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Impaired Fast-Spiking, Suppressed Cortical Inhibition, And Increased Susceptibility To Seizures In Mice Lacking Kv3.2 K+ Channel Proteins, David Lau, Eleazar Vega-Saenz De Miera, Diego Contreras, Alan Chow, Richard Paylor, Christopher S. Leonard, Bernardo Rudy Dec 2000

Impaired Fast-Spiking, Suppressed Cortical Inhibition, And Increased Susceptibility To Seizures In Mice Lacking Kv3.2 K+ Channel Proteins, David Lau, Eleazar Vega-Saenz De Miera, Diego Contreras, Alan Chow, Richard Paylor, Christopher S. Leonard, Bernardo Rudy

NYMC Faculty Publications

Voltage-gated K(+) channels of the Kv3 subfamily have unusual electrophysiological properties, including activation at very depolarized voltages (positive to -10 mV) and very fast deactivation rates, suggesting special roles in neuronal excitability. In the brain, Kv3 channels are prominently expressed in select neuronal populations, which include fast-spiking (FS) GABAergic interneurons of the neocortex, hippocampus, and caudate, as well as other high-frequency firing neurons. Although evidence points to a key role in high-frequency firing, a definitive understanding of the function of these channels has been hampered by a lack of selective pharmacological tools. We therefore generated mouse lines in which one …

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Mrnas Encoding Aquaporins Are Present During Murine Preimplantation Development., H Offenberg, L C Barcroft, A Caveney, D Viuff, P D Thomsen, A J Watson Dec 2000

Mrnas Encoding Aquaporins Are Present During Murine Preimplantation Development., H Offenberg, L C Barcroft, A Caveney, D Viuff, P D Thomsen, A J Watson

Obstetrics & Gynaecology Publications

The present study was conducted to investigate the mechanisms underlying fluid movement across the trophectoderm during blastocyst formation by determining whether aquaporins (AQPs) are expressed during early mammalian development. AQPs belong to a family of major intrinsic membrane proteins and function as molecular water channels that allow water to flow rapidly across plasma membranes in the direction of osmotic gradients. Ten different AQPs have been identified to date. Murine preimplantation stage embryos were flushed from the oviducts and uteri of superovulated CD1 mice. Reverse transcription-polymerase chain reaction (RT-PCR) methods employing primer sets designed to amplify conserved sequences of AQPs (1-9) …

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Ryanodine Receptor Adaptation, Michael Fill, A. Zahradníková, Carlos A. Villalba-Galea, I. Zahradník, A. L. Escobar, S. Györke Dec 2000

Ryanodine Receptor Adaptation, Michael Fill, A. Zahradníková, Carlos A. Villalba-Galea, I. Zahradník, A. L. Escobar, S. Györke

School of Pharmacy Faculty Articles

In the heart, depolarization during the action potential activates voltage-dependent Ca2+ channels that mediate a small, localized Ca2+ influx (ICa). This small Ca2+ signal activates specialized Ca2+ release channels, the ryanodine receptors (RyRs), in the sarcoplasmic reticulum (SR). This process is called Ca2+-induced Ca2+ release (CICR). Intuitively, the CICR process should be self-regenerating because the Ca2+ released from the SR should feedback and activate further SR Ca2+ release. However, the CICR process is precisely controlled in the heart and, consequently, some sort of negative control mechanism(s) must exist to …

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Long-Term Regulation Of Neuronal High-Affinity Glutamate And Glutamine Uptake In Aplysia, J Levenson, S Endo, L S. Kategaya, R I. Fernandez, D G. Brabham, J Chin, J H. Byrne, A Eskin Nov 2000

Long-Term Regulation Of Neuronal High-Affinity Glutamate And Glutamine Uptake In Aplysia, J Levenson, S Endo, L S. Kategaya, R I. Fernandez, D G. Brabham, J Chin, J H. Byrne, A Eskin

