Digital Commons Network^™

Cortisol Exerts Bi-Phasic Regulation Of Inflammation In Humans, Mark P. Yeager, Patricia Pioli, Paul M. Guyre

Dartmouth Scholarship

Natural and synthetic glucocorticoids (GCs) have been used for decades to suppress inflammation. In this paper, we re-examine the role of the endogenous GC, cortisol, as a primary homeostatic regulator of the human inflammatory response to injury. Our data show that cortisol regulation of innate immunity can be both pro-inflammatory and anti-inflammatory. Using a human model of in vivo cortisol depletion, we first show that baseline (diurnal) cortisol concentrations do not exert an anti-inflammatory effect. This is the first clue that cortisol regulation of inflammation is not represented by a linear dose-response relationship. We next show in surgical patients that …

Acaricidal Activity Of Eugenol Based Compounds Against Scabies Mites, Cielo Pasay, Kate Mounsey, Graeme Stevenson, Rohan Davis, Larry G. Arlian, Marjorie Morgan, Diann Vyszenski-Moher, Kathy Andrews, James Mccarthy

Biological Sciences Faculty Publications

Background

Human scabies is a debilitating skin disease caused by the “itch mite” Sarcoptes scabiei. Ordinary scabies is commonly treated with topical creams such as permethrin, while crusted scabies is treated with topical creams in combination with oral ivermectin. Recent reports of acaricide tolerance in scabies endemic communities in Northern Australia have prompted efforts to better understand resistance mechanisms and to identify potential new acaricides. In this study, we screened three essential oils and four pure compounds based on eugenol for acaricidal properties.

Methodology/Principal Findings

Radially Aligned, Electrospun Nanofibers As Dural Substitutes For Wound Closure And Tissue Regeneration Applications, Jingwei Xie, Matthew R. Macewan, Wilson Z. Ray, Wenying Liu, Daku Y. Siewe, Younan Xia

MIIR Faculty Research

This paper reports the fabrication of scaffolds consisting of radially aligned poly(ε-caprolactone) nanofibers by utilizing a collector composed of a central point electrode and a peripheral ring electrode. This novel class of scaffolds was able to present nanoscale topographic cues to cultured cells, directing and enhancing their migration from the periphery to the center. We also established that such scaffolds could induce faster cellular migration and population than nonwoven mats consisting of random nanofibers. Dural fibroblast cells cultured on these two types of scaffolds were found to express type I collagen, the main extracellular matrix component in dural mater. The …

S-Glutathionylation Activates Stim1 And Alters Mitochondrial Homeostasis., Brian J Hawkins, Krishna M Irrinki, Karthik Mallilankaraman, Yu-Chin Lien, Youjun Wang, Cunnigaiper D Bhanumathy, Ramasamy Subbiah, Michael F Ritchie, Jonathan Soboloff, Yoshihiro Baba, Tomohiro Kurosaki, Suresh K Joseph, Donald L Gill, Muniswamy Madesh

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Oxidant stress influences many cellular processes, including cell growth, differentiation, and cell death. A well-recognized link between these processes and oxidant stress is via alterations in Ca(2+) signaling. However, precisely how oxidants influence Ca(2+) signaling remains unclear. Oxidant stress led to a phenotypic shift in Ca(2+) mobilization from an oscillatory to a sustained elevated pattern via calcium release-activated calcium (CRAC)-mediated capacitive Ca(2+) entry, and stromal interaction molecule 1 (STIM1)- and Orai1-deficient cells are resistant to oxidant stress. Functionally, oxidant-induced Ca(2+) entry alters mitochondrial Ca(2+) handling and bioenergetics and triggers cell death. STIM1 is S-glutathionylated at cysteine 56 in response to …

Harnessing The Effect Of Adoptively Transferred Tumor-Reactive T Cells On Endogenous (Host-Derived) Antitumor Immunity, Yolanda Nesbeth, Jose R. Conejo-Garcia

