Life Sciences Commons^™

Morpholino Gene Knockdown In Adult Fundulus Heteroclitus: Role Of Sgk1 In Seawater Acclimation, Emily G. Notch, Joseph R. Shaw, Bonita A. Coutermarsh, Marisa Dzioba, Bruce A. Stanton

Dartmouth Scholarship

The Atlantic killifish (Fundulus heteroclitus) is an environmental sentinel organism used extensively for studies on environmental toxicants and salt (NaCl) homeostasis. Previous research in our laboratory has shown that rapid acclimation of killifish to seawater is mediated by trafficking of CFTR chloride channels from intracellular vesicles to the plasma membrane in the opercular membrane within the first hour in seawater, which enhances chloride secretion into seawater, thereby contributing to salt homeostasis. Acute transition to seawater is also marked by an increase in both mRNA and protein levels of serum glucocorticoid kinase 1 (SGK1) within 15 minutes of transfer. …

A Shared Gene Expression Signature In Mouse Models Of Ebv-Associated And Non-Ebv-Associated Burkitt Lymphoma, Kathryn T. Bieging, Kamonwan Fish, Subbarao Bondada, Richard Longnecker

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional …

Juvenile Hormone Regulates Vitellogenin Gene Expression Through Insulin-Like Peptide Signaling Pathway In The Red Flour Beetle, Tribolium Castaneum, Zhentao Sheng, Jingjing Xu, Hua Bai, Fang Zhu, Subba R. Palli

Entomology Faculty Publications

Our recent studies identified juvenile hormone (JH) and nutrition as the two key signals that regulate vitellogenin (Vg) gene expression in the red flour beetle, Tribolium castaneum. Juvenile hormone regulation of Vg synthesis has been known for a long time in several insects, but the mechanism of JH action is not known. Experiments were conducted to determine the mechanism of action of these two signals in regulation of Vg gene expression. Injection of bovine insulin or FOXO double-stranded RNA into the previtellogenic, starved, or JH-deficient female adults increased Vg mRNA and protein levels, thereby implicating the pivotal role for …

Predator Mediated Selection And The Impact Of Developmental Stage On Viability In Wood Frog Tadpoles (Rana Sylvatica), Ryan Calsbeek, Shawn Kuchta

Dartmouth Scholarship

Complex life histories require adaptation of a single organism for multiple ecological niches. Transitions between life stages, however, may expose individuals to an increased risk of mortality, as the process of metamorphosis typically includes developmental stages that function relatively poorly in both the pre- and post-metamorphic habitat. We studied predator-mediated selection on tadpoles of the wood frog, Rana sylvatica, to identify this hypothesized period of differential predation risk and estimate its ontogenetic onset. We reared tadpoles in replicated mesocosms in the presence of the larval odonate Anax junius, a known tadpole predator.

Maternal Separation Affects Dopamine Transporter Function In The Spontaneously Hypertensive Rat: An In Vivo Electrochemical Study, Jacqueline S. Womersley, Jennifer H. Hsieh, Lauriston A. Kellaway, Greg A. Gerhardt, Vivienne A. Russell

Neuroscience Faculty Publications

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR) is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT) in ways that distinguish SHR …

Functional Genomics Reveals An Essential And Specific Role For Stat1 In Protection Of The Central Nervous System Following Herpes Simplex Virus Corneal Infection, Tracy J. Pasieka, Cristian Cilloniz, Victoria S. Carter, Pamela Rosato, Michael G. Katze, David A. Leib

Dartmouth Scholarship

Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), …

Therapeutic Targeting Of C-Terminal Binding Protein In Human Cancer, Michael W. Straza, Seema Paliwal, Ramesh C. Kovi, Barur R. Rajeshkumar, Peter Trenh, Daniel Parker, Giles F. Whalen, Stephen Lyle, Celia A. Schiffer, Steven R. Grossman

Celia A. Schiffer

The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable …

Accounting For Molecular Mobility In Structure Determination Based On Nuclear Magnetic Resonance Spectroscopic And X-Ray Diffraction Data, Wilfred Van Gunsteren, Roger Brunne, P. Gros, René Van Schaik, Celia Schiffer, Andrew Torda

Celia A. Schiffer

No abstract provided.