Faculty, Staff and Student Publications

An increase in transmitter release accompanying long-term sensitization and facilitation occurs at the glutamatergic sensorimotor synapse of Aplysia. We report that a long-term increase in neuronal Glu uptake also accompanies long-term sensitization. Synaptosomes from pleural-pedal ganglia exhibited sodium-dependent, high-affinity Glu transport. Different treatments that induce long-term enhancement of the siphon-withdrawal reflex, or long-term synaptic facilitation increased Glu uptake. Moreover, 5-hydroxytryptamine, a treatment that induces long-term facilitation, also produced a long-term increase in Glu uptake in cultures of sensory neurons. The mechanism for the increase in uptake is an increase in the V(max) of transport. The long-term increase in Glu uptake …

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The Toxicology Of Aluminum In The Brain: A Review, Robert A. Yokel Oct 2000

The Toxicology Of Aluminum In The Brain: A Review, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Aluminum is environmentally ubiquitous, providing human exposure. Usual human exposure is primarily dietary. The potential for significant Al absorption from the nasal cavity and direct distribution into the brain should be further investigated. Decreased renal function increases human risk of Al-induced accumulation and toxicity. Brain Al entry from blood may involve transferrin-receptor mediated endocytosis and a more rapid process transporting small molecular weight Al species. There appears to be Al efflux from the brain, probably as Al citrate. There is prolonged retention of a fraction of Al that enters the brain, suggesting the potential for accumulation with repeated exposure. Al …

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Genomic Structure Of Murine Mitochondrial Dna Polymerase-Gamma., Justin L. Mott, Grace Denniger, Steve J. Zullo, H. Peter Zassenhaus Oct 2000

Genomic Structure Of Murine Mitochondrial Dna Polymerase-Gamma., Justin L. Mott, Grace Denniger, Steve J. Zullo, H. Peter Zassenhaus

Journal Articles: Biochemistry & Molecular Biology

We have sequenced a genomic clone of the gene encoding the mouse mitochondrial DNA polymerase. The gene consists of 23 exons, which span approximately 13.2 kb, with exons ranging in size from 53 to 768 bp. All intron-exon boundaries conform to the GT-AG rule. By comparison with the human genomic sequence, we found remarkable conservation of the gene structure; the intron-exon borders are in almost identical locations for the 22 introns. The 5' upstream region contains approximately 300 bp of homology between the mouse and human sequences that presumably contain the promoter element. This region lacks any obvious TATA domain …

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Prolonged Cyclooxygenase-2 Induction In Neurons And Glia Following Traumatic Brain Injury In The Rat, Kenneth I. Strauss, Mary F. Barbe, Renee Marshall Demarest, Ramesh Raghupathi, Samir Mehta, Raj K. Narayan Aug 2000

Prolonged Cyclooxygenase-2 Induction In Neurons And Glia Following Traumatic Brain Injury In The Rat, Kenneth I. Strauss, Mary F. Barbe, Renee Marshall Demarest, Ramesh Raghupathi, Samir Mehta, Raj K. Narayan

