Medicine and Health Sciences Commons^™

Medical Literary Messenger (Vol. 1, No. 1, Fall 2013)

Medical Literary Messenger

Before the Laying On / Robert Eastwood -- When the Medical Student Teaches / M. Hoya -- Lesion / Stacy R. Nigliazzo -- The Way Back To Childhood / Christopher Woods -- The Uselessness of Our Hands / Sean Prentiss -- Never Forget You Work in Oncology / Lorraine Waltz -- Going Down / Thom Schwarz -- Past Curfew, At a Time Past (1964) / Barbara A. Carrington -- Approaching Shadows / Christopher Woods -- Virginia Nature / Hannah Kim -- Is Six Always Six / Ken Staley -- Cheers (Desvenlafaxine) / Nick D’Annunzio Jones -- Arm Dissection, MCV Gross …

Biological Characterization Of 3-(2-Amino-Ethyl)-5-[3-(4-Butoxyl-Phenyl)-Propylidene]-Thiazolidine-2,4-Dione (K145) As A Selective Sphingosine Kinase-2 Inhibitor And Anticancer Agent, Kai Liu, Tai L. Guo, Nitai C. Hait, Jeremy Allegood, Hardik I. Parikh, Wenfang Xu, Glen E. Kellogg, Steven Grant, Sarah Spiegel, Shijun Zhang

Medicinal Chemistry Publications

In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione(K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly …

Ethnicity And Gender Comparisons Of Health Consequences In Adults With Alcohol Dependence, Karen G. Chartier, Michie N. Hesselbrock, Victor M. Hesselbrock

Social Work Publications

The moderating effects of ethnicity and gender on factors associated with physical health consequences in adults with alcohol dependence was examined using data from the 2001–2002 U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Black and White respondents with a lifetime diagnosis of DSM-IV alcohol dependence were selected for the study (n = 3,852). A multiple-group structural equation model tested ethnicity, gender, and intervening variables as predictors of physical health status in alcohol dependent men and women. Study findings offer implications for clinical practice with alcohol dependent individuals by identifying likely target groups and problems for intervention.

Suicidal Risk Factors Of Recurrent Major Depression In Han Chinese Women, Yuzhang Zhu, Hongni Zhang, Shenxun Shi, Jingfang Gao, Youhui Li, Ming Tao, Kerang Zhang, Xumei Wang, Chengge Gao, Lijun Yang, Kan Li, Jiangguo Shi, Gang Wang, Lanfen Liu, Jinbei Zhang, Bo Du, Guoqing Jiang, Jianhua Shen, Zhen Zhang, Wei Liang, Jing Sun, Jian Hu, Tiebang Liu, Xueyi Wang, Guodong Miao, Huaqing Meng, Yi Li, Chunmei Hu, Yi Li, Guoping Huang, Gongying Li, Baowei Ha, Hong Deng, Qiyi Mei, Hui Zhong, Shugui Gao, Hong Sang, Yutang Zhang, Xiang Fang, Fengyu Yu, Donglin Yang, Tieqiao Liu, Yunchun Chen, Xiaohong Hong, Wenyuan Wu, Guibing Chen, Min Cai, Yan Song, Jiyang Pan, Jicheng Dong, Runde Pan, Wei Zhang, Zhenming Shen, Zhengrong Liu, Danhua Gu, Xiaoping Wang, Xiaojuan Liu, Qiwen Zhang, Yihan Li, Yiping Chen, Kenneth S. Kendler, Jonathan Flint, Ying Liu