Design Of Hiv-1 Protease Inhibitors Active On Multidrug-Resistant Virus, Dominique Surleraux, Herman De Kock, Wim Verschueren, Geert Pille, Louis Maes, Anik Peeters, Sandrine Vendeville, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck

Celia A. Schiffer

On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile …

Prediction Of Homologous Protein Structures Based On Conformational Searches And Energetics, Celia Schiffer, James Caldwell, Peter Kollman, Robert Stroud

Celia A. Schiffer

A "knowledge-based" method of predicting the unknown structure of a protein from a homologous known structure using energetics to determine a sidechain conformation is proposed. The method consists of exchanging the residues in the known structure for the sequence of the unknown protein. Then a conformational search with molecular mechanics energy minimization is done on the exchanged residues. The lowest energy conformer is the one picked to be the predicted structure. In the structure of bovine trypsin, the importance of including a solvation energy term in the search is demonstrated for solvent accessible residues, while molecular mechanics alone is enough …

Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck

Celia A. Schiffer

The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high …

Additive Functions In Boolean Models Of Gene Regulatory Network Modules, Christian Darabos, Ferdinando Ferdinando Di Cunto, Marco Tomassini, Jason H. Moore

Dartmouth Scholarship

Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome’s evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We …

Age-Associated Disruption Of Molecular Clock Expression In Skeletal Muscle Of The Spontaneously Hypertensive Rat, Mitsunori Miyazaki, Elizabeth Schroder, Stephanie E. Edelmann, Michael E. Hughes, Karl Kornacker, C. William Balke, Karyn A. Esser

Physiology Faculty Publications

It is well known that spontaneously hypertensive rats (SHR) develop muscle pathologies with hypertension and heart failure, though the mechanism remains poorly understood. Woon et al. (2007) linked the circadian clock gene Bmal1 to hypertension and metabolic dysfunction in the SHR. Building on these findings, we compared the expression pattern of several core-clock genes in the gastrocnemius muscle of aged SHR (80 weeks; overt heart failure) compared to aged-matched control WKY strain. Heart failure was associated with marked effects on the expression of Bmal1, Clock and Rora in addition to several non-circadian genes important in regulating skeletal muscle phenotype including …

Differential Il-21 Signaling In Apcs Leads To Disparate Th17 Differentiation In Diabetes-Susceptible Nod And Diabetes-Resistant Nod.Idd3 Mice., Sue M. Liu, David H. Lee, Jenna M. Sullivan, Denise Chung, Anneli Jäger, Bennett O V. Shum, Nora E. Sarvetnick, Ana C. Anderson, Vijay K. Kuchroo

Journal Articles: Regenerative Medicine

Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated. Here we show that T cells from NOD mice produce more Il21 and less Il2 and exhibit enhanced Th17 cell generation compared with …

Erect Wing Facilitates Context-Dependent Wnt/Wingless Signaling By Recruiting The Cell-Specific Armadillo-Tcf Adaptor Earthbound To Chromatin, Nan Xin, Hassina Benchabane, Ai Tian, Kerrie Nguyen, Lindsay Klofas, Yashi Ahmed

Dartmouth Scholarship

During metazoan development, the Wnt/Wingless signal transduction pathway is activated repetitively to direct cell proliferation, fate specification, differentiation and apoptosis. Distinct outcomes are elicited by Wnt stimulation in different cellular contexts; however, mechanisms that confer context specificity to Wnt signaling responses remain largely unknown. Starting with an unbiased forward genetic screen in Drosophila, we recently uncovered a novel mechanism by which the cell-specific co-factor Earthbound 1 (Ebd1), and its human homolog jerky, promote interaction between the Wnt pathway transcriptional co-activators B-catenin/Armadillo and TCF to facilitate context-dependent Wnt signaling responses. Here, through the same genetic screen, we find an unanticipated requirement …

Reversal Of Glial And Neurovascular Markers Of Unhealthy Brain Aging By Exercise In Middle-Aged Female Mice, Caitlin S. Latimer, James L. Searcy, Michael T. Bridges, Lawrence D. Brewer, Jelena Popović, Eric M. Blalock, Philip W. Landfield, Olivier Thibault, Nada M. Porter