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Cyclooxygenase-2 (COX2) is a primary inflammatory mediator that converts arachidonic acid into precursors of vasoactive prostaglandins, producing reactive oxygen species in the process. Under normal conditions COX2 is not detectable, except at low abundance in the brain. This study demonstrates a distinctive pattern of COX2 increases in the brain over time following traumatic brain injury (TBI). Quantitative lysate ribonuclease protection assays indicate acute and sustained increases in COX2 mRNA in two rat models of TBI. In the lateral fluid percussion model, COX2 mRNA is significantly elevated (>twofold, p < 0.05, Dunnett) at 1 day postinjury in the injured cortex and bilaterally in the hippocampus, compared to sham-injured controls. In the lateral cortical impact model (LCI), COX2 mRNA peaks around 6 h postinjury in the ipsilateral cerebral cortex (fivefold induction, p < 0.05, Dunnett) and in the ipsilateral and contralateral hippocampus (two- and six-fold induction, respectively, p < 0.05, Dunnett). Increases are sustained out to 3 days postinjury in the injured cortex in both models. Further analyses use the LCI model to evaluate COX2 induction. Immunoblot analyses confirm increased levels of COX2 protein in the cortex and hippocampus. Profound increases in COX2 protein are observed in the cortex at 1-3 days, that return to sham levels by 7 days postinjury (p < 0.05, Dunnett). The cellular pattern of COX2 induction following TBI has been characterized using immunohistochemistry. COX2-immunoreactivity (-ir) rises acutely (cell numbers and intensity) and remains elevated for several days following TBI. Increases in COX2-ir colocalize with neurons (MAP2-ir) and glia (GFAP-ir). Increases in COX2-ir are observed in cerebral cortex and hippocampus, ipsilateral and contralateral to injury as early as 2 h postinjury. Neurons in the ipsilateral parietal, perirhinal and piriform cortex become intensely COX2-ir from 2 h to at least 3 days postinjury. In agreement with the mRNA and immunoblot results, COX2-ir appears greatest in the contralateral hippocampus. Hippocampal COX2-ir progresses from the pyramidal cell layer of the CA1 and CA2 region at 2 h, to the CA3 pyramidal cells and dentate polymorphic and granule cell layers by 24 h postinjury. These increases are distinct from those observed following inflammatory challenge, and correspond to brain areas previously identified with the neurological and cognitive deficits associated with TBI. While COX2 induction following TBI may result in selective beneficial responses, chronic COX2 production may contribute to free radical mediated cellular damage, vascular dysfunction, and alterations in cellular metabolism. These may cause secondary injuries to the brain that promote neuropathology and worsen behavioral outcome.

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Differential Involvement Of Na(+),K(+)-Atpase Isozymes In Preimplantation Development Of The Mouse., D J Macphee, D H Jones, K J Barr, D H Betts, A J Watson, G M Kidder Jun 2000

Differential Involvement Of Na(+),K(+)-Atpase Isozymes In Preimplantation Development Of The Mouse., D J Macphee, D H Jones, K J Barr, D H Betts, A J Watson, G M Kidder

Obstetrics & Gynaecology Publications

Na(+),K(+)-ATPase plays an essential role in mammalian blastocoel formation (cavitation) by driving trans-epithelial sodium transport. Previously, the alpha1 and beta1 subunit isoforms of this enzyme were identified in preimplantation mouse embryos and were assumed to be responsible for this function. Here we show that mRNAs encoding an additional alpha subunit isoform (alpha3) and the remaining two beta subunit isoforms are also present in preimplantation embryos. Whereas alpha3 mRNA accumulates between the four-cell and the blastocyst stages and thus results from embryonic transcription, the same could not be demonstrated for beta2 and beta3 mRNAs. Immunoblot analyses confirmed that these subunits are …

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Inhibition Of Antiviral Ctl Responses By Virus-Infected Cells: Line Item Veto (Cells) Revisited, Robert F. Rich, William R. Green Apr 2000

Inhibition Of Antiviral Ctl Responses By Virus-Infected Cells: Line Item Veto (Cells) Revisited, Robert F. Rich, William R. Green

Dartmouth Scholarship

No abstract provided.

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Anti-Gag Cytolytic T Lymphocytes Specific For An Alternative Translational Reading Frame-Derived Epitope And Resistance Versus Susceptibility To Retrovirus-Induced Murine Aids In F1 Mice, Shawn-Marie Mayrand, Patricia A. Healy, Bruce E. Torbett, William R. Green Apr 2000

Anti-Gag Cytolytic T Lymphocytes Specific For An Alternative Translational Reading Frame-Derived Epitope And Resistance Versus Susceptibility To Retrovirus-Induced Murine Aids In F1 Mice, Shawn-Marie Mayrand, Patricia A. Healy, Bruce E. Torbett, William R. Green