Psychiatry Publications

The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of …

Clinical Features Of Patients With Dysthymia In A Large Cohort Of Han Chinese Women With Recurrent Major Depression, Wenqing Wu, Zhoubing Wang, Yan Wei, Guanghua Zhang, Shenxun Shi, Jingfang Gao, Youhui Li, Ming Tao, Kerang Zhang, Xumei Wang, Chengge Gao, Lijun Yang, Kan Li, Jianguo Shi, Gang Wang, Lanfen Liu, Jinbei Zhang, Bo Du, Guoqing Jiang, Jianhua Shen, Ying Liu, Wei Liang, Jing Sun, Jian Hu, Tiebang Liu, Xueyi Wang, Guodong Miao, Huaqing Meng, Yi Li, Guoping Huang, Gongying Li, Baowei Ha, Hong Deng, Qiyi Mei, Hui Zhong, Shugui Gao, Hong Sang, Yutang Zhang, Xiang Fang, Fengyu Yu, Donglin Yang, Tieqiao Liu, Yunchun Chen, Xiaohong Hong, Wenyuan Wu, Guibing Chen, Min Cai, Yan Song, Jiyang Pan, Jicheng Dong, Runde Pan, Wei Zhang, Zhenming Shen, Zhengrong Liu, Danhua Gu, Xiaoping Wang, Xiaojuan Liu, Qiwen Zhang, Yihan Li, Yiping Chen, Kenneth S. Kendler, Jonathan Flint, Zhen Zhang

Psychiatry Publications

Background

Dysthymia is a form of chronic mild depression that has a complex relationship with major depressive disorder (MDD). Here we investigate the role of environmental risk factors, including stressful life events and parenting style, in patients with both MDD and dysthymia. We ask whether these risk factors act in the same way in MDD with and without dysthymia.

Results

We examined the clinical features in 5,950 Han Chinese women with MDD between 30–60 years of age across China. We confirmed earlier results by replicating prior analyses in 3,950 new MDD cases. There were no significant differences between the two …

Genotype-Based Ancestral Background Consistently Predicts Efficacy And Side Effects Across Treatments In Catie And Star*D, Daniel E. Adkins, Renan P. Souza, Karolina A. Aberg, Shaunna L. Clark, Joseph L. Mcclay, Patrick F. Sullivan, Edwin J. C. G. Van Den Oord

Biomarker Research and Personalized Medicine Publications

Only a subset of patients will typically respond to any given prescribed drug. The time it takes clinicians to declare a treatment ineffective leaves the patient in an impaired state and at unnecessary risk for adverse drug effects. Thus, diagnostic tests robustly predicting the most effective and safe medication for each patient prior to starting pharmacotherapy would have tremendous clinical value. In this article, we evaluated the use of genetic markers to estimate ancestry as a predictive component of such diagnostic tests. We first estimated each patient’s unique mosaic of ancestral backgrounds using genome-wide SNP data collected in the Clinical …

Lipopolysaccharide-Induced Neuronal Activation In The Paraventricular And Dorsomedial Hypothalamus Depends On Ambient Temperature, Samuel P. Wanner, Kyoko Yoshida, Vladimir A. Kulchitsky, Andrei I. Ivanov, Kazuyuki Kanosue, Andrej A. Romanovsky

Human and Molecular Genetics Publications

Systemic inflammatory response syndrome is associated with either fever or hypothermia, but the mechanisms responsible for switching from one to the other are unknown. In experimental animals, systemic inflammation is often induced by bacterial lipopolysaccharide (LPS). To identify the diencephalic and brainstem structures involved in the fever-hypothermia switch, we studied the expression of c-Fos protein, a marker of neuronal activation, in rats treated with the same high dose of LPS (0.5 mg/kg, intravenously) either in a thermoneutral (30°C) or cool (24°C) environment. At 30°C, LPS caused fever; at 24°C, the same dose caused profound hypothermia. Both fever and hypothermia were …

Microglial Activation Decreases Retention Of The Protease Inhibitor Saquinavir: Implications For Hiv Treatment, Shannon Dallas, Michelle L. Block, Deborah M. Thompson, Marcelo G. Bonini, Patrick T. Ronaldson, Reina Bendayan, David S. Miller

Anatomy and Neurobiology Publications

Background

Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide.