Pharmacology and Nutritional Sciences Faculty Publications

Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for …

Thrombospondin1 Deficiency Reduces Obesity-Associated Inflammation And Improves Insulin Sensitivity In A Diet-Induced Obese Mouse Model, Yanzhang Li, Xiaopeng Tong, Courtney Rumala, Kate Clemons, Shuxia Wang

Graduate Center for Nutritional Sciences Faculty Publications

BACKGROUND: Obesity is prevalent worldwide and is associated with insulin resistance. Advanced studies suggest that obesity-associated low-grade chronic inflammation contributes to the development of insulin resistance and other metabolic complications. Thrombospondin 1 (TSP1) is a multifunctional extracellular matrix protein that is up-regulated in inflamed adipose tissue. A recent study suggests a positive correlation of TSP1 with obesity, adipose inflammation, and insulin resistance. However, the direct effect of TSP1 on obesity and insulin resistance is not known. Therefore, we investigated the role of TSP1 in mediating obesity-associated inflammation and insulin resistance by using TSP1 knockout mice.

METHODOLOGY/PRINCIPAL FINDINGS: Male TSP1-/- mice …

Splice Variant–Specific Cellular Function Of The Formin Inf2 In Maintenance Of Golgi Architecture, Vinay Ramabhadran, Farida Korobova, Gilbert J. Rahme, Henry N. Higgs

Dartmouth Scholarship

INF2 is a unique formin that can both polymerize and depolymerize actin filaments. Mutations in INF2 cause the kidney disease focal and segmental glomerulosclerosis. INF2 can be expressed as two C-terminal splice variants: CAAX and non-CAAX. The CAAX isoform contains a C-terminal prenyl group and is tightly bound to endoplasmic reticulum (ER). The localization pattern and cellular function of the non-CAAX isoform have not been studied. Here we find that the two isoforms are expressed in a cell type-dependent manner, with CAAX predominant in 3T3 fibroblasts and non-CAAX predominant in U2OS, HeLa, and Jurkat cells. Although INF2-CAAX is ER localized …

Wolbachia Infections That Reduce Immature Insect Survival: Predicted Impacts On Population Replacement, Philip R. Crain, James W. Mains, Eunho Suh, Yunxin Huang, Philip H. Crowley, Stephen L. Dobson

Entomology Faculty Publications

BACKGROUND: The evolutionary success of Wolbachia bacteria, infections of which are widespread in invertebrates, is largely attributed to an ability to manipulate host reproduction without imposing substantial fitness costs. Here, we describe a stage-structured model with deterministic immature lifestages and a stochastic adult female lifestage. Simulations were conducted to better understand Wolbachia invasions into uninfected host populations. The model includes conventional Wolbachia parameters (the level of cytoplasmic incompatibility, maternal inheritance, the relative fecundity of infected females, and the initial Wolbachia infection frequency) and a new parameter termed relative larval viability (RLV), which is the survival of infected larvae relative to …

Demasculinization And Feminization Of Male Gonads By Atrazine: Consistent Effects Across Vertebrate Classes, Krista A. Mccoy

Integrative Biology Faculty and Staff Publications

Atrazine is the most commonly detected pesticide contaminant of ground water, surface water, and precipitation. Atrazine is also an endocrine disruptor that, among other effects, alters male reproductive tissues when animals are exposed during development. Here, we apply the nine so-called “Hill criteria” (Strength, Consistency, Specificity, Temporality, Biological Gradient, Plausibility, Coherence, Experiment, and Analogy) for establishing cause–effect relationships to examine the evidence for atrazine as an endocrine disruptor that demasculinizes and feminizes the gonads of male vertebrates. We present experimental evidence that the effects of atrazine on male development are consistent across all vertebrate classes examined and we present a …

Differential Interactions Of The Formins Inf2, Mdia1, And Mdia2 With Microtubules, Jeremie Gaillard, Bvinay Ramabhadran, Emmanuelle Neumanne, Pinar Gurel, Laurent Blanchoin, Marylin Vantard, Henry N. Higgs