Dartmouth Scholarship

Murine AIDS (MAIDS) develops in susceptible mouse strains after infection with the LP-BM5 murine leukemia virus complex that contains causative defective, and ecotropic helper, retroviruses. We previously demonstrated that the MAIDSresistant H-2d strains BALB/cByJ and C57BL/KsJ generate MHC class I (Kd ) restricted virus-specific CD81 cytolytic T lymphocytes (CTLs) that lyse cells expressing either defective or ecotropic gag proteins. In contrast, the congenic BALB.B and closely related C57BL/6J MAIDS-susceptible H-2b strains were unable to serve as a source of gag-specific CTLs (Schwarz and Green, 1994), suggesting that anti-gag CTLs might provide a basis for resistance to MAIDS. Although its susceptibility …

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Membrane Cholesterol Content Modulates Activation Of Volume-Regulated Anion Current In Bovine Endothelial Cells., I Levitan, A E Christian, T N Tulenko, G H Rothblat Apr 2000

Membrane Cholesterol Content Modulates Activation Of Volume-Regulated Anion Current In Bovine Endothelial Cells., I Levitan, A E Christian, T N Tulenko, G H Rothblat

Department of Biochemistry and Molecular Biology Faculty Papers

Activation of volume-regulated anion current (VRAC) plays a key role in the maintenance of cellular volume homeostasis. The mechanisms, however, that regulate VRAC activity are not fully understood. We have examined whether VRAC activation is modulated by the cholesterol content of the membrane bilayer. The cholesterol content of bovine aortic endothelial cells was increased by two independent methods: (a) exposure to a methyl-beta-cyclodextrin saturated with cholesterol, or (b) exposure to cholesterol-enriched lipid dispersions. Enrichment of bovine aortic endothelial cells with cholesterol resulted in a suppression of VRAC activation in response to a mild osmotic gradient, but not to a strong …

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Ubinuclein, A Novel Nuclear Protein Interacting With Cellular And Viral Transcription Factors., S Aho, M Buisson, T Pajunen, Y W Ryoo, J F Giot, H Gruffat, A Sergeant, Jouni Uitto Mar 2000

Ubinuclein, A Novel Nuclear Protein Interacting With Cellular And Viral Transcription Factors., S Aho, M Buisson, T Pajunen, Y W Ryoo, J F Giot, H Gruffat, A Sergeant, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

The major target tissues for Epstein-Barr virus (EBV) infection are B lymphocytes and epithelial cells of the oropharyngeal zone. The product of the EBV BZLF1 early gene, EB1, a member of the basic leucine-zipper family of transcription factors, interacts with both viral and cellular promoters and transcription factors, modulating the reactivation of latent EBV infection. Here, we characterize a novel cellular protein interacting with the basic domains of EB1 and c-Jun, and competing of their binding to the AP1 consensus site. The transcript is present in a wide variety of human adult, fetal, and tumor tissues, and the protein is …

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The Pl(A2) Polymorphism Of Integrin Beta(3) Enhances Outside-In Signaling And Adhesive Functions., K Vinod Vijayan, Pascal J. Goldschmidt-Clermont, Christine Roos, Paul F. Bray Mar 2000

The Pl(A2) Polymorphism Of Integrin Beta(3) Enhances Outside-In Signaling And Adhesive Functions., K Vinod Vijayan, Pascal J. Goldschmidt-Clermont, Christine Roos, Paul F. Bray

Cardeza Foundation for Hematologic Research

Genetic factors are believed to influence the development of arterial thromboses. Because integrin alpha(IIb)beta(3) plays a crucial role in thrombus formation, we analyzed receptor adhesive properties using Chinese hamster ovary and human kidney embryonal 293 cells overexpressing the Pl(A1) or Pl(A2) polymorphic forms of alpha(IIb)beta(3). Soluble fibrinogen binding was no different between Pl(A1) and Pl(A2) cells, either in a resting state or when alpha(IIb)beta(3) was activated with anti-LIBS6. Pl(A1) and Pl(A2) cells bound equivalently to immobilized fibronectin. In contrast, significantly more Pl(A2) cells bound to immobilized fibrinogen in an alpha(IIb)beta(3)-dependent manner than did Pl(A1) cells. Disruption of the actin cytoskeleton …

