Digital Commons Network^™

Control Of Candida Albicans Metabolism And Biofilm Formation By Pseudomonas Aeruginosa Phenazines, Diana K. Morales, Nora Grahl, Chinweike Okegbe, Lars E. P. Dietrich, Nicholas J. Jacobs, Deborah A. Hogan

Dartmouth Scholarship

Candidaalbicanshasdevelopmentalprogramsthatgoverntransitionsbetweenyeastandfilamentousmorphologies and between unattached and biofilm lifestyles. Here, we report that filamentation, intercellular adherence, and biofilm develop- ment were inhibited during interactions between Candida albicans and Pseudomonas aeruginosa through the action of P. aeruginosa-produced phenazines. While phenazines are toxic to C. albicans at millimolar concentrations, we found that lower concentrations of any of three different phenazines (pyocyanin, phenazine methosulfate, and phenazine-1-carboxylate) allowed growth but affected the development of C. albicans wrinkled colony biofilms and inhibited the fungal yeast-to-filament transition. Phenazines impaired C. albicans growth on nonfermentable carbon sources and led to increased production of fer- mentation products (ethanol, glycerol, and …

What Is The Origin Of Pancreatic Adenocarcinoma?, Parviz M. Pour, K. K. Panday, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

No abstract provided.

Klf2 Is Required For Normal Mouse Cardiovascular Development, Aditi Raghunath Chiplunkar

Theses and Dissertations

Krüppel-like factor 2 (KLF2) is expressed in endothelial cells in the developing heart, particularly in areas of high shear stress, such as the atrioventricular (AV) canal. KLF2 ablation leads to myocardial thinning, high output cardiac failure and death by mouse embryonic day 14.5 (E14.5) in a mixed genetic background. This work identifies an earlier and more fundamental role for KLF2 in mouse cardiac development in FVB/N mice. FVB/N KLF2-/- embryos die earlier, by E11.5. E9.5 FVB/N KLF2-/- hearts have multiple, disorganized cell layers lining the AV cushions, the primordia of the AV valves, rather than the normal single layer. By …

The Role Of Dax-1 In Regulating Pluripotency In Mouse Embryonic Stem Cells, Anthony Torres

Master's Theses

The orphan receptor Dax-1 is highly expressed in pluripotent embryonic stem (ES) cells and shows a correlative reduction in expression as these cells differentiate. While it is known that Dax-1 is expressed in pluripotent mouse ES cells, the precise function of Dax-1 in these cells is not as well understood. Recent studies employing RNA interference (RNAi) to specifically reduce the expression of the Dax-1 gene in mouse ES cells found that upon the knock down of Dax-1, ES cells differentiated. These findings indicate that Dax-1 functions in a novel role in the maintenance of a relatively undifferentiated state in ES …

Cyclooxygenase-2 Dependent Metabolism Of 20-Hete Increases Adiposity And Adipocyte Enlargement In Mesenchymal Stem Cell-Derived Adipocytes, Dong Hyun Kim, Nitin Puri, Komal Sodhi, John R. Falck, Nader G. Abraham, Joseph I. Shapiro M.D., Michal L. Schwartzman

Biochemistry and Microbiology

Abstract 20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a product of the cytochrome P450 (CYP)-catalyzed [1] -hydroxylation of arachidonic acid, induces oxidative stress and, in clinical studies, is associated with increased body mass index (BMI) and the metabolic syndrome. This study was designed to examine the effects of exogenous 20- HETE on mesenchymal stem cell (MSC)-derived adipocytes.