Dartmouth Scholarship

A number of cellular processes use both microtubules and actin filaments, but the molecular machinery linking these two cytoskeletal elements remains to be elucidated in detail. Formins are actin-binding proteins that have multiple effects on actin dynamics, and one formin, mDia2, has been shown to bind and stabilize microtubules through its formin homology 2 (FH2) domain. Here we show that three formins, INF2, mDia1, and mDia2, display important differences in their interactions with microtubules and actin. Constructs containing FH1, FH2, and C-terminal domains of all three formins bind microtubules with high affinity (K(d) < 100 nM). However, only mDia2 binds microtubules at 1:1 stoichiometry, with INF2 and mDia1 showing saturating binding at approximately 1:3 (formin dimer:tubulin dimer). INF2-FH1FH2C is a potent microtubule-bundling protein, an effect that results in a large reduction in catastrophe rate. In contrast, neither mDia1 nor mDia2 is a potent microtubule bundler. The C-termini of mDia2 and INF2 have different functions in microtubule interaction, with mDia2's C-terminus required for high-affinity binding and INF2's C-terminus required for bundling. mDia2's C-terminus directly binds microtubules with submicromolar affinity. These formins also differ in their abilities to bind actin and microtubules simultaneously. Microtubules strongly inhibit actin polymerization by mDia2, whereas they moderately inhibit mDia1 and have no effect on INF2. Conversely, actin monomers inhibit microtubule binding/bundling by INF2 but do not affect mDia1 or mDia2. These differences in interactions with microtubules and actin suggest differential function in cellular processes requiring both cytoskeletal elements.

A Mathematical Model Of Muscle Containing Heterogeneous Half-Sarcomeres Exhibits Residual Force Enhancement, Stuart G. Campbell, P. Chris Hatfield, Kenneth S. Campbell

Physiology Faculty Publications

A skeletal muscle fiber that is stimulated to contract and then stretched from L₁ to L₂ produces more force after the initial transient decays than if it is stimulated at L₂. This behavior has been well studied experimentally, and is known as residual force enhancement. The underlying mechanism remains controversial. We hypothesized that residual force enhancement could reflect mechanical interactions between heterogeneous half-sarcomeres. To test this hypothesis, we subjected a computational model of interacting heterogeneous half-sarcomeres to the same activation and stretch protocols that produce residual force enhancement in real preparations. Following a transient period of elevated force associated with …

Functional Plasticity Of Central Trpv1 Receptors In Brainstem Dorsal Vagal Complex Circuits Of Streptozotocin-Treated Hyperglycemic Mice, Andrea Zsombok, Muthu D. Bhaskaran, Hong Gao, Andrei V. Derbenev, Bret N. Smith

Physiology Faculty Publications

Emerging data indicate that central neurons participate in diabetic processes by modulating autonomic output from neurons in the dorsal motor nucleus of the vagus (DMV). We tested the hypothesis that synaptic modulation by transient receptor potential vanilloid type 1 (TRPV1) receptors is reduced in the DMV in slices from a murine model of type 1 diabetes. The TRPV1 agonist capsaicin robustly enhanced glutamate release onto DMV neurons by acting at preterminal receptors in slices from intact mice, but failed to do so in slices from diabetic mice. TRPV1 receptor protein expression in the vagal complex was unaltered. Brief insulin preapplication …

Ecology And Genetic Structure Of A Northern Temperate Vibrio Cholerae Population Related To Toxigenic Isolates, Brian M. Schuster, Anna L. Tyzik, Rachel A. Donner, Megan J. Striplin, Salvador Almagro-Moreno

Dartmouth Scholarship

Although Vibrio cholerae is an important human pathogen, little is known about its populations in regions where the organism is endemic but where cholera disease is rare. A total of 31 independent isolates confirmed as V. cholerae were collected from water, sediment, and oysters in 2008 and 2009 from the Great Bay Estuary (GBE) in New Hampshire, a location where the organism has never been detected. Environmental analyses suggested that abundance correlates most strongly with rainfall events, as determined from data averaged over several days prior to collection. Phenotyping, genotyping, and multilocus sequence analysis (MLSA) revealed a highly diverse endemic …

Despotism And Risk Of Infanticide Influence Grizzly Bear Den-Site Selection, Nathan S. Libal, Jerrold L. Belant, Bruce D. Leopold, Guiming Wang, Patricia A. Owen