Methods

To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent …

Cyanine 5.5 Conjugated Nanobubbles As A Tumor Selective Contrast Agent For Dual Ultrasound-Fluorescence Imaging In A Mouse Model, Liyi Mai, Anna Yao, Jing Li, Qiong Wei, Ming Yuchi, Xiaoling He, Mingyue Ding, Qibing Zhou

Medicinal Chemistry Publications

Nanobubbles and microbubbles are non-invasive ultrasound imaging contrast agents that may potentially enhance diagnosis of tumors. However, to date, both nanobubbles and microbubbles display poor in vivo tumor-selectivity over non-targeted organs such as liver. We report here cyanine 5.5 conjugated nanobubbles (cy5.5-nanobubbles) of a biocompatible chitosan–vitamin C lipid system as a dual ultrasound-fluorescence contrast agent that achieved tumor-selective imaging in a mouse tumor model. Cy5.5-nanobubble suspension contained single bubble spheres and clusters of bubble spheres with the size ranging between 400–800 nm. In the in vivo mouse study, enhancement of ultrasound signals at tumor site was found to persist over …

Virginia Dental Journal (Vol. 90, No. 2, 2013)

Virginia Dental Journal

No abstract provided.

A Networks Method For Ranking Microrna Dysregulation In Cancer, William Budd, Sarah Seashols, Danielle Weaver, Cyriac Joseph, Zendra E. Zehner

Biochemistry and Molecular Biology Publications

Background

Despite the lack of agreement on their exact roles, it is known that miRNAs contribute to cancer progression. Many studies utilize methods to detect differential regulation of miRNA expression. It is prohibitively expensive to examine all potentially dysregulated miRNAs and traditionally, researchers have focused their efforts on the most extremely dysregulated miRNAs. These methods may overlook the contribution of less differentially expressed but more functionally relevant miRNAs. The purpose of this study was to outline a method that not only utilizes differential expression but ranks miRNAs based on the functional relevance of their targets. This work uses a networks …

Microbes Bind Complement Inhibitor Factor H Via A Common Site, T. Meri, H. Amdahl, M. J. Lehtinen, S. Hyvarinen, J. V. Mcdowell, A. Bhattachargee, S. Meri, R. Marconi, A. Goldman, T. S. Jokiranta

VCU Health Publications

To cause infections microbes need to evade host defense systems, one of these being the evolutionarily old and important arm of innate immunity, the alternative pathway of complement. It can attack all kinds of targets and is tightly controlled in plasma and on host cells by plasma complement regulator factor H (FH). FH binds simultaneously to host cell surface structures such as heparin or glycosaminoglycans via domain 20 and to the main complement opsonin C3b via domain 19. Many pathogenic microbes protect themselves from complement by recruiting host FH. We analyzed how and why different microbes bind FH via domains …

Isozyme-Specific Ligands For O-Acetylserine Sulfhydrylase, A Novel Antibiotic Target, Francesca Spyrakis, Ratna Singh, Pietro Cozzini, Enea Salsi, Paolo Felici, Samanta Raboni, Paolo Benedetti, Gabriele Cruciani, Glen E. Kellogg, Paul F. Cook, Andrea Mozzarelli

Medicinal Chemistry Publications

The last step of cysteine biosynthesis in bacteria and plants is catalyzed by O-acetylserine sulfhydrylase. In bacteria, two isozymes, O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, have been identified that share similar binding sites, although the respective specific functions are still debated. O-acetylserine sulfhydrylase plays a key role in the adaptation of bacteria to the host environment, in the defense mechanisms to oxidative stress and in antibiotic resistance. Because mammals synthesize cysteine from methionine and lackO-acetylserine sulfhydrylase, the enzyme is a potential target for antimicrobials. With this aim, we first identified potential inhibitors of the two …

Fyn-Dependent Gene Networks In Acute Ethanol Sensitivity, Sean P. Farris, Michael F. Miles

Pharmacology and Toxicology Publications

Studies in humans and animal models document that acute behavioral responses to ethanol are predisposing factor for the risk of long-term drinking behavior. Prior microarray data from our laboratory document strain- and brain region-specific variation in gene expression profile responses to acute ethanol that may be underlying regulators of ethanol behavioral phenotypes. The non-receptor tyrosine kinase Fyn has previously been mechanistically implicated in the sedative-hypnotic response to acute ethanol. To further understand how Fyn may modulate ethanol behaviors, we used whole-genome expression profiling. We characterized basal and acute ethanol-evoked (3 g/kg) gene expression patterns in nucleus accumbens (NAC), prefrontal cortex …