The expression levels of CYP4A11 and CYP4F2 (major 20-HETE synthases in humans) in MSCs decreased during adipocyte differentiation; however, exogenous administration of 20-HETE (0.1–1 M) increased adipogenesis in a dose dependent manner in these cells ( P < 0.05). The inability of a 20-HETE analog to reproduce these effects suggested the involvement of a metabolic product of 20-HETE in mediating its pro-adipogenic effects. A cyclooxygenase (COX)-1 selective inhibitor enhanced, whereas a COX-2 selective or a dual COX-1/2 inhibitor attenuated adipogenesis induced by 20-HETE. The COX-derived metabolite of 20-HETE, 20-OH-PGE 2 , enhanced adipogenesis and lipid accumulation in MSCs. The pro-adipogenic effects of 20-HETE and 20-OH-PGE 2 resulted in the increased expression of the adipogenic regulators PPAR and -catenin in MSC-derived adipocytes. Taken together we show for the fi rst time that 20-HETE-derived COX-2-dependent 20-OH-PGE 2 enhances mature infl amed adipocyte hypertrophy in MSC undergoing adipogenic differentiation. — Kim, D. H., N. Puri, K. Sodhi, J. R. Falck, N. G. Abraham, J. Shapiro, and M. L. Schwartzman. Cyclooxygenase-2 dependent metabolism of 20-HETE increasesadiposity and adipocyte enlargement in mesenchymal stem cell-derived adipocytes.

Increased Frequency Of Micronuclei In Adults With A History Of Childhood Sexual Abuse: A Discordant Monozygotic Twin Study, Timothy P. York, Jenni Brumelle, Jane Juusola, Kenneth S. Kendler, Lindon J. Eaves, Ananda B. Amstadler, Steven H. Aggen, Kimberly H. Jones, Andrea Ferreira-Gonzalez, Colleen Jackson-Cook

Human and Molecular Genetics Publications

Background

Childhood sexual abuse (CSA) is a traumatic life event associated with an increased lifetime risk for psychopathology/morbidity. The long-term biological consequences of CSA-elicited stress on chromosomal stability in adults are unknown. The primary aim of this study was to determine if the rate of acquired chromosomal changes, measured using the cytokinesis-block micronucleus assay on stimulated peripheral blood lymphocytes, differs in adult female monozygotic twins discordant for CSA.

Methods

Monozygotic twin pairs discordant for CSA were identified from a larger population-based sample of female adult twins for whom the experience of CSA was assessed by self-report (51 individuals including a …

Identification Of Genes Potentially Regulated By Human Polynucleotide Phosphorylase (Hpnpaseold-35) Using Melanoma As A Model, Upneet K. Sokhi, Manny D. Bacolod, Santanu Dasgupta, Luni Emdad, Swadesh K. Das

Human and Molecular Genetics Publications

Human Polynucleotide Phosphorylase (hPNPaseold-35 or PNPT1) is an evolutionarily conserved 3′→5′ exoribonuclease implicated in the regulation of numerous physiological processes including maintenance of mitochondrial homeostasis, mtRNA import and aging-associated inflammation. From an RNase perspective, little is known about the RNA or miRNA species it targets for degradation or whose expression it regulates; except for c-myc and miR-221. To further elucidate the functional implications of hPNPaseold-35 in cellular physiology, we knocked-down and overexpressed hPNPaseold-35 in human melanoma cells and performed gene expression analyses to identify differentially expressed transcripts. Ingenuity Pathway Analysis indicated that knockdown of hPNPaseold-35 resulted in significant …

The Krüppel-Like Factor 2 And Krüppel-Like Factor 4 Genes Interact To Maintain Endothelial Integrity In Mouse Embryonic Vasculogenesis, Aditi R. Chiplunkar, Benjamin C. Curtis, Gabriel L. Eades, Megan S. Kane, Sean J. Fox, Jack L. Haar, Joyce A. Lloyd

Human and Molecular Genetics Publications

Background Krüppel-like Factor 2 (KLF2) plays an important role in vessel maturation during embryonic development. In adult mice, KLF2 regulates expression of the tight junction protein occludin, which may allow KLF2 to maintain vascular integrity. Adult tamoxifen-inducible Krüppel-like Factor 4 (KLF4) knockout mice have thickened arterial intima following vascular injury. The role of KLF4, and the possible overlapping functions of KLF2 and KLF4, in the developing vasculature are not well-studied.