Dartmouth Scholarship

Adoptive T cell transfer therapy, the ex vivo activation, expansion, and subsequent administration of tumor-reactive T cells, is already the most effective therapy against certain types of cancer. However, recent evidence in animal models and clinical trials suggests that host conditioning interventions tailored for some of the most aggressive and frequent epithelial cancers will be needed to maximize the benefit of this approach. Similarly, the subsets, stage of differentiation, and ex vivo expansion procedure of tumor-reactive T cells to be adoptively transferred influence their in vivo effectiveness and may need to be adapted for different types of cancer and host …

Cannabinoid Receptors In The 3d Reconstructed Mouse Brain: Function And Regulation, Peter Nguyen

Theses and Dissertations

CB1 receptors (CB1R) mediate the psychoactive and therapeutic effects of cannabinoids including ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent in marijuana. However, therapeutic use is limited by side effects and tolerance and dependence with chronic administration. Tolerance to cannabinoid-mediated effects is associated with CB1R adaptations, including desensitization (receptor-G-protein uncoupling) and downregulation (receptor degradation). The objectives of this thesis are to investigate the regional-specificity in CB1R function and regulation. Previous studies have investigated CB1Rs in a subset of regions involved in cannabinoid effects, but an inclusive regional comparison of the relative efficacies of different classes of cannabinoids to activate G-proteins has not …

Cross-Reactivity Of Antibodies Against Leptospiral Recurrent Uveitis-Associated Proteins A And B (Lrua And Lrub) With Eye Proteins, Ashutosh Verma, Pawan Kumar, Kelly Babb, John F. Timoney, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Infection by Leptospira interrogans has been causally associated with human and equine uveitis. Studies in our laboratories have demonstrated that leptospiral lipoprotein LruA and LruB are expressed in the eyes of uveitic horses, and that antibodies directed against LruA and LruB react with equine lenticular and retinal extracts, respectively. These reactivities were investigated further by performing immunofluorescent assays on lenticular and retinal tissue sections. Incubation of lens tissue sections with LruA-antiserum and retinal sections with LruB-antiserum resulted in positive fluorescence. By employing two-dimensional gel analyses followed by immunoblotting and mass spectrometry, lens proteins cross-reacting with LruA antiserum were identified to …

A Coupled Finite Element-Boundary Element Method For Modeling Diffusion Equation In 3d Multi-Modality Optical Imaging, Subhadra Srinivasan, Hamid R. Ghadyani, Brian W. Pogue, Keith D. Paulsen

Dartmouth Scholarship

Three dimensional image reconstruction for multi-modality optical spectroscopy systems needs computationally efficient forward solvers with minimum meshing complexity, while allowing the flexibility to apply spatial constraints. Existing models based on the finite element method (FEM) require full 3D volume meshing to incorporate constraints related to anatomical structure via techniques such as regularization. Alternate approaches such as the boundary element method (BEM) require only surface discretization but assume homogeneous or piece-wise constant domains that can be limiting. Here, a coupled finite element-boundary element method (coupled FE-BEM) approach is demonstrated for modeling light diffusion in 3D, which uses surfaces to model exterior …

Age, Reproduction, Growth, Condition And Diet Of The Introduced Yellow Bass, Morone Mississippiensis, In Barren River Lake, Kentucky, Peter Zervas

Masters Theses & Specialist Projects

Introduction of fish species to North American drainages has occurred for over 100 years. Introduced fish species have been documented to have adverse effects on both the environment and native species of the drainage into which they have been introduced. To better understand the effects that introduced species may have on a particular drainage, it is essential to understand aspects of the introduced species' life history. The objectives of the current study is to quantify the age, reproduction, growth, condition and diet of the yellow bass, Morone mississippiensis, in Barren River Lake, Kentucky. Monthly collections from three areas on Barren …

A Smac Mimetic Reduces Tnf Related Apoptosis Inducing Ligand (Trail)-Induced Invasion And Metastasis Of Cholangiocarcinoma Cells., Christian D. Fingas, Boris R.A. Blechacz, Rory L. Smoot, Maria E. Guicciardi, Justin L. Mott, Steve F. Bronk, Nathan W. Werneburg, Alphonse E. Sirica, Gregory J. Gores