Contribution Of Nadph Oxidase To Membrane Cd38 Internalization And Activation In Coronary Arterial Myocytes, Ming Xu, Xiao-Xue Li, Joseph K. Ritter, Justine M. Abais, Yang Zhang, Pin-Lan Li

Pharmacology and Toxicology Publications

The CD38-ADP-ribosylcyclase-mediated Ca2+ signaling pathway importantly contributes to the vasomotor response in different arteries. Although there is evidence indicating that the activation of CD38-ADP-ribosylcyclase is associated with CD38 internalization, the molecular mechanism mediating CD38 internalization and consequent activation in response to a variety of physiological and pathological stimuli remains poorly understood. Recent studies have shown that CD38 may sense redox signals and is thereby activated to produce cellular response and that the NADPH oxidase isoform, NOX1, is a major resource to produce superoxide (O2·−) in coronary arterial myocytes (CAMs) in response to muscarinic receptor agonist, which uses CD38-ADP-ribosylcyclase …

Association Study Of 167 Candidate Genes For Schizophrenia Selected By A Multi-Domain Evidence-Based Prioritization Algorithm And Neurodevelopmental Hypothesis, Zhongming Zhao, Bradley T. Webb, Peilin Jia, T. Bernard Bigdeli, Brion S. Maher, Edwin Van Den Oord, Sarah Bergen, Richard L. Amdur, Francis A. O'Neill, Dermot Walsh, Dawn L. Thiselton, Xianging Chen, Carlos N. Pato, The International Schizophrenia Consortium, Brien P. Riley, Kenneth S. Kendler, Ayman H. Fanous

Psychiatry Publications

Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene …

Association Testing Strategy For Data From Dense Marker Panels, Donghyung Lee, Silviu-Alin Bacanu

Psychiatry Publications

Genome wide association studies have been usually analyzed in a univariate manner. The commonly used univariate tests have one degree of freedom and assume an additive mode of inheritance. The experiment-wise significance of these univariate statistics is obtained by adjusting for multiple testing. Next generation sequencing studies, which assay 10-20 million variants, are beginning to come online. For these studies, the strategy of additive univariate testing and multiple testing adjustment is likely to result in a loss of power due to (1) the substantial multiple testing burden and (2) the possibility of a non-additive causal mode of inheritance. To reduce …

Methylpca: A Toolkit To Control For Confounders In Methylome-Wide Association Studies, Wenan Chen, Guimin Gao, Srilaxmi Nerella, Christina M. Hultman, Patrik K.E. Magnusson, Patrick F. Sullivan, Karolina A. Aberg, Edwin J.C.G. Van Den Oord

Biostatistics Publications

Background

In methylome-wide association studies (MWAS) there are many possible differences between cases and controls (e.g. related to life style, diet, and medication use) that may affect the methylome and produce false positive findings. An effective approach to control for these confounders is to first capture the major sources of variation in the methylation data and then regress out these components in the association analyses. This approach is, however, computationally very challenging due to the extremely large number of methylation sites in the human genome.

Result

We introduce MethylPCA that is specifically designed to control for potential confounders in studies …

An Inferential Framework For Biological Network Hypothesis Tests, Phillip D. Yates, Nitai D. Mukhopadhyay

Biostatistics Publications

Background

Networks are ubiquitous in modern cell biology and physiology. A large literature exists for inferring/proposing biological pathways/networks using statistical or machine learning algorithms. Despite these advances a formal testing procedure for analyzing network-level observations is in need of further development. Comparing the behaviour of a pharmacologically altered pathway to its canonical form is an example of a salient one-sample comparison. Locating which pathways differentiate disease from no-disease phenotype may be recast as a two-sample network inference problem.

