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Anti-Inflammatory And Cardioprotective Effects Of Tadalafil In Diabetic Mice, Amit Varma, Anindita Das, Nicholas N. Hoke, David E. Durrant, Fadi N. Salloum, Rakesh C. Kukreja

Internal Medicine Publications

Background

Insulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic inflammation and damages the vascular endothelium. Phosphodiesterase-5 inhibitors restore NO signaling and may reduce circulating inflammatory markers, and improve metabolic parameters through a number of mechanisms. We hypothesized that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice.

Methods

Twenty leptin receptor null (db/db) mice underwent treatment with TAD (1 mg/Kg) or 10% DMSO for 28 days. Body weight and fasting …

Acrolein Induces Endoplasmic Reticulum Stress And Causes Airspace Enlargement, Yoshiaki Kitaguchi, Laimute Taraseviciene-Stewart, Masayuki Hanaoka, Ramesh Natarajan, Donatas Kraskauskas, Norbert F. Voelkel

Internal Medicine Publications

Background

Given the relative abundance and toxic potential of acrolein in inhaled cigarette smoke, it is surprising how little is known about the pulmonary and systemic effects of acrolein. Here we test the hypothesis whether systemic administration of acrolein could cause endoplasmic reticulum (ER) stress, and lung cell apoptosis, leading to the enlargement of the alveolar air spaces in rats.

Methods

Acute and chronic effects of intraperitoneally administered acrolein were tested. Mean alveolar airspace area was measured by using light microscopy and imaging system software. TUNEL staining and immunohistochemistry (IHC) for active caspase 3 and Western blot analysis for active …

Copper Deficiency Induced Emphysema Is Associated With Focal Adhesion Kinase Inactivation, Shiro Mizuno, Masanori Yasuo, Harm J. Bogaard, Donatas Kraskauskas, Aysar A. Alhussini, Jose Gomez-Arroyo, Daniela Farkas, Laszlo Farkas, Norbert F. Voelkel

Internal Medicine Publications

Background

Copper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1α) dependent vascular endothelial growth factor (VEGF) expression, and is also required for the activity of lysyl oxidase (LOX) to effect matrix protein cross-linking. Cell detachment from the extracellular matrix can induce apoptosis (anoikis) via inactivation of focal adhesion kinase (FAK).

Methodology

To examine the molecular mechanisms whereby copper depletion causes the destruction of the normal alveolar architecture via anoikis, Male Sprague-Dawley rats were fed a copper deficient diet for 6 weeks while being treated with the copper chelator, tetrathiomolybdate. Other groups of rats were treated with the …

From Cox-2 Inhibitor Nimesulide To Potent Anti-Cancer Agent: Synthesis, In Vitro, In Vivo And Pharmacokinetic Evaluation, Bo Zhong, Xiaohan Cai, Snigdha Chennamaneni, Xin Yi, Lili Liu, John J. Pink, Afshin Dowlati, Yan Xu, Aimin Zhou, Bin Su

Chemistry Faculty Publications

Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure–function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC50s around 100 nM–200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC50s around 100 nM–500 nM. …

Reverse Orientalism: Laila Halaby's Once In A Promised Land, Amanda Lloyd

ETD Archive

Laila Halaby's Once in a Promised Land (2007) offers instructive insight into the struggles facing Arab Americans in post 9/11 America. Specifically, Halaby inverts the Western gaze upon the Arab world in doing so, she represents an America that is conspiratorial and inundated with religious zealotry. After 9/11, Halaby's American characters become increasingly intolerant and distrustful of Arabs and Islamic cultures. Halaby, then, portrays intolerant and xenophobic American characters overwrought with suspicion and paranoia and reveals a post 9/11 America that is rife with anti-Arab racism. Halaby also suggests that the pervasive American perception of a world distinctly divided between …

Controlled Delivery Of Tgf-Ss1 From Plga Nanoparticles, Pratik K. Vaidya

ETD Archive

Abdominal aortic aneurysms (AAAs) typically manifest as localized wall weakening and dilation of the infrarenal aorta, which grows gradually, and ultimately leads to fatal rupture. It is caused due to overexpression of proteolytic enzymes (matrix metalloproteases or MMPs) resulting into disruption of tissue structure, especially elastic matrix, which cannot be regenerated by adult vascular cells. On account of post-operative complications associated with their surgical repair, there is a critical need for developing non-surgical strategies for slowing and even regressing AAA growth. Recent studies in our laboratory have demonstrated that 1 ng/mL of transforming growth factor-β1 (TGF-β1) enhances regenerative repair by …

Elastogenic Characterization Of Rat Bm-Msc-Derived Smcs Towards Use In Soft Tissue Engineering, Sahithya Wintrich

ETD Archive

No abstract provided.