Journal Articles: Biochemistry & Molecular Biology

UNLABELLED: Cholangiocarcinoma (CCA) cells paradoxically express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that, failing to kill CCA cells, instead promotes their tumorigenicity and especially the metastatic behaviors of cell migration and invasion. Second mitochondria-derived activator of caspase (smac) mimetics are promising cancer therapeutic agents that enhance proapoptotic death receptor signaling by causing cellular degradation of inhibitor of apoptosis (IAP) proteins. Our aim was to examine the in vitro and in vivo effects of the smac mimetic JP1584 in CCA. Despite JP1584-mediated loss of cellular inhibitor of apoptosis-1 (cIAP-1) and cIAP-2, TRAIL failed to induce apoptosis in KMCH-1, …

Effect Of Acute Administration Of Angiopoietin-1 In Experimental Traumatic Spinal Cord Injury: Magnetic Resonance Imaging And Neurobehavioral Studies, Chirag B. Patel

Dissertations and Theses (Open Access)

Spinal cord injury (SCI) is a devastating condition that affects people in the prime of their lives. A myriad of vascular events occur after SCI, each of which contributes to the evolving pathology. The primary trauma causes mechanical damage to blood vessels, resulting in hemorrhage. The blood-spinal cord barrier (BSCB), a neurovascular unit that limits passage of most agents from systemic circulation to the central nervous system, breaks down, resulting in inflammation, scar formation, and other sequelae. Protracted BSCB disruption may exacerbate cellular injury and hinder neurobehavioral recovery in SCI.

In these studies, angiopoietin-1 (Ang1), an agent known to reduce …

The Impact Of Adolescent Nicotine Exposure On Drug Dependence In Adulthood, Mai Alajaji

Theses and Dissertations

Nicotine is one of the first and most commonly abused drugs in adolescence. According to The Center for Disease Control, every day more than 6000 adolescents try their first cigarette and over 3000 of them become daily smokers. Smoking among adolescents is a strong predictor of future drug abuse and dependence in adulthood. A number of studies has suggests that adolescents pre-exposed to nicotine may suffer permanent disruption of the brain’s reward systems through changes in dopamine receptor function. We hypothesize that nicotine exposure during adolescence causes long lasting neurobiological alterations that increase the likelihood of cocaine use in adulthood. …

The Mechanism Of Obesity In Rai1+/- Mice, Kristie Schmidt

Theses and Dissertations

Smith-Magenis syndrome (SMS) is a genetic disorder caused by a deletion or mutation of the retinoic acid induced 1 (RAI1) gene on chromosome 17p11.2 that results in haploinsufficiency. SMS patients with a deletion account for 90% of the cases, while the other 10% have a mutation in RAI1. The syndrome is characterized by cognitive impairment, craniofacial abnormalities, sleep disturbances, developmental delay, obesity, and behavioral phenotypes. SMS is thought to affect 1:25,000 live births, although due to similar infantile phenotypes with Down syndrome and Prader-Willi syndrome, SMS may be mis- or under-diagnosed. In a study of 54 children, it was shown …

Passive Transfer Of Igg Anti-Gm1 Antibodies Impairs Peripheral Nerve Repair, Pablo H Lopez, Gang Zhang, Jiangyang Zhang, Helmar C Lehmann, John W Griffin, Ronald L Schnaar, Kazim A Sheikh

Faculty, Staff and Student Publications

Anti-GM1 antibodies are present in some patients with autoimmune neurological disorders. These antibodies are most frequently associated with acute immune neuropathy called Guillain-Barré syndrome (GBS). Some clinical studies associate the presence of these antibodies with poor recovery in GBS. The patients with incomplete recovery have failure of nerve repair, particularly axon regeneration. Our previous work indicates that monoclonal antibodies can inhibit axon regeneration by engaging cell surface gangliosides (Lehmann et al., 2007). We asked whether passive transfer of human anti-GM1 antibodies from patients with GBS modulate axon regeneration in an animal model. Human anti-GM1 antibodies were compared with other GM1 …