Results

We outline an inferential method for performing one- and two-sample hypothesis tests where the sampling unit is a network and the …

Individual, Environmental, And Meteorological Predictors Of Daily Personal Ultraviolet Radiation Exposure Measurements In A United States Cohort Study, Elizabeth K. Cahoon, David C. Wheeler, Michael G. Kimlin, Richard K. Kwok, Bruce H. Alexander, Mark P. Little, Martha S. Linet, Daryl M. Freedman

Biostatistics Publications

Background

Individual exposure to ultraviolet radiation (UVR) is challenging to measure, particularly for diseases with substantial latency periods between first exposure and diagnosis of outcome, such as cancer. To guide the choice of surrogates for long-term UVR exposure in epidemiologic studies, we assessed how well stable sun-related individual characteristics and environmental/meteorological factors predicted daily personal UVR exposure measurements.

Methods

We evaluated 123 United States Radiologic Technologists subjects who wore personal UVR dosimeters for 8 hours daily for up to 7 days (N = 837 days). Potential predictors of personal UVR derived from a self-administered questionnaire, and public databases that provided …

A Cohort Study Evaluation Of Maternal Pcb Exposure Related To Time To Pregnancy In Daughters, Chris Gennings, Caroline Carrico, Pam Factor-Litvak, Nickilou Krigbaum, Piera M. Cirillo, Barbara Cohn

Biostatistics Publications

Background Polychlorinated biphenyls (PCBs) remain ubiquitous environmental contaminants. Developmental exposures are suspected to impact reproduction. Analysis of mixtures of PCBs may be problematic as components have a complex correlation structure, and along with limited sample sizes, standard regression strategies are problematic. We compared the results of a novel, empirical method to those based on categorization of PCB compounds by (1) hypothesized biological activity previously proposed and widely applied, and (2) degree of ortho- substitution (mono, di, tri), in a study of the relation of maternal serum PCBs and daughter’s time to pregnancy.

Methods We measured PCBs in maternal serum samples …

Physician Trainees’ Decision Making And Information Processing: Choice Size And Medicare Part D, Andrew J. Barnes, Yaniv Hanoch, Melissa Martynenko, Stacey Wood, Thomas Rice, Alex D. Federman

Health Policy Publications

Many patients expect their doctor to help them choose a Medicare prescription drug plan. Whether the size of the choice set affects clinicians’ decision processes and strategy selection, and the quality of their choice, as it does their older patients, is an important question with serious financial consequences. Seventy medical students and internal medicine residents completed a within-subject design using Mouselab, a computer program that allows the information-acquisition process to be examined. We examined highly numerate physician trainees’ decision processes, strategy, and their ability to pick the cheapest drug plan—as price was deemed the most important factor in Medicare beneficiaries’ …

Associations Of Occupational Attributes And Excessive Drinking, Andrew J. Barnes, Frederick J. Zimmerman

Health Policy Publications

Numerous work-related drinking mechanisms have been posited and, oftentimes, examined in isolation. We combined data from over 100 occupational attributes into several factors and tested the association of these factors with measures of alcohol use. We used the NLSY79 2006 wave, a U.S. representative sample of 6,426 workers ages 41 to 49 and the 2006 Occupational Information Network database (O*NET), a nationally representative sample of nearly 1,000 occupations. We conducted exploratory factor analysis on 119 occupational attributes and found three independent workplace characteristics – physical demands, job autonomy, and social engagement - explained the majority of the variation. We then …

Relationship Between Untreated Dental Caries And Weight And Height Of 6- To 12-Year-Old Primary School Children In Bangladesh, Masuma Pervin Mishu, Martin Hobdell, Mahfujul Haq Khan, Richard M. Hubbard, Wael Sabbah

Dental Public Health and Policy Publications

Background. Children in low-income developing countries are likely to suffer from undergrowth. Dental caries is another common problem in these countries. Aim. To examine the association between untreated dental caries in primary and permanent teeth with age-adjusted height and weight among 6–12-year-old children in Bangladesh. Design. Social, behavioural, and clinical data were collected from 1699 children in nine different randomly selected primary schools in socially deprived areas of Bangladesh. The associations of age-adjusted weight and height and being underweight with dental caries were examined adjusting for sex, area of residence, socioeconomic position, skipping meals, tooth cleaning, and …

Virginia Dental Journal (Vol. 90, No. 3, 2013)

Virginia Dental Journal

No abstract provided.

