Medical Physiology Commons^™

Causality Analysis And Cell Network Modeling Of Spatial Calcium Signaling Patterns In Liver Lobules., Aalap Verma, Anil Noronha Antony, Babatunde A. Ogunnaike, Jan B. Hoek, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Dynamics as well as localization of Ca2+ transients plays a vital role in liver function under homeostatic conditions, repair, and disease. In response to circulating hormonal stimuli, hepatocytes exhibit intracellular Ca2+ responses that propagate through liver lobules in a wave-like fashion. Although intracellular processes that control cell autonomous Ca2+ spiking behavior have been studied extensively, the intra- and inter-cellular signaling factors that regulate lobular scale spatial patterns and wave-like propagation of Ca2+ remain to be determined. To address this need, we acquired images of cytosolic Ca2+ transients in 1300 hepatocytes situated across several mouse liver lobules over a period of …

Myocyte [Na+]I Dysregulation In Heart Failure And Diabetic Cardiomyopathy, Sanda Despa

Pharmacology and Nutritional Sciences Faculty Publications

By controlling the function of various sarcolemmal and mitochondrial ion transporters, intracellular Na⁺ concentration ([Na⁺]_i) regulates Ca²⁺ cycling, electrical activity, the matching of energy supply and demand, and oxidative stress in cardiac myocytes. Thus, maintenance of myocyte Na⁺ homeostasis is vital for preserving the electrical and contractile activity of the heart. [Na⁺]_i is set by the balance between the passive Na⁺ entry through numerous pathways and the pumping of Na⁺ out of the cell by the Na⁺/K⁺-ATPase. This equilibrium is perturbed in heart failure, …

Repetitive Transcranial Electrical Stimulation Induces Quantified Changes In Resting Cerebral Perfusion Measured From Arterial Spin Labeling, Matthew Sherwood, Aaron T. Madaris, Casserly R. Mullenger, R. Andy Mckinley

Neuroscience, Cell Biology & Physiology Faculty Publications

The use of transcranial electrical stimulation (TES) as a method to augment neural activity has increased in popularity in the last decade and a half. The specific application of TES to the left prefrontal cortex has been shown to produce broad cognitive effects; however, the neural mechanisms underlying these effects remain unknown. In this work, we evaluated the effect of repetitive TES on cerebral perfusion. Stimulation was applied to the left prefrontal cortex on three consecutive days, and resting cerebral perfusion was quantified before and after stimulation using arterial spin labeling. Perfusion was found to decrease significantly more in a …

Propofol Inhibits The Voltage-Gated Sodium Channel Nachbac At Multiple Sites., Yali Wang, Elaine Yang, Marta M. Wells, Vasyl Bondarenko, Kellie Woll, Vincenzo Carnevale, Daniele Granata, Michael L. Klein, Roderic G. Eckenhoff, William P. Dailey, Manuel Covarrubias, Pei Tang, Yan Xu

Department of Neuroscience Faculty Papers

Voltage-gated sodium (Na_V) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic Na_V channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects …

Gender- And Region-Specific Changes In Estrogen Signaling In Aging Rat Brain Mitochondria, Christopher M. Evola, Tanner L. Hudson, Luping Huang, Adrian M. Corbett, Debra A. Mayes

Neuroscience, Cell Biology & Physiology Faculty Publications

Recently epidemiological studies suggest females lose neuroprotection from neurodegenerative diseases as they go through menopause. It has been hypothesized that this neuroprotection is hormone‐dependent. The current study characterized cell signaling molecules downstream of estrogen receptor beta that are known to play a role in memory, PKC, ERK, and connexin‐43, in regions of the brain associated with memory decline in an attempt to elucidate significant changes that occur post‐estrus. Total whole cell lysates were compared to isolated mitochondrial protein because mitochondrial function is known to be altered during aging. As hypothesized, protein concentrations differed depending on age, gender, and brain region. …

High Fat Diet Upregulates Fatty Acid Oxidation And Ketogenesis Via Intervention Of Ppar-Γ., Kunal Sikder, Sanket Kumar Shukla, Neel Patel, Harpreet Singh, Khadija Rafiq

Center for Translational Medicine Faculty Papers

BACKGROUND/AIMS: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis.

METHODS: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and …

Volitional Down-Regulation Of The Primary Auditory Cortex Via Directed Attention Mediated By Real-Time Fmri Neurofeedback, Matthew Sherwood, Jason G. Parker, Emily E. Diller, Subhashini Ganapathy, Kevin B. Bennett, Jeremy T. Nelson

Neuroscience, Cell Biology & Physiology Faculty Publications

The present work assessed the efficacy of training volitional down-regulation of the primary auditory cortex (A1) based on real-time functional magnetic resonance imaging neurofeedback (fMRI-NFT). A1 has been shown to be hyperactive in chronic tinnitus patients, and has been implicated as a potential source for the tinnitus percept. 27 healthy volunteers with normal hearing underwent 5 fMRI-NFT sessions: 18 received real neurofeedback and 9 sham neurofeedback. Each session was composed of a simple auditory fMRI followed by 2 runs of A1 fMRI-NFT. The auditory fMRI alternated periods of no auditory with periods of white noise stimulation at 90 dB. A1 …