Teratology Primer-2nd Edition (7/9/2010), Sura Alwan, Steven B. Bleyl, Robert L. Brent, Christina D. Chambers, George P. Daston, Elaine M. Faustman, Richard H. Finnell, F. Clarke Fraser, Jan M. Freidman, Adriane Fugh-Berman, John M. Graham, Jr., Barbara F. Hales, Deborah K. Hansen, Lewis B. Holmes, Ronald D. Hood, Robert J. Kavlock, Thomas B. Knudsen, Joseph Lary, Donald R. Mattison, Richard K. Miller, James L. Mills, Janine E. Polifka, Sonja A. Rasmussen, Bernard Robaire, John M. Rogers, Gary C. Schoenwolf, Anthony R. Scialli, Gary M. Shaw, Amar V. Singh, William Slikker, Jr., Ann P. Streissguth, Melissa S. Tassinari, Janet Uriu-Adams, Charles V. Vorhees, Elora J. Weringer

Department of Pediatrics Faculty Papers

Foreword:

What is Teratology?

“What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or …

Avirulent Uracil Auxotrophs Based On Disruption Of Orotidine-5′-Monophosphate Decarboxylase Elicit Protective Immunity To Toxoplasma Gondii, Barbara A. Fox, David J. Bzik

Dartmouth Scholarship

The orotidine-5'-monophosphate decarboxylase (OMPDC) gene, encoding the final enzyme of the de novo pyrimidine biosynthesis pathway, was deleted using Toxoplasma gondii KU80 knockouts to develop an avirulent nonreverting pyrimidine auxotroph strain. Additionally, to functionally address the role of the pyrimidine salvage pathway, the uridine phosphorylase (UP) salvage activity was knocked out and a double knockout of UP and OMPDC was also constructed. The nonreverting DeltaOMPDC, DeltaUP, and DeltaOMPDC DeltaUP knockout strains were evaluated for pyrimidine auxotrophy, for attenuation of virulence, and for their ability to elicit potent immunity to reinfection. The DeltaUP knockout strain was replication competent and virulent. In …

Pcif1 Modulates Pdx1 Protein Stability And Pancreatic Β Cell Function And Survival In Mice, Kathryn C. Claiborn, Mira M. Sachdeva, Corey E. Cannon, David N. Groff, Jeffrey D. Singer, Doris A. Stoffers

Biology Faculty Publications and Presentations

The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus–interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 …

Fenotipo Y Genotipo Del Virus De La Diarrea Viral Aislado De Bovinos En El Perú., Mariluz Araínga, Hermelinda Rivera G., Juan Carlos Huaman G., Alberto Manchego S.

Journal Articles: Pharmacology & Experimental Neuroscience

The aim of this study was to determine the phenotype and genotype of Bovine Viral Diarrhoea Virus (BVDV) in Peruvian cattle. During the period 1998-2007, tissues of aborted fetus, blood, serum or plasma samples of bovine with acute infection or persistently infected from dairy herds of various locations in the country were collected and the BVDV antigen was detected by immnunofluorescence or capture ELISA tests, and positive samples were inoculated en BVDV free BT cells and cultured until third passage to determine the biotype. Both animal tissues and third passage of positive samples were tested by a Real Time Reverse …

Prolongation Of Carrageenan-Induced Inflammation In Human Colonic Epithelial Cells By Activation Of An Nfκb-Bcl10 Loop, Alip Borthakur, Sumit Bhattacharyya, Arivarasu N. Anbazhagan, Anoop Kumar, Pradeep K. Dudeja, Joanne K. Tobacman

Clinical & Translational Sciences

Carrageenan, a sulfated polysaccharide that is widely used as a food additive, induces inflammatory responses in animal models and human cells. The carrageenan-induced inflammatory cascades involve tolllike receptor (TLR)4- and B-cell leukemia/lymphoma (BCL)10-dependent activation of NF-κB, leading to increased IL-8 production. Translocations involving BCL10 in the mucosa-associated lymphoid tissue (MALT) lymphomas are associated with constitutive activation of NF-κB. This report presents a mechanism by which carrageenan exposure leads to prolonged activation of both BCL10 and NF-κB in human colonic epithelial cells. Study findings demonstrate that nuclear RelA and RelB bind to an NF-κB binding motif in the BCL10 promoter in …