College of Forest Resources Publications and Scholarship

Given documented social dominance and intraspecific predation in bear populations, the ideal despotic distribution model and sex hypothesis of sexual segregation predict adult female grizzly bears (Ursus arctos) will avoid areas occupied by adult males to reduce risk of infanticide. Under ideal despotic distribution, juveniles should similarly avoid adult males to reduce predation risk. Den-site selection and use is an important component of grizzly bear ecology and may be influenced by multiple factors, including risk from conspecifics. To test the role of predation risk and the sex hypothesis of sexual segregation, we compared adult female (n = 142), adult male …

Toxoplasma Gondii Rhoptry Kinase Rop16 Activates Stat3 And Stat6 Resulting In Cytokine Inhibition And Arginase-1-Dependent Growth Control, Barbara A. Butcher, Barbara A. Fox, Leah M. Rommereim, Sung Guk Kim, Kirk J. Maurer, Felix Yarovinsky, De'broski R. Herbert, David J. Bzik, Eric Y. Denkers

Dartmouth Scholarship

The ROP16 kinase of Toxoplasma gondii is injected into the host cell cytosol where it activates signal transducer and activator of transcription (STAT)-3 and STAT6. Here, we generated a ROP16 deletion mutant on a Type I parasite strain background, as well as a control complementation mutant with restored ROP16 expression. We investigated the biological role of the ROP16 molecule during T. gondii infection. Infection of mouse bone marrow-derived macrophages with rop16-deleted (ΔROP16) parasites resulted in increased amounts of IL-12p40 production relative to the ROP16-positive RH parental strain. High level IL-12p40 production in ΔROP16 infection was dependent on the host …

Type Ii Toxoplasma Gondii Ku80 Knockout Strains Enable Functional Analysis Of Genes Required For Cyst Development And Latent Infection, Barbara A. Fox, Alejandra Falla, Leah M. Rommereim, Tadakimi Tomita

Dartmouth Scholarship

Type II Toxoplasma gondii KU80 knockouts (Δku80) deficient in nonhomologous end joining were developed to delete the dominant pathway mediating random integration of targeting episomes. Gene targeting frequency in the type II Δku80 Δhxgprt strain measured at the orotate (OPRT) and the uracil (UPRT) phosphoribosyltransferase loci was highly efficient. To assess the potential of the type II Δku80 Δhxgprt strain to examine gene function affecting cyst biology and latent stages of infection, we targeted the deletion of four parasite antigen genes (GRA4, GRA6, ROP7, and tgd057 …

Utah’S Adaptive Resources Management Greater Sage-Grouse Local Working Groups Accomplishment Report, Utah State University Extension

All Current Publications

No abstract provided.

An Evolutionarily Conserved Rit Gtpase-P38 Mapk Signaling Pathway Mediates Oxidative Stress Resistance, Weikang Cai, Jennifer L. Rudolph, Susan M. W. Harrison, Ling Jin, Aubrey L. Frantz, Douglas A. Harrison, Douglas A. Andres

Molecular and Cellular Biochemistry Faculty Publications

Ras-related small GTP-binding proteins control a wide range of cellular processes by regulating a variety of effector pathways, including prominent roles in the control of mitogen-activated protein kinase (MAPK) cascades. Although the regulatory role(s) for many Ras family GTPases are well established, the physiological function for the Rit/Rin subfamily has been lacking. Here, using both knockout mice and Drosophila models, we demonstrate an evolutionarily conserved role for Rit subfamily GTPases (mammalian Rit and Rin, and the Drosophila RIC homologue) in governing survival in response to oxidative stress. Primary embryonic fibroblasts derived from Rit knockout mice display increased apoptosis and selective …

A Model Of Intracellular Θ Phase Precession Dependent On Intrinsic Subthreshold Membrane Currents., L Stan Leung

Physiology and Pharmacology Publications

A hippocampal place cell fires at an increasingly earlier phase in relation to the extracellular theta rhythm as a rodent moves through the place field. The present report presents a compartment model of a CA1 pyramidal cell that explains the increase in amplitude and the phase precession of intracellular theta oscillations, with the assumption that the cell receives an asymmetric ramp depolarization (<10 >mV) in the place field and rhythmic inhibitory and/or excitatory synaptic driving. Intracellular subthreshold membrane potential oscillations (MPOs) increase in amplitude and frequency, and show phase precession within the place field. Theta phase precession and MPO power …