Artificial Gravity As A Countermeasure To The Cardiovascular Deconditioning Of Spaceflight: Gender Perspectives, Joyce M. Evans, Charles F. Knapp, Nandu Goswami

Biomedical Engineering Faculty Publications

Space flight-induced physiological deconditioning resulting from decreased gravitational input, decreased plasma volume, and disruption of regulatory mechanisms is a significant problem in returning astronauts as well as in normal aging. Here we review effects of a promising countermeasure on cardiovascular systems of healthy men and women undergoing Earth-based models of space-flight. This countermeasure is produced by a centrifuge and called artificial gravity (AG). Numerous studies have determined that AG improves orthostatic tolerance (as assessed by various protocols) of healthy ambulatory men, of men deconditioned by bed rest or by immersion (both wet and dry) and, in one case, following spaceflight. …

Spinal Control Of Locomotion: Individual Neurons, Their Circuits And Functions, Marie-Pascale Côté, Lynda M. Murray, Maria Knikou

Publications and Research

Systematic research on the physiological and anatomical characteristics of spinal cord interneurons along with their functional output has evolved for more than one century. Despite significant progress in our understanding of these networks and their role in generating and modulating movement, it has remained a challenge to elucidate the properties of the locomotor rhythm across species. Neurophysiological experimental evidence indicates similarities in the function of interneurons mediating afferent information regarding muscle stretch and loading, being affected by motor axon collaterals and those mediating presynaptic inhibition in animals and humans when their function is assessed at rest. However, significantly different muscle …

Gene Delivery Of Adenoviral-Tmbim6 Vector Protects The Neonatal Brain After Hypoxic-Ischemic Injury, Desislava Doycheva

Loma Linda University Electronic Theses, Dissertations & Projects

Neonatal hypoxia ischemia (HI) is an injury caused to the immature brain due to reduced cerebral blood flow which is associated with life-long neurological impairments. HI causes oxidative protein folding in the endoplasmic reticulum (ER), which results in ER stress. Generation of reactive oxygen species (ROS), from cytochrome P450 members (CYP) and NADPH-P450 reductases (NPR), in combination with activation of the unfolded protein response (UPR) are two major consequences of ER stress that cause oxidative damage and cell death. Herein we identified the role of Bax Inhibitor-1 (BI-1), an evolutionary conserved protein encoded by the Transmembrane Bax inhibitor Motif Containing …

Changes In The Morphology Of Hypoglossal Motor Neurons In The Brainstem Of Developing Rats, Paul Allen Williams

Loma Linda University Electronic Theses, Dissertations & Projects

The autonomic brainstem generates and modifies breathing rhythm by integrating inputs from chemo- and mechanosensors in the viscera while coordinating descending outputs from higher CNS structures. Hypoglossal motoneurons (XII MNs) receive inputs from respiratory premotor neurons in the medulla. Previous studies in rodents have demonstrated significant changes in breathing control during the first three weeks of life, with a sensitive period at 10 to 13 days post-birth (P10–P13) characterized by pronounced changes in neurotransmitters, receptors, excitation-inhibition balance, and breathing. However, age-dependent morphological changes of XII MNs during the first three weeks post-birth and especially during this sensitive period, have not …

The Role Of Glucocorticoid Signaling In Prostate Cancer Health Disparities, Leanne W. Burnham

Loma Linda University Electronic Theses, Dissertations & Projects

African-American men are more likely to develop aggressive prostate cancer (PCa) and die from the disease than other ethnic groups. Glucocorticoid signaling is a contributing biological factor to worse PCa prognosis, and is emerging as a key driver of PCa progression in the absence of androgens. The mechanism involves glucocorticoids binding to glucocorticoid receptor (GR) and bypassing the androgen receptor (AR) signaling pathway to activate AR-target genes that promote tumor aggressiveness and therapy-resistance. This is problematic as African-American men have hypersensitive GR signaling and chronically-elevated levels of glucocorticoids linked to cumulative stressful life events. To explore the role of glucocorticoid …

Systematic Pan-Cancer Analysis Of Somatic Allele Frequency., Liam Spurr, Muzi Li, Nawaf Alomran, Qianqian Zhang, Paula Restrepo, Mercedeh Movassagh, Chris Trenkov, Nerissa Tunnessen, Tatiyana Apanasovich, Keith A Crandall, Nathan Edwards, Anelia Horvath

Pharmacology and Physiology Faculty Publications

Imbalanced expression of somatic alleles in cancer can suggest functional and selective features, and can therefore indicate possible driving potential of the underlying genetic variants. To explore the correlation between allele frequency of somatic variants and total gene expression of their harboring gene, we used the unique data set of matched tumor and normal RNA and DNA sequencing data of 5523 distinct single nucleotide variants in 381 individuals across 10 cancer types obtained from The Cancer Genome Atlas (TCGA). We analyzed the allele frequency in the context of the variant and gene functional features and linked it with changes in …