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Single-Channel Properties In Endoplasmic Reticulum Membrane Of Recombinant Type 3 Inositol Trisphosphate Receptor., D O Mak, S Mcbride, V Raghuram, Y Yue, Suresh K. Joseph, J K Foskett Mar 2000

Single-Channel Properties In Endoplasmic Reticulum Membrane Of Recombinant Type 3 Inositol Trisphosphate Receptor., D O Mak, S Mcbride, V Raghuram, Y Yue, Suresh K. Joseph, J K Foskett

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The inositol 1,4,5-trisphosphate receptor (InsP(3)R) is an intracellular Ca(2+)-release channel localized in endoplasmic reticulum (ER) with a central role in complex Ca(2+) signaling in most cell types. A family of InsP(3)Rs encoded by several genes has been identified with different primary sequences, subcellular locations, variable ratios of expression, and heteromultimer formation. This diversity suggests that cells require distinct InsP(3)Rs, but the functional correlates of this diversity are largely unknown. Lacking are single-channel recordings of the recombinant type 3 receptor (InsP(3)R-3), a widely expressed isoform also implicated in plasma membrane Ca(2+) influx and apoptosis. Here, we describe functional expression and single-channel …

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Impact Of Bovine Oocyte Maturation Media On Oocyte Transcript Levels, Blastocyst Development, Cell Number, And Apoptosis., A J Watson, P De Sousa, A Caveney, L C Barcroft, D Natale, J Urquhart, M E Westhusin Feb 2000

Impact Of Bovine Oocyte Maturation Media On Oocyte Transcript Levels, Blastocyst Development, Cell Number, And Apoptosis., A J Watson, P De Sousa, A Caveney, L C Barcroft, D Natale, J Urquhart, M E Westhusin

Obstetrics & Gynaecology Publications

The objectives were 1) to investigate the effects of oocyte maturation in serum-free and amino acid-supplemented defined media on oocyte transcript levels, blastocyst cell number, and apoptosis; 2) to investigate the influence of oocyte maturation culture atmosphere on blastocyst development, total cell number, and apoptosis; and 3) to examine the influence of epidermal growth factor (EGF) during oocyte maturation on blastocyst cell number and apoptosis. The results demonstrate that blastocysts derived from in vitro maturation, fertilization, and embryo culture protocols undergo apoptosis but that apoptotic levels are not greatly influenced by the oocyte maturation environment. Amino acid supplementation of oocyte …

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Vanadate Induces P53 Transactivation Through Hydrogen Peroxide And Causes Apoptosis, Chuanshu Huang, Zhuo Zhang, Min Ding, Yongyut Rojanasakul Jan 2000

Vanadate Induces P53 Transactivation Through Hydrogen Peroxide And Causes Apoptosis, Chuanshu Huang, Zhuo Zhang, Min Ding, Yongyut Rojanasakul

Faculty & Staff Scholarship

No abstract provided.

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Effects Of Superovulated Heifer Diet Type And Quantity On Relative Mrna Abundances And Pyruvate Metabolism In Recovered Embryos., C Wrenzycki, P De Sousa, E W Overström, R T Duby, D Herrmann, A J Watson, H Niemann, D O'Callaghan, M P Boland Jan 2000

Effects Of Superovulated Heifer Diet Type And Quantity On Relative Mrna Abundances And Pyruvate Metabolism In Recovered Embryos., C Wrenzycki, P De Sousa, E W Overström, R T Duby, D Herrmann, A J Watson, H Niemann, D O'Callaghan, M P Boland

Obstetrics & Gynaecology Publications

This study investigated the effects of quantity and type of diet fed to superovulated donor heifers on molecular and metabolic indices of embryonic development. These effects included the relative abundances of mRNAs for the alpha 1 subunit of Na/K-ATPase and the antioxidant enzyme Cu/Zn-SOD, as well as pyruvate utilization in bovine morulae and blastocysts developed in vivo. Heifers were fed a daily ration of either grass silage and a citrus-beet pulp-based concentrate or grass silage and a barley-based concentrate for 116 days, both at 3 kg per day or ad libitum. In embryos derived from heifers fed the pulp-based diets, …

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Pet Animals: What Happens When Their Humans Die?, Gerry W. Beyer Jan 2000

Pet Animals: What Happens When Their Humans Die?, Gerry W. Beyer

Santa Clara Law Review

No abstract provided.