Adenovirus-36 Is Associated With Obesity In Children And Adults In Sweden As Determined By Rapid Elisa, Malin Almgren, Richard Atkinson, Jia He, Agenta Hilding, Emilia Hagman, Alicia Wolk, Anders Thorell, Claude Marcus, Erik Naslund, Claes-Goren Ostenson, Martin Schalling, Catherina Lavebratt

Pathology Publications

Background

Experimental and natural human adenovirus-36 (Adv36) infection of multiple animal species results in obesity through increasing adipogenesis and lipid accumulation in adipocytes. Presence of Adv36 antibodies detected by serum neutralization assay has previously been associated with obesity in children and adults living in the USA, South Korea and Italy, whereas no association with adult obesity was detected in Belgium/the Netherlands nor among USA military personnel. Adv36 infection has also been shown to reduce blood lipid levels, increase glucose uptake by adipose tissue and skeletal muscle biopsies, and to associate with improved glycemic control in non-diabetic individuals.

Principal Findings

Using …

Lipid Environment Modulates The Development Of Acute Tolerance To Ethanol In Caenorhabditis Elegans, Jill C. Bettinger, Kapo Leung, Mia H. Bolling, Andrew D. Goldsmith, Andrew G. Davies

Pharmacology and Toxicology Publications

The development of tolerance to a drug at the level of the neuron reflects a homeostatic mechanism by which neurons respond to perturbations of their function by external stimuli. Acute functional tolerance (AFT) to ethanol is a fast compensatory response that develops within a single drug session and normalizes neuronal function despite the continued presence of the drug. We performed a genetic screen to identify genes required for the development of acute functional tolerance to ethanol in the nematode C. elegans. We identified mutations affecting multiple genes in a genetic pathway known to regulate levels of triacylglycerols (TAGs) via …

Morphine Decreases Enteric Neuron Excitability Via Inhibition Of Sodium Channels, Tricia H. Smith, John R. Grider, William L. Dewey, Hamid I. Akbarali

Pharmacology and Toxicology Publications

Gastrointestinal peristalsis is significantly dependent on the enteric nervous system. Constipation due to reduced peristalsis is a major side-effect of morphine, which limits the chronic usefulness of this excellent pain reliever in man. The ionic basis for the inhibition of enteric neuron excitability by morphine is not well characterized as previous studies have mainly utilized microelectrode recordings from whole mount myenteric plexus preparations in guinea pigs. Here we have developed a Swiss-Webster mouse myenteric neuron culture and examined their electrophysiological properties by patch-clamp techniques and determined the mechanism for morphine-induced decrease in neuronal excitability. Isolated neurons in culture were confirmed …

The Fairfax County Hoarding Task Force, Michael Congleton

Case Studies from Age in Action

Educational Objectives

1. Describe the reasons for forming the Fairfax County Hoarding Task Force.

2. Explain the organizational makeup of the Hoarding Task Force.

3. Understand the risk factors in hoarding and what is being done to address them.

Otx But Not Mitf Transcription Factors Are Required For Zebrafish Retinal Pigment Epithelium Development, Brandon M. Lane, James A. Lister

Human and Molecular Genetics Publications

Otx and Mitf transcription factors have been implicated in the development of the retinal pigmented epithelium (RPE), but the relationship between these factors and their specific roles in the development of the RPE have not been fully defined. The role of the three Otx transcription factors (Otx1a, Otx1b, and Otx2) and two Mitf transcription factors (Mitfa and Mitfb) in the development of the zebrafish RPE was explored in these experiments. The loss of Otx activity through morpholino knockdown produced variable eye defects, ranging from delayed RPE pigmentation to severe coloboma, depending on the combination of Otx factors that were targeted. …

A First-Generation Multi-Functional Cytokine For Simultaneous Optical Tracking And Tumor Therapy, Shawn Hingtgen, Randa Kasmieh, Elizabeth Elbayly, Irina Nesterenko, Jose-Luiz Figueiredo, Rupesh Dash, Devanand Sarkar, David Hall, Dima Kozakov, Sandor Vajda, Paul B. Fisher, Khalid Shah

Human and Molecular Genetics Publications

Creating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant …

Genetic Dissection Of Acute Ethanol Responsive Gene Networks In Prefrontal Cortex: Functional And Mechanistic Implications, Aaron R. Wolen, Charles A. Phillips, Michael A. Langston, Alex H. Putman, Paul J. Vorster, Nathan A. Bruce, Timothy P. York, Robert W. Williams, Michael F. Miles

Human and Molecular Genetics Publications

Background

Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol.