Results Endothelial breaks are observed in a major vessel, the primary head vein (PHV), in KLF2-/-KLF4-/- embryos at E9.5. KLF2-/-KLF4-/- embryos die by E10.5, which is earlier than either single …

Krüppel-Like Factor 2 Is Required For Normal Mouse Cardiac Development, Aditi R. Chiplunkar, Tina K. Lung, Yousef Alhashem, Benjamin A. Koppenhaver, Fadi N. Salloum, Rakesh C. Kukreja, Jack L. Haar, Joyce A. Lloyd

Human and Molecular Genetics Publications

Krüppel-like factor 2 (KLF2) is expressed in endothelial cells in the developing heart, particularly in areas of high shear stress, such as the atrioventricular (AV) canal. KLF2 ablation leads to myocardial thinning, high output cardiac failure and death by mouse embryonic day 14.5 (E14.5) in a mixed genetic background. This work identifies an earlier and more fundamental role for KLF2 in mouse cardiac development in FVB/N mice. FVB/N KLF2−/− embryos die earlier, by E11.5. E9.5 FVB/N KLF2−/− hearts have multiple, disorganized cell layers lining the AV cushions, the primordia of the AV valves, rather than the normal single layer. By …

Targeted Apoptotic Effects Of Thymoquinone And Tamoxifen On Xiap Mediated Akt Regulation In Breast Cancer, Shashi Rajput, B. N. P. Kumar, Siddik Sarkar, Subhasis Das, Belal Azab, Prasanna K. Santhekadur, Swadesh K. Das, Luni Emdad, Devanand Sarkar, Paul B. Fisher, Mahitosh Mandal

Human and Molecular Genetics Publications

X-linked inhibitor of apoptosis protein (XIAP) is constitutively expressed endogenous inhibitor of apoptosis, exhibit its antiapoptotic effect by inactivating key caspases such as caspase-3, caspase-7 and caspase-9 and also play pivotal role in rendering cancer chemoresistance. Our studies showed the coadministration of TQ and TAM resulting in a substantial increase in breast cancer cell apoptosis and marked inhibition of cell growth both in vitro and in vivo. Anti-angiogenic and anti-invasive potential of TQ and TAM was assessed through in vitro studies. This novel combinatorial regimen leads to regulation of multiple cell signaling targets including inactivation of Akt and XIAP degradation. …

Transcriptional Responses Of In Vivo Praziquantel Exposure In Schistosomes Identifies A Functional Role For Calcium Signalling Pathway Member Camkii, Hong You, Donald P. Mcmanus, Wei Hu, Michael J. Smout, Paul J. Brindley, Geoffrey N. Gobert

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Treatment for clinical schistosomiasis has relied centrally on the broad spectrum anthelmintic praziquantel; however, there is limited information on its mode of action or the molecular response of the parasite. This paper presents a transcriptional and functional approach to defining the molecular responses of schistosomes to praziquantel. Differential gene expression in Schistosoma japonicum was investigated by transcriptome-wide microarray analysis of adult worms perfused from infected mice after 0.5 to 24 hours after oral administration of sub-lethal doses of praziquantel. Genes up-regulated initially in male parasites were associated with “Tegument/Muscle Repair” and “Lipid/Ion Regulation” functions and were followed by “Drug Resistance” …

Thrombospondin-1 Signaling Through Cd47 Inhibits Self-Renewal By Regulating C-Myc And Other Stem Cell Transcription Factors, Sukhbir Kaur, David R. Soto-Pantoja, Erica V. Stein, Chengyu Liu, Abdel G. Elkahloun, Michael L. Pendrak, Alina Nicolae, Satya P. Singh, Zuqin Nie, David Levens, Jeffrey S. Isenberg, David D. Roberts

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. c-Myc, Klf4, Oct4, and Sox2 expression is elevated in CD47-null endothelial cells, in several tissues of CD47- and thrombospondin-1-null mice, and in a human T cell line lacking CD47. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells and in vivo, …

Cd56negcd16+ Nk Cells Are Activated Mature Nk Cells With Impaired Effector Function During Hiv-1 Infection, Jeffrey M. Milush, Sandra López-Vergès, Vanessa A. York, Steven G. Deeks, Jeffrey N. Martin, Frederick M. Hecht, Lewis L. Lanier, Douglas F. Nixon

Microbiology, Immunology, and Tropical Medicine Faculty Publications

BACKGROUND: A subset of CD3(neg)CD56(neg)CD16⁺ Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations.