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Response Of The Tick Dermacentor Variabilis (Acari: Ixodidae) To Hemocoelic Inoculation Of Borrelia Burgdorferi (Spirochetales), Robert Johns, Daniel E. Sonenshine, Wayne L. Hynes Jan 2000

Response Of The Tick Dermacentor Variabilis (Acari: Ixodidae) To Hemocoelic Inoculation Of Borrelia Burgdorferi (Spirochetales), Robert Johns, Daniel E. Sonenshine, Wayne L. Hynes

Biological Sciences Faculty Publications

When Borrelia burgdorferi B31 low passage strain spirochetes were directly injected into the hemocoel of Dermacentor variabilis(Say) females, the bacteria were cleared from the hemocoel within < 24 h. Viable spirochetes were not found in hemolymph, salivary gland, or ovary tissues by subculturing or by IFA. The hemocyte population increased ≈6 times within the first 6 h after inoculation compared with the uninoculated controls. In contrast, the soluble total hemolymph protein content decreased inversely with the increase in hemocytes. Borreliacidal activity was demonstrated with cell-free hemolymph from D. variabilis. In vitro antimicrobial assays using hemolymph from borrelia-challenged and nonchallenged ticks resulted in 72% spirochete reductions compared with only 11.5%, respectively, within 1 h. Additional evidence of induced antimicrobial hemolymph protein activity was demonstrated by SDS-PAGE, which revealed upregulation of a lysozyme-like peptide (≈ 15 kDa) (22% increase) and the induction of a ≈ 5.8 kDa peptide in the B. burgdorferi-challenged ticks. In contrast with the nonvector borne Bacillus subtilis …

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Lineage-Restricted Function Of Nuclear Factor Kappab-Inducing Kinase (Nik) In Transducing Signals Via Cd40., Norman Garceau, Yoko Kosaka, Sally Masters, John Hambor, Reiko Shinkura, Tasuko Honjo, Randolph J. Noelle Jan 2000

Lineage-Restricted Function Of Nuclear Factor Kappab-Inducing Kinase (Nik) In Transducing Signals Via Cd40., Norman Garceau, Yoko Kosaka, Sally Masters, John Hambor, Reiko Shinkura, Tasuko Honjo, Randolph J. Noelle

Dartmouth Scholarship

CD40 signaling in B cells and dendritic cells (DCs) is critical for the development of humoral and cell-mediated immunity, respectively. Nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK) has been implicated as a central transducing kinase in CD40-dependent activation. Here, we show that although NIK is essential for B cell activation, it is dispensable for activation of DCs. Such data provide compelling evidence that different intermediary kinases are used by different cellular lineages to trigger NF-kappaB activation via CD40.

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A Cultivated Taste For Yeast., C Brenner Jan 2000

A Cultivated Taste For Yeast., C Brenner

Kimmel Cancer Center Faculty Papers

The availability of complete genomic sequences of Saccharomyces cerevisiae has catalyzed a cultural change in the practice of yeast biology, providing opportunities to develop high throughput techniques to define protein function, to define drug targets, and to discover and characterize drugs.

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Introducing Animals To New Foods, Behave Jan 2000

Introducing Animals To New Foods, Behave

All Current Publications

This publication explains different ways of successfully introducing animals to new foods.