Effect Of Exercise And Hypoxia On Plasma Telomerase, Charli D. Aguilar

UNLV Theses, Dissertations, Professional Papers, and Capstones

Introduction: Telomerase reverse transcriptase (TERT) is the enzyme that adds telomeric sequences to the end of linear chromosomes. Exercise has shown to upregulate acutely leukocyte TERT after just 30 minutes of running on a treadmill at 80% of VO2max (Denham et al., 2016). Hypoxia inducible factor 1 (HIF-1) is also a mediator of TERT in in vitro (Nishi et al., 2004). Moderate acute exposure to hypoxia was associated with substantial increases in plasma TERT in a recent study on rats (Wang et al., 2014). The specific aim of the current study was to identify if acute hypoxia upregulates plasma TERT …

Disruption Of Neonatal Cardiomyocyte Physiology Following Exposure To Bisphenol-A., Manelle Ramadan, Meredith Sherman, Rafael Jaimes, Ashika Chaluvadi, Luther Swift, Nikki Gillum Posnack

Pharmacology and Physiology Faculty Publications

Bisphenol chemicals are commonly used in the manufacturing of polycarbonate plastics, polyvinyl chloride plastics, resins, and thermal printing applications. Humans are inadvertently exposed to bisphenols through contact with consumer products and/or medical devices. Recent reports have shown a link between bisphenol-a (BPA) exposure and adverse cardiovascular outcomes; although these studies have been limited to adult subjects and models. Since cardiac physiology differs significantly between the developing and adult heart, we aimed to assess the impact of BPA exposure on cardiac function, using a neonatal cardiomyocyte model. Neonatal rat ventricular myocytes were monitored to assess cell viability, spontaneous beating rate, beat …

Tissue Engineered Micro And Macrovasculature Utilizing Stromal Vascular Fraction., Joseph Samir Zakhari

Electronic Theses and Dissertations

This dissertation describes the use of stromal vascular fraction to tissue engineer 3D microvasculature and macrovasculature. Stromal vascular fraction is an easily isolatable cell source from adipose tissue depots. It has demonstrated remarkable potential both in vitro and in vivo for forming microcirculation capable of perfusion upon implantation. SVF is clinically utilized as a therapeutic cell source for anti-inflammation for osteoarthritis and is being studied for ischemic tissue application to stimulate revascularization. The work described herein is divided within four chapters. Chapter I provides an introductory overview and lists the aims and hypothesis for the dissertation. Chapter II describes experiments …

Protein Trafficking Of Bk Channel Β1 Subunits In Cerebral Artery Myocytes, Xue Zhai

Theses and Dissertations (ETD)

Rationale: Large-conductance calcium (Ca²⁺)-activated potassium channels (BK) are expressed in arterial myocytes to control arterial contractility. It is composed of pore- forming BKα and auxiliary β1 subunits. Auxiliary β1 subunits associate with BKα which modulate Ca²⁺ sensitivity of BK channel. Previous data showed that BKα locates at cell membrane, whereas β1 subunits are primarily intracellular which regulated by Rab11A- positive recycling endosomes. Endothelin-1 (ET-1), a vasoconstrictor, induces contraction of myocytes. ET-1 inhibits BK channel but mechanisms are not fully understood. It is unclear that vasoconstrictors regulate the cellular distribution of BK channels. Furthermore, BK channels are involved …

Characterization Of The Hepatotoxicity Of Rifampicin And Isoniazid, Christopher T. Brewer

Theses and Dissertations (ETD)

In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase of protoporphyrin ix (PPIX), the penultimate heme precursor. Excess PPIX is believed to bind to bile acids, precipitate in bile canaliculi, and form bile plugs leading to cholestasis fol owed by liver injury. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to up-regulate Alas1 but down-regulate Fech protein levels in mice; however the mechanism of isoniazid mediated heme synthesis …

Spinal Cord Trauma: An Overview Of Normal Structure And Function, Primary And Secondary Mechanisms Of Injury, And Emerging Treatment Modalities, Daniel Morin

Senior Honors Theses

The structures of the spinal cord and vertebral column are designed to provide flexibility, while still providing ample protection for the spinal cord deep within. While it does offer remarkable protection against most routine trauma, the spinal cord is still vulnerable to high-force etiologies of trauma and may become damaged as a result. These events are referred to as primary injury. Following the initial injury, the body’s own physiological responses cause a cascade of deleterious effects, known as secondary injury. Secondary injury is a major therapeutic target in mitigating the effects of spinal cord injury (SCI), and much research is …

Effects Of Load Carriage And Surface Inclination On Linear And Non-Linear Postural Variability, Rahul Soangra, Hema Bhatt, Ehsan Rashedi

Physical Therapy Faculty Articles and Research

Understanding of inclined-work-related risk of falls and developing novel practical engineering controls for reducing this risk of falls among hilly working population remains in high demand. Standing on sloped surfaces provides a unique environment for examining the biomechanics and neural control of standing. The present investigation examined the variability of postural signals when standing on inclined surfaces and with load carriages by linear and nonlinear analysis. The purpose of this study was to determine if the sloped surface deteriorated in postural stability among healthy individuals with two distinctive kinds of load carriage methods head versus posterior load carriage. We also …