Results

Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted …

A Duplication Cnv That Conveys Traits Reciprocal To Metabolic Syndrome And Protects Against Diet-Induced Obesity In Mice And Men, Melanie Lacaria, Pradip Saha, Lorraine Potocki, Weimin Bi, Jiong Yan, Santhosh Girirajan, Brooke Burns, Sarah H. Elsea, Katherina Walz, Lawrence Chan, James R. Lupski, Wenli Gu

Human and Molecular Genetics Publications

The functional contribution of CNV to human biology and disease pathophysiology has undergone limited exploration. Recent observations in humans indicate a tentative link between CNV and weight regulation. Smith-Magenis syndrome (SMS), manifesting obesity and hypercholesterolemia, results from a deletion CNV at 17p11.2, but is sometimes due to haploinsufficiency of a single gene, RAI1. The reciprocal duplication in 17p11.2 causes Potocki-Lupski syndrome (PTLS). We previously constructed mouse strains with a deletion,Df(11)17, or duplication, Dp(11)17, of the mouse genomic interval syntenic to the SMS/PTLS region. We demonstrate that Dp(11)17 is obesity-opposing; it conveys a highly penetrant, strain-independent phenotype …

A Preliminary Study On The Potential Of Manuka Honey And Platelet-Rich Plasma In Wound Healing, Scott A. Sell, Patricia Wolfe, Andrew J. Spence, Isaac Rodriguez, Jennifer M. Mccool, Rebecca L. Petrella, Koyal Garg, Jeffery J. Ericksen, Gary L. Bowlin

Biomedical Engineering Publications

Aim. The purpose of this study was to determine the in vitro response of cells critical to the wound healing process in culture media supplemented with a lyophilized preparation rich in growth factors (PRGF) and Manuka honey. Materials and Methods. This study utilized cell culture media supplemented with PRGF, as well as whole Manuka honey and the medical-grade Medihoney (MH), a Manuka honey product. The response of human fibroblasts (hDF), macrophages, and endothelial cells (hPMEC) was evaluated, with respect to cell proliferation, chemotaxis, collagen matrix production, and angiogenic potential, when subjected to culture with media containing PRGF, MH, Manuka honey, …

An Automated Method For Analysis Of Microcirculation Videos For Accurate Assessment Of Tissue Perfusion, Kayvan Najarian

Electrical and Computer Engineering Publications

Background

Imaging of the human microcirculation in real-time has the potential to detect injuries and illnesses that disturb the microcirculation at earlier stages and may improve the efficacy of resuscitation. Despite advanced imaging techniques to monitor the microcirculation, there are currently no tools for the near real-time analysis of the videos produced by these imaging systems. An automated system tool that can extract microvasculature information and monitor changes in tissue perfusion quantitatively might be invaluable as a diagnostic and therapeutic endpoint for resuscitation.

Methods

The experimental algorithm automatically extracts microvascular network and quantitatively measures changes in the microcirculation. There are …

Immunotherapy Of Cancer: Reprogramming Tumor-Immune Crosstalk, Kyle K. Payne, Amir A. Toor, Xiang-Yang Wang, Masoud H. Manjili

Microbiology and Immunology Publications

The advancement of cancer immunotherapy faces barriers which limit its efficacy. These include weak immunogenicity of the tumor, as well as immunosuppressive mechanisms which prevent effective antitumor immune responses. Recent studies suggest that aberrant expression of cancer testis antigens (CTAs) can generate robust antitumor immune responses, which implicates CTAs as potential targets for immunotherapy. However, the heterogeneity of tumor cells in the presence and quantity of CTA expression results in tumor escape from CTA-specific immune responses. Thus, the ability to modulate the tumor cell epigenome to homogenously induce expression of such antigens will likely render the tumor more immunogenic. Additionally, …

Identification And Characterization Of A Novel Calcium-Activated Apyrase Fromcryptosporidium Parasites And Its Potential Role In Pathogenesis, Patricio A. Manque, Ute Woehlbier, Ana M. Lara, Fernando Tenjo, João M. Alves, Gregory A. Buck

Microbiology and Immunology Publications

Herein, we report the biochemical and functional characterization of a novel Ca2+-activated nucleoside diphosphatase (apyrase), CApy, of the intracellular gut pathogen Cryptosporidium. The purified recombinant CApy protein displayed activity, substrate specificity and calcium dependency strikingly similar to the previously described human apyrase, SCAN-1 (soluble calcium-activated nucleotidase 1). CApy was found to be expressed in both Cryptosporidium parvum oocysts and sporozoites, and displayed a polar localization in the latter, suggesting a possible co-localization with the apical complex of the parasite. In vitro binding experiments revealed that CApy interacts with the host cell in a dose-dependent fashion, implying the presence of …

Cpg And Interleukin-15 Synergize To Enhance Ifn- Production By Activated Cd8+ T Cells, Dustin Cobb, Siqi Guo, Ronald B. Smeltz

Microbiology and Immunology Publications

Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8+ T cells. Paradoxically, we previously reported that IL-15 could enhance CD8+ T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8+ T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN- by CD8+ T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN- production. The effect of CpG and IL-15 was also evident with CD8+ T …