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A Pdz-Interacting Domain In Cftr Is An Apical Membrane Polarization Signal, Bryan D. Moyer, Jerod Denton, Katherine H. Karlson, Donna Reynolds, Shusheng Wang, John E. Mickle, Michael Milewski, Garry R. Cutting, William B. Guggino, Min Li, Bruce A. Stanton Nov 1999

A Pdz-Interacting Domain In Cftr Is An Apical Membrane Polarization Signal, Bryan D. Moyer, Jerod Denton, Katherine H. Karlson, Donna Reynolds, Shusheng Wang, John E. Mickle, Michael Milewski, Garry R. Cutting, William B. Guggino, Min Li, Bruce A. Stanton

Dartmouth Scholarship

Polarization of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, to the apical plasma membrane of epithelial cells is critical for vectorial transport of chloride in a variety of epithelia, including the airway, pancreas, intestine, and kidney. However, the motifs that localize CFTR to the apical membrane are unknown. We report that the last 3 amino acids in the COOH-terminus of CFTR (T-R-L) comprise a PDZ-interacting domain that is required for the polarization of CFTR to the apical plasma membrane in human airway and kidney epithelial cells. In addition, the CFTR mutant, S1455X, which lacks the 26 …

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Dynactin Is Required For Microtubule Anchoring At Centrosomes, N J. Quintyne, S. R. Gill, D M. Eckley, C L. Crego, D A. Compton, T A. Schroer Oct 1999

Dynactin Is Required For Microtubule Anchoring At Centrosomes, N J. Quintyne, S. R. Gill, D M. Eckley, C L. Crego, D A. Compton, T A. Schroer

Dartmouth Scholarship

The multiprotein complex, dynactin, is an integral part of the cytoplasmic dynein motor and is required for dynein-based motility in vitro and in vivo. In living cells, perturbation of the dynein–dynactin interaction profoundly blocks mitotic spindle assembly, and inhibition or depletion of dynein or dynactin from meiotic or mitotic cell extracts prevents microtubules from focusing into spindles. In interphase cells, perturbation of the dynein–dynactin complex is correlated with an inhibition of ER-to-Golgi movement and reorganization of the Golgi apparatus and the endosome–lysosome system, but the effects on microtubule organization have not previously been defined. To explore this question, we overexpressed …

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A Defect In Interleukin 12-Induced Activation And Interferon Gamma Secretion Of Peripheral Natural Killer T Cells In Nonobese Diabetic Mice Suggests New Pathogenic Mechanisms For Insulin-Dependent Diabetes Mellitus., Marika Falcone, Brian Yeung, Lee Tucker, Enrique Rodriguez, Nora Sarvetnick Oct 1999

A Defect In Interleukin 12-Induced Activation And Interferon Gamma Secretion Of Peripheral Natural Killer T Cells In Nonobese Diabetic Mice Suggests New Pathogenic Mechanisms For Insulin-Dependent Diabetes Mellitus., Marika Falcone, Brian Yeung, Lee Tucker, Enrique Rodriguez, Nora Sarvetnick

Journal Articles: Regenerative Medicine

The function of natural killer T (NKT) cells in the immune system has yet to be determined. There is some evidence that their defect is associated with autoimmunity, but it is still unclear how they play a role in regulating the pathogenesis of T cell-mediated autoimmune diseases. It was originally proposed that NKT cells could control autoimmunity by shifting the cytokine profile of autoimmune T cells toward a protective T helper 2 cell (Th2) type. However, it is now clear that the major function of NKT cells in the immune system is not related to their interleukin (IL)-4 secretion. In …

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Phosphoinositide-Ap-2 Interactions Required For Targeting To Plasma Membrane Clathrin-Coated Pits., I Gaidarov, James H. Keen Aug 1999

Phosphoinositide-Ap-2 Interactions Required For Targeting To Plasma Membrane Clathrin-Coated Pits., I Gaidarov, James H. Keen

