunoprecipitation showed that ATF6 bound to the ERSE in the PDIA6 promoter, in vitro, and in the mouse heart, in vivo. Gain- and loss-of-function studies showed that PDIA6 protected cardiac myocytes against simulated ischemia/reperfusion-induced death in a manner that was dependent on the catalytic activity of PDIA6. Thus, by facilitating disulfide bond formation, and enhanced ER protein folding, PDIA6 may contribute to the protective effects of ATF6 in the ischemic mouse heart.
    Journal of Molecular and Cellular Cardiology 05/2012; 53(2):259-67. · 5.15 Impact Factor
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    Peter J Belmont, Wenqiong J Chen, Donna J Thuerauf, Christopher C Glembotski
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    ABSTRACT: A nodal regulator of endoplasmic reticulum stress is the transcription factor, ATF6, which is activated by ischemia and protects the heart from ischemic damage, in vivo. To explore mechanisms of ATF6-mediated protection in the heart, a whole-genome microRNA (miRNA) array analysis of RNA from the hearts of ATF6 transgenic (TG) mice was performed. The array identified 13 ATF6-regulated miRNAs, eight of which were downregulated, suggesting that they could contribute to increasing levels of their mRNAs. The down-regulated miRNAs, including miR-455, were predicted to target 45 mRNAs that we had previously shown by microarray analysis to be up-regulated by ATF6 in the heart. One of the miR-455 targets was calreticulin (Calr), which is up-regulated in the pathologic heart, where it modulates hypertrophic growth, potentially reducing the impact of the pathology. To validate the effects of miR-455, we showed that Calr protein was increased by ATF6 in mouse hearts, in vivo. In cultured cardiac myocytes, treatment with the ER stressor, tunicamycin, or with adenovirus encoding activated ATF6 decreased miR-455 and increased Calr levels, consistent with the effects of ATF6 on miR-455 and Calr, in vivo. Moreover, transfection of cultured cardiac myocytes with a synthetic precursor, premiR-455, decreased Calr levels, while transfection with an antisense, antimiR-455, increased Calr levels. The results of this study suggest that ER stress can regulate gene expression via ATF6-mediated changes in micro-RNA levels. Moreover, these findings support the hypothesis that ATF6-mediated down-regulation of miR-455 augments Calr expression, which may contribute to the protective effects of ATF6 in the heart.
    Journal of Molecular and Cellular Cardiology 02/2012; 52(5):1176-82. · 5.15 Impact Factor
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    Shirin Doroudgar, Christopher C Glembotski
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    ABSTRACT: Intercellular communication depends on many factors, including proteins released via the classical or non-classical secretory pathways, many of which must be properly folded to be functional. Owing to their adverse effects on the secretion machinery, stresses such as ischemia can impair the folding of secreted proteins. Paradoxically, cells rely on secreted proteins to mount a response designed to resist stress-induced damage. This review examines this paradox using proteins secreted from the heart, cardiokines, as examples, and focuses on how the ischemic heart maintains or even increases the release of select cardiokines that regulate important cellular processes in the heart, including excitation-contraction coupling, hypertrophic growth, myocardial remodeling and stem cell function, in ways that moderate ischemic damage and enhance cardiac repair.
    Trends in Molecular Medicine 02/2011; 17(4):207-14. · 9.57 Impact Factor
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    Christopher C Glembotski
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    ABSTRACT: We define cardiomyokines as heart-derived secreted proteins that affect cardiovascular function via autocrine, paracrine and/or endocrine mechanisms. The subject of this review is the cardiomyokine, mesencephalic astrocyte-derived neurotrophic factor (MANF). The expression of MANF is increased in the ischemic heart, in part, through activation of ER stress, a condition that drastically impairs the expression and secretion of most cardiomyokines. This novel function of MANF suggests that it may have important roles in the ER stressed, ischemic heart. Consistent with this are recent findings showing that MANF protects against ischemic damage, and that it is anti-hypertrophic. Accordingly, in light of its function as a potentially secreted cardiomyokine, MANF has translational potential as a novel therapy for ischemic heart disease. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