Antispasmodic, Bronchodilator And Blood Pressure Lowering Properties Of Hypericum Oblongifolium - Possible Mechanism Of Action, Arif-Ullah Khan, Munasib Khan, Fazal Subhan, Anwar Gilani

Department of Biological & Biomedical Sciences

The crude extract of Hypericum oblongifolium (Ho.Cr), which tested positive for flavonoids, saponins and tannins caused concentration-dependent (0.1-1.0 mg/mL) relaxation of spontaneous and high K(+) (80 mM)-induced contractions in isolated rabbit jejunum preparations, suggesting a Ca(++) antagonistic effect, which was confirmed when pretreatment of the tissue with Ho.Cr produced a rightward shift in the Ca(++) concentration-response curves, like that caused by verapamil. Ho.Cr relaxed carbachol (1 mu M) and high K(+)-induced contractions in guinea pig tracheal preparations. It caused a dose-dependent (3-100 mg/kg) fall in arterial blood pressure of rats under anesthesia. In isolated guinea pig atria, Ho.Cr caused inhibition …

Dopaminergic Neurons Derived From Human Induced Pluripotent Stem Cells Survive And Integrate Into 6-Ohda-Lesioned Rats., Jingli Cai, Ming Yang, Elizabeth Poremsky, Sarah Kidd, Jay S Schneider, Lorraine Iacovitti

Farber Institute for Neuroscience Faculty Papers

Cell replacement therapy could be an important treatment strategy for Parkinson's disease (PD), which is caused by the degeneration of dopamine neurons in the midbrain (mDA). The success of this approach greatly relies on the discovery of an abundant source of cells capable of mDAergic function in the brain. With the paucity of available human fetal tissue, efforts have increasingly focused on renewable stem cells. Human induced pluripotent stem (hiPS) cells offer great promise in this regard. If hiPS cells can be differentiated into authentic mDA neuron, hiPS could provide a potential autologous source of transplant tissue when generated from …

Rabies Virus Infection Induces Type I Interferon Production In An Ips-1 Dependent Manner While Dendritic Cell Activation Relies On Ifnar Signaling., Elizabeth J Faul, Celestine N Wanjalla, Mehul S Suthar, Michael Gale, Christoph Wirblich, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

As with many viruses, rabies virus (RABV) infection induces type I interferon (IFN) production within the infected host cells. However, RABV has evolved mechanisms by which to inhibit IFN production in order to sustain infection. Here we show that RABV infection of dendritic cells (DC) induces potent type I IFN production and DC activation. Although DCs are infected by RABV, the viral replication is highly suppressed in DCs, rendering the infection non-productive. We exploited this finding in bone marrow derived DCs (BMDC) in order to differentiate which pattern recognition receptor(s) (PRR) is responsible for inducing type I IFN following infection …

Breast Cancer Dna Methylation Profiles Are Associated With Tumor Size And Alcohol And Folate Intake, Brock C. Christensen, Karl T. Kelsey, Shichun Zheng, E. Andres Houseman, Carmen J. Marsit, Margaret R. Wrensch, Joseph L. Wiemels, Heather H. Nelson, Margaret R. Karagas

Dartmouth Scholarship

Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage I-IV) women from the Kaiser Division of Research Pathways Study and the Illumina GoldenGate methylation bead-array platform, we measured 1,413 autosomal CpG loci associated with 773 cancer-related genes and validated select CpG loci with Sequenom EpiTYPER. Tumor grade, size, estrogen and progesterone receptor status, and triple negative status were significantly (Q-values <0.05) associated with altered methylation of 209, 74, 183, 69, and 130 loci, respectively. Unsupervised clustering, using a recursively partitioned mixture model (RPMM), of all autosomal CpG loci revealed eight distinct methylation classes. Methylation class membership was significantly associated with patient race (P<0.02) and tumor size (P<0.001) in univariate tests. Using multinomial logistic regression to adjust for potential confounders, patient age and tumor size, as well as known disease risk factors of alcohol intake and total dietary folate, were all significantly (P<0.0001) associated with methylation class membership. Breast cancer prognostic characteristics and risk-related exposures appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns.