Adam10 Regulates Transcription Factor Expression Required For Plasma Cell Function, Natalia S. Chaimowitz, Dae-Joong Kang, Lee M. Dean, Daniel H. Conrad

Microbiology and Immunology Publications

A disintegrin and metalloprotease 10 (ADAM10) is a key regulator of cellular processes by shedding extracellular domains of transmembrane proteins. We have previously demonstrated that deletion of B cell expressed ADAM10 results in changes in lymphoid tissue architecture and impaired germinal center (GC) formation. In this study, mice were generated in which ADAM10 is deleted in B cells following class switch recombination (ADAM10Δ/ΔIgG1-cre+/−mice). Despite normal GC formation, antibody responses were impaired in ADAM10Δ/ΔIgG1-cre+/− mice, implicating ADAM10 in post-GC and extrafollicular B cell terminal differentiation. Surprisingly, plasma cell (PC) numbers were normal in ADAM10Δ/ΔIgG1-cre+/− mice when compared to controls. However, PCs …

Mouse Rc/Btb2, A Member Of The Rcc1 Superfamily, Localizes To Spermatid Acrosomal Vesicles, Jiannan Wang, Maria E. Teves, Xuening Shen, David R. Nagarkatti-Gude, Rex A. Hess, Scott C. Henderson, Jerome F. Strauss Iii, Zhibing Zhang

Obstetrics and Gynecology Publications

Mouse RC/BTB2 is an unstudied protein of the RCC1 (Regulator of Chromosome Condensation) superfamily. Because of the significant remodeling of chromatin that occurs during spermiogenesis, we characterized the expression and localization of mouse RC/BTB2 in the testis and male germ cells. The Rc/btb2 gene yields two major transcripts: 2.3 kb Rc/btb2-s, present in most somatic tissues examined; and 2.5 kb Rc/btb2-t, which contains a unique non-translated exon in its 5′-UTR that is only detected in the testis. During the first wave of spermatogenesis, Rc/btb2-t mRNA is expressed from day 8 after birth, reaching highest levels of expression at day …

Coexistence Patterns Of Two Invasive Thistle Species, Carduus Nutans And C. Acanthoides, At Three Spatial Scales, Emily S.J. Rauschert, Katriona Shea, Ottar N. Bjørnstad

Biological, Geological, and Environmental Faculty Publications

To better understand the competitive processes involved in invasion by congeners, we examine coexistence patterns of two invasive species, Carduus nutans and C. acanthoides, at three spatial scales. A roadside survey of 5 × 5 km blocks in a previously identified overlap zone provided information about the regional scale. At smaller scales, we surveyed four fields of natural co-occurrence, quantifying the spatial patterns at the field scale by randomly placed 1 × 1 m quadrats and at the smallest scale by detailing plant position within the quadrats. The patterns observed are strikingly different at the different scales. At the regional …

Tennessee Oversight Agreement Status Report To The Public Fiscal Year 2012, Tennessee. Department Of Environment And Conservation. Division Of Department Of Energy Oversight

Annual Status Reports

This report was produced by the Tennessee Department of Environment and Conservation, Division of Remediation, DOE Oversight Office.

Fy 2012 Annual Report, Tennessee. Division Of Forestry, Tennessee. Department Of Agriculture

Forestry Annual Reports

This annual report presents an overview of Tennessee Forestry Commission programs and management.

The Budget, Fiscal Year 2012-2013, Volume 2: Base Budget Reductions, Tennessee. Department Of Finance And Administration

Budget Volume 2

This supplement to the budget provides the detail of base budget reductions proposed to foster efficiency improvements in state government.

Annual Report Of The Selectmen, Treasurer, And Other Town Officers For The Town Of Newbury, New Hampshire For The Fiscal Year Ending December 31, 2011 And The Vital Statistics For The Year 2011., Newbury Town Representatives

Newbury, NH Annual Reports

This is an annual report containing vital statistics for a town/city in the state of New Hampshire.

Annual Report Of The Town Officers Northwood, Nh For The Fiscal Year Ending December 31, 2011 And Of The School District For The Fiscal Year Ending June 30, 2011., Northwood Town Representatives

Northwood, NH Annual Reports

This is an annual report containing vital statistics for a town/city in the state of New Hampshire.

The Annual Reports Of The Town Of Newmarket And Newmarket School District For The Fiscal Year Ending June 30, 2012., Newmarket Town Representatives

Newmarket, NH Annual Reports

This is an annual report containing vital statistics for a town/city in the state of New Hampshire.

Annual Report For The Town Of Northfield, New Hampshire For The Year Ending December 31, 2011., Northfield Town Representatives

Northfield, NH Annual Reports

This is an annual report containing vital statistics for a town/city in the state of New Hampshire.