    Journal of Molecular and Cellular Cardiology 10/2010; 51(4):512-7. · 5.15 Impact Factor
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    ABSTRACT: Cardioprotective signaling mediates antiapoptotic actions through multiple mechanisms including maintenance of mitochondrial integrity. Pim-1 kinase is an essential downstream effector of AKT-mediated cardioprotection but the mechanistic basis for maintenance of mitochondrial integrity by Pim-1 remains unexplored. This study details antiapoptotic actions responsible for enhanced cell survival in cardiomyocytes with elevated Pim-1 activity. The purpose of this study is to demonstrate that the cardioprotective kinase Pim-1 acts to inhibit cell death by preserving mitochondrial integrity in cardiomyocytes. A combination of biochemical, molecular, and microscopic analyses demonstrate beneficial effects of Pim-1 on mitochondrial integrity. Pim-1 protein level increases in the mitochondrial fraction with a corresponding decrease in the cytosolic fraction of myocardial lysates from hearts subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Cardiac-specific overexpression of Pim-1 results in higher levels of antiapoptotic Bcl-X(L) and Bcl-2 compared to samples from normal hearts. In response to oxidative stress challenge, Pim-1 preserves the inner mitochondrial membrane potential. Ultrastructure of the mitochondria is maintained by Pim-1 activity, which prevents swelling induced by calcium overload. Finally, mitochondria isolated from hearts created with cardiac-specific overexpression of Pim-1 show inhibition of cytochrome c release triggered by a truncated form of proapoptotic Bid. Cardioprotective action of Pim-1 kinase includes preservation of mitochondrial integrity during cardiomyopathic challenge conditions, thereby raising the potential for Pim-1 kinase activation as a therapeutic interventional approach to inhibit cell death by antagonizing proapoptotic Bcl-2 family members that regulate the intrinsic apoptotic pathway.
    Circulation Research 03/2010; 106(7):1265-74. · 11.86 Impact Factor
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    ABSTRACT: Stresses, such as ischemia, impair folding of nascent proteins in the rough endoplasmic reticulum (ER), activating the unfolded protein response, which restores efficient ER protein folding, thus leading to protection from stress. In part, the unfolded protein response alleviates ER stress and cell death by increasing the degradation of terminally misfolded ER proteins via ER-associated degradation (ERAD). ERAD is increased by the ER stress modulator, activating transcription factor (ATF)6, which can induce genes that encode components of the ERAD machinery. Recently, it was shown that the mouse heart is protected from ischemic damage by ATF6; however, ERAD has not been studied in the cardiac context. A recent microarray study showed that the Derlin-3 (Derl3) gene, which encodes an important component of the ERAD machinery, is robustly induced by ATF6 in the mouse heart. In the present study, activated ATF6 induced Derl3 in cultured cardiomyocytes, and in the heart, in vivo. Simulated ischemia (sI), which activates ER stress, induced Derl3 in cultured myocytes, and in an in vivo mouse model of myocardial infarction, Derl3 was also induced. Derl3 overexpression enhanced ERAD and protected cardiomyocytes from simulated ischemia-induced cell death, whereas dominant-negative Derl3 decreased ERAD and increased simulated ischemia-induced cardiomyocyte death. This study describes a potentially protective role for Derl3 in the heart, and is the first to investigate the functional consequences of enhancing ERAD in the cardiac context.
    Circulation Research 11/2009; 106(2):307-16. · 11.86 Impact Factor

Publication Stats

4k Citations
681.75 Total Impact Points

Institutions

  • 1987–2014
    • San Diego State University
      • • Department of Biology
      • • Heart Institute
      • • Molecular Biology Institute
      San Diego, California, United States
  • 2009
    • Wageningen University
      Wageningen, Gelderland, Netherlands
  • 1990–1991
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States
  • 1985–1990
    • Hospital of the University of Pennsylvania
      • • Department of Ophthalmology
      • • Department of Pharmacology
      Philadelphia, Pennsylvania, United States
  • 1985–1988
    • University of Pennsylvania
      • • Department of Biochemistry and Biophysics
      • • Department of Medicine
      Philadelphia, PA, United States