RESULTS: Using CD7 as an additional NK cell marker, we found that CD3(neg)CD56(neg)CD16⁺ cells are a heterogeneous population comprised of CD7⁺ NK cells and CD7(neg) non-classical myeloid cells. CD7⁺CD56(neg)CD16⁺ NK cells are significantly expanded in HIV-1 infection. CD7⁺CD56(neg)CD16⁺ NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to …

Clinical Manifestations Of 16 Oropharyngeal Tularemia Patients: Experience Of A Referral Hospital In The City Of Konya, Turkey, Mesut Sabri̇ Tezer, Gülteki̇n Övet, Necat Alataş, Mehmet Hakan Görgülü, Ersen Koç, Mehmet Aki̇f Öztürk

Turkish Journal of Medical Sciences

In recent years, tularemia's importance has been reemerging in Turkey. However, the majority of tularemia cases were reported in the northern cities of Turkey. In this study, we report 16 oropharyngeal tularemia patients living in rural areas of the city of Konya, which is located in the southern zone of the Central Anatolia Region of Turkey. Materials and methods: Sixteen patients (12 males, 4 females; mean age: 33.7 years, range: 10–73 years) were included in this study. All patients were admitted to our clinic for the evaluation of intractable cervical mass lesions. The diagnosis of tularemia was made after exclusion …

Impact Of Acute Sleep Deprivation On Aortic Elastic Properties In Healthy Workers, İlyas Akdemi̇r, Gökhan Altunbaş, Süleyman Ercan, Selve Arslan, Vedat Davutoğlu

Turkish Journal of Medical Sciences

People are more frequently exposed to acute sleep loss nowadays due to extensive working. Epidemiologic studies suggest that sleep deprivation (SD) increases the risk of cardiovascular events. Aortic stiffness is also shown to predict cardiovascular events, stroke, and death even in healthy populations. The association between SD and aortic stiffness remains unknown. We sought to determine the impact of acute SD on aortic elastic properties in healthy workers. Materials and methods: The study population consisted of 34 healthy medical personnel working in shifts (17 men and 17 women). Less than half of the mean daily sleep time, or less than …

Anterior Segment Morphometry And Intraocular Pressure Change After Uneventful Phacoemulsification, Tamer Takmaz, Pinar Kösekahya, Pi̇raye Zeynep Kürkçüoğlu

Turkish Journal of Medical Sciences

To evaluate the changes in anterior segment morphometry and intraocular pressure (IOP) with 3D rotating Scheimpflug camera-topography system after uneventful phacoemulsification. Materials and methods: In 56 eyes of 54 patients, anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA), and central corneal thickness (CCT) were measured with the Sirius 3D Rotating Scheimpflug camera-topography system preoperatively and 1 month after surgery. IOP was measured with applanation tonometer. The preoperative and postoperative results were compared. Results: Preoperative and postoperative anterior segment parameters were as follows: ACD 2.7 ± 0.4 and 3.5 ± 0.3 mm, ACV 143.6 ± 48.8 and …

Influence Of Exposure To Benzo[A]Pyrene On Mice Testicular Germ Cells During Spermatogenesis, Hueiwang Anna Jeng, Silvina M. Bocca

Community & Environmental Health Faculty Publications

The objective of this study was to assess the toxicological effect of exposure to benzo(a)pyrene, B[a]P, on germ cells during spermatogenesis. Mice were exposed to B[a]P at 1, 10, 50, and 100 mg/kg/day for 30 days via oral ingestion. Germ cells, including spermatogonia, spermatocytes, pachytene spermatocytes, and round spermatids, were recovered from testes of mice exposed to B[a]P, while mature spermatozoa were isolated from vas deferens. Reproductive organs were collected and weighed. Apoptotic response of germ cells and mature spermatozoa were qualified using the terminal deoxynucleotidyl transferase mediated deoxy-UTP nick end labeling (TUNEL) assay. B[a]P exposure at

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 …

Pyrazinamide Monoresistance In Clinical Isolates, Nezaket Kalir, Ayşe Aydan Özkütük, Nuran Esen, Nuri̇ Özkütük