Involvement Of Noradrenergic Neurotransmission In The Stress- But Not Cocaine-Induced Reinstatement Of Extinguished Cocaine-Induced Conditioned Place Preference In Mice: Role For Β-2 Adrenergic Receptors, John R. Mantsch, Andy Meyer, Oliver Vranjkovic, Chad E. Beyer, David A. Baker, Holly Caretta

Biomedical Sciences Faculty Research and Publications

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine …

Synaptotoxicity Of Alzheimer Beta Amyloid Can Be Explained By Its Membrane Perforating Property, Fernando Sepulveda, Jorge Parodi, Robert W. Peoples, Carlos Opazo, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The mechanisms that induce Alzheimer’s disease (AD) are largely unknown thereby deterring the development of disease-modifying therapies. One working hypothesis of AD is that Aβ excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes. Here we show that similar to other pore forming toxins, Aβ induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Aβ is not another membrane protein, but that Aβ itself is the cellular target …

Pathologically Activated Neuroprotection Via Uncompetitive Blockade Of N-Methyl-D-Aspartate Receptors With Fast Off-Rate By Novel Multifunctional Dimer Bis(Propyl)-Cognitin, Jialie Luo, Wenming Li, Yuming Zhao, Hongjun Fu, Dik-Lung Ma, Jing Tang, Chaoying Li, Robert W. Peoples, Fushun Li, Qinwen Wang, Pingbo Huang, Jun Xia, Yuanping Pang, Yifan Han

Biomedical Sciences Faculty Research and Publications

Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and γ-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate …

Probiotic Therapy - Recruiting Old Friends To Fight New Foes, Roy D. Sleator

Department of Biological Sciences Publications

Against a backdrop of increasing antibiotic resistance, and the emergence of new and evolving pathogens, clinicians are increasingly forced to consider alternative therapies - probiotics are one such alternative.

The Vision Of Toxicity Testing In The 21st Century: Moving From Discussion To Action, Melvin E. Andersen, Daniel Krewski

Toxicology and Animal Models in Research Collection

Over the past year, a series on commentaries have appeared in the Toxicological Sciences Forum Series related to the 2007 National Research Council (NRC) publication, Toxicity Testing in the 21st Century: A Vision and A Strategy. The first article in the series provided an overview of the vision and was accompanied by an editorial by the three editors of Toxicological Sciences. During the past year, eight invited commentaries from the academic, industrial, and regulatory sectors have provided diverse perspectives on the vision, noted challenges to its implementation, and highlighted aspects of toxicity testing that were not addressed in …

High-Throughput Experimental Studies To Identify Mirna Targets Directly, With Special Focus On The Mammalian Brain, Peter T. Nelson, Marianthi Kiriakidou, Zissimos Mourelatos, Grace S. Tan, Mary H. Jennings, Kevin Xie, Wang-Xia Wang

Pathology and Laboratory Medicine Faculty Publications

We review the pertinent literature on methods used in high-throughput experimental identification of microRNA (miRNA) "targets" with emphasis on neurochemical studies. miRNAs are short regulatory noncoding RNAs that play important roles in the mammalian brain. The functions of miRNAs are related to their binding of RNAs including mRNAs. Since mammalian miRNAs tend to bind to target mRNAs via imperfect complementarity, understanding exactly which target mRNAs are recognized by which specific miRNAs is a challenge. Based on early experimental evidence, a set of "binding rules" for miRNAs has been described. These have focused on the 5' "seed" region of miRNAs binding …

Biomarkers For Aging, Philip W. Landfield, Eric M. Blalock, Kuey-Chu Chen, Thomas S. Foster

Pharmacology and Nutritional Sciences Faculty Patents

A statistical and functional correlation strategy to identify changes in cellular pathways specifically linked to impaired cognitive function with aging. Analyses using the strategy identified multiple groups of genes expressed in the hippocampi of mammals, where the genes were expressed at different levels for several ages. The aging changes in expression began before mid-life. Many of the genes were involved in specific neuronal and glial pathways with previously unrecognized relationships to aging and/or cognitive decline. These identified genes and the proteins they encode can be used as novel biomarkers of brain aging and as targets for developing treatment methods against …