Department of Microbiology and Immunology Faculty Papers

The clathrin-associated AP-2 adaptor protein is a major polyphosphoinositide-binding protein in mammalian cells. A high affinity binding site has previously been localized to the NH(2)-terminal region of the AP-2 alpha subunit (Gaidarov et al. 1996. J. Biol. Chem. 271:20922-20929). Here we used deletion and site- directed mutagenesis to determine that alpha residues 21-80 comprise a discrete folding and inositide-binding domain. Further, positively charged residues located within this region are involved in binding, with a lysine triad at positions 55-57 particularly critical. Mutant peptides and protein in which these residues were changed to glutamine retained wild-type structural and functional characteristics by …

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Insulin-Like Growth Factor Ii Signaling In Neoplastic Proliferation Is Blocked By Transgenic Expression Of The Metalloproteinase Inhibitor Timp-1, David C. Martin, John L. Fowlkes, Bojana Babic, Rama Khokha Aug 1999

Insulin-Like Growth Factor Ii Signaling In Neoplastic Proliferation Is Blocked By Transgenic Expression Of The Metalloproteinase Inhibitor Timp-1, David C. Martin, John L. Fowlkes, Bojana Babic, Rama Khokha

Pediatrics Faculty Publications

Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])-induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1-overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were …

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Global Cns Gene Transfer For A Childhood Neurogenetic Enzyme Deficiency: Canavan Disease., Paola Leone, Christopher G Janson, Scott J Mcphee, Matthew J During Aug 1999

Global Cns Gene Transfer For A Childhood Neurogenetic Enzyme Deficiency: Canavan Disease., Paola Leone, Christopher G Janson, Scott J Mcphee, Matthew J During

Department of Neurosurgery Faculty Papers

The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant …

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Interaction Between Fgf And Bmp Signaling Pathways Regulates Development Of Metanephric Mesenchyme., Andrew T. Dudley, R. E. Godin, E. J. Robertson Jun 1999

Interaction Between Fgf And Bmp Signaling Pathways Regulates Development Of Metanephric Mesenchyme., Andrew T. Dudley, R. E. Godin, E. J. Robertson

Journal Articles: Genetics, Cell Biology & Anatomy

Nephrogenesis in the mouse kidney begins at embryonic day 11 and ends approximately 10 days postpartum. During this period, new nephrons are continually being generated from a stem-cell population-the nephrogenic mesenchyme-in response to signals emanating from the tips of the branching ureter. Relatively little is known about the mechanism by which the nephrogenic mesenchyme cell population is maintained at the tips of the ureter in the presence of signals promoting tubulogenesis. Previous studies have shown that a loss of Bmp7 function leads to kidney defects that are a likely result of progressive loss of nephrogenic mesenchyme by apoptosis. The studies …

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Beta- And Gamma-Catenin Mutations, But Not E-Cadherin Inactivation, Underlie T-Cell Factor/Lymphoid Enhancer Factor Transcriptional Deregulation In Gastric And Pancreatic Cancer., K Caca, F T Kolligs, X Ji, M Hayes, J Qian, Alan M. Yahanda Md, Facs, D L Rimm, J Costa, E R Fearon Jun 1999

Beta- And Gamma-Catenin Mutations, But Not E-Cadherin Inactivation, Underlie T-Cell Factor/Lymphoid Enhancer Factor Transcriptional Deregulation In Gastric And Pancreatic Cancer., K Caca, F T Kolligs, X Ji, M Hayes, J Qian, Alan M. Yahanda Md, Facs, D L Rimm, J Costa, E R Fearon

PCI Publications and Projects

Adenomatous polyposis coli (APC) mutations are present in >70% of colon cancers. The APC protein binds to beta-catenin (beta-cat), a protein first identified because of its role in E-cadherin (E-cad) cell adhesion. In some colon cancers lacking APC defects, mutations in presumptive glycogen synthase kinase 3beta phosphorylation sites near the beta-cat NH2 terminus appear to render beta-cat resistant to regulation by APC and glycogen synthase kinase 3beta. In cells with APC or beta-cat defects, beta-cat is stabilized and, in turn, binds to and activates T-cell factor (Tcf)/lymphoid enhancer factor (Lef) transcription factors. To further explore the role of APC, beta-cat, …

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