Turkish Journal of Medical Sciences

To determine pyrazinamide (PZA) monoresistance in clinical isolates of Mycobacterium tuberculosis complex (MTBC) isolated in hospitals in and around İzmir. Materials and methods: The study was performed between 2004 and 2009 with 150 streptomycin, isoniazid, rifampicin, and ethambutol susceptible MTBC clinical strains isolated in the university hospitals of İzmir and Manisa. The PZA susceptibility of the isolates was determined by the BACTEC 460 TB test. Results: The results indicated that resistance to PZA was present in 5 (3.3%) of the 150 MTBC isolates susceptible to all primary drugs except PZA. Conclusion: It is not essential to perform PZA susceptibility tests …

Gender Differences In The Development Of Uremic Cardiomyopathy Following Partial Nephrectomy: Role Of Progesterone, Christopher A. Drummond, George Buddny, Steven T. Haller, Jiang Liu, Yanling Yan, Zijian Xie, Deepak Malhotra, Joseph I. Shapiro Md, Jiang Tian

Biochemistry and Microbiology

Gender difference has been suggested as a risk factor for developing cardiovascular and renal diseases in humans and experimental animals. As a major sex hormone, progesterone was reported to compete with cardiotonic steroid binding to Na/K-ATPase. Our previous publication demonstrated that cardiotonic steroids (e.g., marinobufagenin) play an important role in the development of experimental uremic cardiomyopathy. We also observed that the putative mineralocorticoid antagonists, spironolactone and its major metabolite canrenone, antagonize binding of cardiotonic steroids to Na/K-ATPase in a competitive manner and also ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy. In the following studies, we noted that progesterone displayed …

Habituation Of Reflexive And Motivated Behavior In Mice With Deficient Bk Channel Function., Marei Typlt, Magdalena Mirkowski, Erin Azzopardi, Peter Ruth, Peter K D Pilz, Susanne Schmid

Brain and Mind Institute Researchers' Publications

Habituation is considered the most basic form of learning. It describes the decrease of a behavioral response to a repeated non-threatening sensory stimulus and therefore provides an important sensory filtering mechanism. While some neuronal pathways mediating habituation are well described, underlying cellular/molecular mechanisms are not yet fully understood. In general, there is an agreement that short-term and long-term habituation are based on different mechanisms. Historically, a distinction has also been made between habituation of motivated versus reflexive behavior. In recent studies in invertebrates the large conductance voltage- and calcium-activated potassium (BK) channel has been implicated to be a key player …

White Matter Integrity And Age Related Differences In Reaction Time Components, Yiqin Yang

Wayne State University Dissertations

Reduced speed in information processing is a well-documented phenomenon associated with advanced aging. Age-related deterioration in white matter integrity might play a role in age-related increase in reaction time (RT). However, the association between microstructural differences in particular white matter regions or tracts with RT is unclear. Decomposing RT into parts might be a better way to understand the relationship due to multiple processes involved in RT. In a lifespan sample of 90 healthy normotensive participants, this study examined the association between RT components derived from the Ratcliff diffusion model with age related difference in DTI indices of a wide …

Androgen Receptor-Target Genes In African American Prostate Cancer Disparities, Bi-Dar Wang, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas W. Jarrett, Harold A. Frazier, Steven R. Patierno, Norman H. Lee

Pharmacology and Physiology Faculty Publications

The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter …

Nutrition Political Economy, Pakistan. Province Report: Punjab, Shehla Zaidi, Zulfiqar Ahmed Bhutta, Akhtar Rashid, Gul Nawaz, Noorya Hayat, Shandara Khan Mohmand, Andres Mejia Acosta

Epidemiology and Biostatistics Section

No abstract provided.

The Political Economy Of Undernutrition National Report: Pakistan, Shehla Zaidi, Zulfiqar Ahmed Bhutta, Shandana Khan Mohmand, Andres Mejia Acosta

Epidemiology and Biostatistics Section

No abstract provided.

Strengthening Vendor Standards In The Supplemental Nutrition Assistance Program: Are Healthier Foods Within Reach?, Mary E. Kennelly, Roni Neff, Lainie Rutkow

Journal of Health Care Law and Policy

No abstract provided.