Mexican Health Paradox, Merit George

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Despite the broad array of research that exists on the Hispanic health paradox, no single explanation has been marked as the dominant reason for the disparities in life expectancy that exist between Mexican Americans and other Hispanic and non-Hispanic ethnic groups. This indicates that researchers must adopt a more open perspective that examines the influence of multidimensional factors that integrate culture, religious tradition, and lifestyle. The purpose of the current study is to 1) readily define the paradox and provide a thorough review of existing literature on the topic; 2) suggest a transition from exploring statistical explanations of the paradox …

Factors That Lead To The Immunotherapy Gap In Multiple Sclerosis Testing, Karthika Solai

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Multiple sclerosis is a disease that affects the central nervous system. Most doctors and scientists believe that it is an autoimmune disease. Simply put, the immune system attacks the nerves in a person’s body, thereby causing myelin damage, inflammation, and neurodegeneration. The plaque that then builds up on the nerves is scar tissue created when the wounds made by the immune system heal. It is this plaque that inhibits communication between the axons in the body and causes the symptoms of MS, which includes problems with movement, pain, vision problems, trouble swallowing, fatigue, and heat sensitivity (Baker et al., 2011, …

Distinctive G Protein-Dependent Signaling By Protease-Activated Receptor 2 (Par2) In Smooth Muscle: Feedback Inhibition Of Rhoa By Camp-Independent Pka, Wimolpak Sriwai, Sunila Mahavadi, Othman Al-Shboul, John R. Grider, Karnam S. Murthy

Physiology and Biophysics Publications and Presentations

We examined expression of protease-activated receptors 2 (PAR2) and characterized their signaling pathways in rabbit gastric muscle cells. The PAR2 activating peptide SLIGRL (PAR2-AP) stimulated Gq, G13, Gi1, PI hydrolysis, and Rho kinase activity, and inhibited cAMP formation. Stimulation of PI hydrolysis was partly inhibited in cells expressing PAR2 siRNA, Gaq or Gai minigene and in cells treated with pertussis toxin, and augmented by expression of dominant negative regulator of G protein signaling (RGS4(N88S)). Stimulation of Rho kinase activity was abolished by PAR-2 or Ga13 siRNA, and by Ga13 minigene. PAR2-AP induced a biphasic contraction; initial contraction was …

Building Kcnq1/Kcne1 Channel Models And Probing Their Interactions By Molecular-Dynamics Simulations, Yu Xu, Yuhong Wang, Xuan-Yu Meng, Mei Zhang, Min Jiang, Meng Cui, Gea-Ny Tseng

Physiology and Biophysics Publications and Presentations

The slow delayed rectifier (I_Ks) channel is composed of KCNQ1 (pore-forming) and KCNE1 (auxiliary) subunits, and functions as a repolarization reserve in the human heart. Design of I_Ks-targeting anti-arrhythmic drugs requires detailed three-dimensional structures of the KCNQ1/KCNE1 complex, a task made possible by Kv channel crystal structures (templates for KCNQ1 homology-modeling) and KCNE1 NMR structures. Our goal was to build KCNQ1/KCNE1 models and extract mechanistic information about their interactions by molecular-dynamics simulations in an explicit lipid/solvent environment. We validated our models by confirming two sets of model-generated predictions that were independent from the spatial restraints used …

S3-S4 Linker Length Modulates The Relaxed State Of A Voltage-Gated Potassium Channel, Michael F. Priest, Jérôme J. Lacroix, Carlos A. Villalba-Galea, Fancisco Bezanilla

Physiology and Biophysics Publications and Presentations

Abstract

Voltage-sensing domains (VSDs) are membrane protein modules found in ion channels and enzymes that are responsible for a large number of fundamental biological tasks, such as neuronal electrical activity. The VSDs switch from a resting to an active conformation upon membrane depolarization, altering the activity of the protein in response to voltage changes. Interestingly, numerous studies describe the existence of a third distinct state, called the relaxed state, also populated at positive potentials. Although some physiological roles for the relaxed state have been suggested, little is known about the molecular determinants responsible for the development and modulation of VSD …