Copper Triflate-Mediated Synthesis Of 1,3,5-Triarylpyrazoles In [Bmim][Pf6] Ionic Liquid And Evaluation Of Their Anticancer Activities, V. Kameshwara Rao, Rakesh Tiwari, Bhupender S. Chhikara, Amir Nasrolahi Shirazi, Keykavous Parang, Anil Kumar

Pharmacy Faculty Articles and Research

A simple, efficient, and environment friendly protocol for the synthesis of 1,3,5-triarylpyrazoles and 1,3,5-triarylpyrazolines in [bmim][PF6] ionic liquid mediated by Cu(OTf)2 is described. The reaction protocol gave 1,3,5-triarylpyrazoles in good to high yields (71–84%) via a one-pot addition–cyclocondensation between chalcones and arylhydrazines, and oxidative aromatization without the requirement for an additional oxidizing reagent. The catalyst can be reused for up to four cycles without much loss in the catalytic activity. The pyrazoles (4a–o) and pyrazolines (3a–n) were evaluated for their antiproliferative activity in SK-OV-3, HT-29, and HeLa human cancer cells lines. Among all the compounds, 3b inhibited cell proliferation of …

Clade C Hiv-1 Isolates Circulating In Southern Africa Exhibit A Greater Frequency Of Dicysteine Motif-Containing Tat Variants Than Those In Southeast Asia And Cause Increased Neurovirulence, Vasudev R. Rao, Ujjwal Neogi, Joshua S, Talboom, Ligia Padilla, Mustafizur Rahman, Cari Fritz-French, Sandra Gonzalez-Ramirez, Anjali Verma, Charles Wood, Ruth M. Ruprecht, Udaykumar Ranga, Tasnim Azim, Vinayaka R. Prasad

Nebraska Center for Virology: Faculty Publications

Background: HIV-1 Clade C (Subtype C; HIV-1C) is responsible for greater than 50% of infections worldwide. Unlike clade B HIV-1 (Subtype B; HIV-1B), which is known to cause HIV associated dementia (HAD) in approximately 15% to 30% of the infected individuals, HIV-1C has been linked with lower prevalence of HAD (0 to 6%) in India and Ethiopia. However, recent studies report a higher prevalence of HAD in South Africa, Zambia and Botswana, where HIV-1C infections predominate. Therefore, we examined whether Southern African HIV-1C is genetically distinct and investigated its neurovirulence. HIV-1 Tat protein is a viral determinant of neurocognitive dysfunction. …

Heterogeneity In Platelet Exocytosis, Deepa Jonnalagadda

Theses and Dissertations--Molecular and Cellular Biochemistry

Platelet exocytosis is essential for hemostasis and for many of its sequelae. Platelets release numerous bioactive molecules stored in their granules enabling them to exert a wide range of effects on the vascular microenvironment. Are these granule cargo released thematically in a context-specific pattern or via a stochastic, kinetically-controlled process? My work describes platelet exocytosis using a systematic examination of platelet secretion kinetics. Platelets were stimulated for increasing times with different agonists (i.e. thrombin, PAR1-agonist, PAR4-agonist, and convulxin) and micro-ELISA arrays were used to quantify the release of 28 distinct α-granule cargo molecules. Agonist potency directly correlated with the speed …

Investigating Therapeutic Options For Lafora Disease Using Structural Biology And Translational Methods, Amanda R. Sherwood

Theses and Dissertations--Molecular and Cellular Biochemistry

Lafora disease (LD) is a rare yet invariably fatal form of epilepsy characterized by progressive degeneration of the central nervous and motor systems and accumulation of insoluble glucans within cells. LD results from mutation of either the phosphatase laforin, an enzyme that dephosphorylates cellular glycogen, or the E3 ubiquitin ligase malin, the binding partner of laforin. Currently, there are no therapeutic options for LD, or reported methods by which the specific activity of glucan phosphatases such as laforin can be easily measured. To facilitate our translational studies, we developed an assay with which the glucan phosphatase activity of laforin as …