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Local, nonlinear effects of cGMP and Ca2+ reduce single photon response variability in retinal rods.
Caruso G, Gurevich VV, Klaus C, Hamm H, Makino CL, DiBenedetto E
(2019) PLoS One 14: e0225948
MeSH Terms: Algorithms, Animals, Biomarkers, Calcium, Cyclic GMP, Mice, Models, Biological, Photons, Retinal Rod Photoreceptor Cells, Rod Cell Outer Segment, Signal Transduction
Show Abstract · Added March 18, 2020
The single photon response (SPR) in vertebrate photoreceptors is inherently variable due to several stochastic events in the phototransduction cascade, the main one being the shutoff of photoactivated rhodopsin. Deactivation is driven by a random number of steps, each of random duration with final quenching occurring after a random delay. Nevertheless, variability of the SPR is relatively low, making the signal highly reliable. Several biophysical and mathematical mechanisms contributing to variability suppression have been examined by the authors. Here we investigate the contribution of local depletion of cGMP by PDE*, the non linear dependence of the photocurrent on cGMP, Ca2+ feedback by making use of a fully space resolved (FSR) mathematical model, applied to two species (mouse and salamander), by varying the cGMP diffusion rate severalfold and rod outer segment diameter by an order of magnitude, and by introducing new, more refined, and time dependent variability functionals. Globally well stirred (GWS) models, and to a lesser extent transversally well stirred models (TWS), underestimate the role of nonlinearities and local cGMP depletion in quenching the variability of the circulating current with respect to fully space resolved models (FSR). These distortions minimize the true extent to which SPR is stabilized by locality in cGMP depletion, nonlinear effects linking cGMP to current, and Ca2+ feedback arising from the physical separation of E* from the ion channels located on the outer shell, and the diffusion of these second messengers in the cytoplasm.
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11 MeSH Terms
The novel interaction between Neisseria gonorrhoeae TdfJ and human S100A7 allows gonococci to subvert host zinc restriction.
Maurakis S, Keller K, Maxwell CN, Pereira K, Chazin WJ, Criss AK, Cornelissen CN
(2019) PLoS Pathog 15: e1007937
MeSH Terms: Amino Acid Sequence, Animals, Bacterial Outer Membrane Proteins, Gonorrhea, Host-Pathogen Interactions, Humans, Mice, Neisseria gonorrhoeae, S100 Calcium Binding Protein A7, Zinc
Show Abstract · Added March 11, 2020
Neisseria gonorrhoeae causes the sexually-transmitted infection gonorrhea, a global disease that is difficult to treat and for which there is no vaccine. This pathogen employs an arsenal of conserved outer membrane proteins called TonB-dependent transporters (TdTs) that allow the gonococcus to overcome nutritional immunity, the host strategy of sequestering essential nutrients away from invading bacteria to handicap infectious ability. N. gonorrhoeae produces eight known TdTs, of which four are utilized for acquisition of iron or iron chelates from host-derived proteins or xenosiderophores produced by other bacteria. Of the remaining TdTs, two of them, TdfH and TdfJ, facilitate zinc uptake. TdfH was recently shown to bind Calprotectin, a member of the S100 protein family, and subsequently extract its zinc, which is then internalized by N. gonorrhoeae. Like Calprotectin, other S100s are also capable of binding transition metals such as zinc and copper, and thus have demonstrated growth suppression of numerous other pathogens via metal sequestration. Considering the functional and structural similarities of the TdTs and of the S100s, as well as the upregulation in response to Zn limitation shown by TdfH and TdfJ, we sought to evaluate whether other S100s have the ability to support gonococcal growth by means of zinc acquisition and to frame this growth in the context of the TdTs. We found that both S100A7 and S10012 are utilized by N. gonorrhoeae as a zinc source in a mechanism that depends on the zinc transport system ZnuABC. Moreover, TdfJ binds directly to S100A7, from which it internalizes zinc. This interaction is restricted to the human version of S100A7, and zinc presence in S100A7 is required to fully support gonococcal growth. These studies highlight how gonococci co-opt human nutritional immunity, by presenting a novel interaction between TdfJ and human S100A7 for overcoming host zinc restriction.
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MeSH Terms
Identification of a pro-angiogenic functional role for FSP1-positive fibroblast subtype in wound healing.
Saraswati S, Marrow SMW, Watch LA, Young PP
(2019) Nat Commun 10: 3027
MeSH Terms: Actins, Animals, Bone Marrow Transplantation, Calcium-Binding Proteins, Cell Differentiation, Disease Models, Animal, Fibroblasts, Fibrosis, Green Fluorescent Proteins, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardial Infarction, Myocardium, Neovascularization, Physiologic, S100 Calcium-Binding Protein A4, Transplantation Chimera, Wound Healing
Show Abstract · Added March 24, 2020
Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Although activated fibroblasts are phenotypically heterogeneous, they are not recognized as distinct functional entities. Using mice that express GFP under the FSP1 or αSMA promoter, we characterized two non-overlapping fibroblast subtypes from mouse hearts after myocardial infarction. Here, we report the identification of FSP1-GFP cells as a non-pericyte, non-hematopoietic fibroblast subpopulation with a predominant pro-angiogenic role, characterized by in vitro phenotypic/cellular/ultrastructural studies and in vivo granulation tissue formation assays combined with transcriptomics and proteomics. This work identifies a fibroblast subtype that is functionally distinct from the pro-fibrotic αSMA-expressing myofibroblast subtype. Our study has the potential to shift our focus towards viewing fibroblasts as molecularly and functionally heterogeneous and provides a paradigm to approach treatment for organ fibrosis.
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Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.
Zurawski Z, Thompson Gray AD, Brady LJ, Page B, Church E, Harris NA, Dohn MR, Yim YY, Hyde K, Mortlock DP, Jones CK, Winder DG, Alford S, Hamm HE
(2019) Sci Signal 12:
MeSH Terms: Animals, Calcium, Exocytosis, GTP-Binding Protein alpha Subunits, Gi-Go, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Neural Inhibition, Phenotype, Protein Binding, Receptors, G-Protein-Coupled, Synaptic Transmission, Synaptosomal-Associated Protein 25
Show Abstract · Added February 22, 2019
G protein-coupled receptors (GPCRs) that couple to G proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction. SNAP25Δ3 homozygote mice exhibited normal presynaptic inhibition by GABA receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT receptors and adrenergic α receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP25Δ3 homozygote mice had various behavioral phenotypes, including increased stress-induced hyperthermia, defective spatial learning, impaired gait, and supraspinal nociception. These data suggest that the inhibition of exocytosis by G-coupled GPCRs through the Gβγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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15 MeSH Terms
S100 Proteins in the Innate Immune Response to Pathogens.
Kozlyuk N, Monteith AJ, Garcia V, Damo SM, Skaar EP, Chazin WJ
(2019) Methods Mol Biol 1929: 275-290
MeSH Terms: Calcium, Host-Pathogen Interactions, Humans, Immunity, Innate, Inflammation, Manganese, Models, Molecular, Protein Conformation, S100 Proteins, Toll-Like Receptor 4
Show Abstract · Added March 26, 2019
S100 proteins are distinct dimeric EF-hand Ca-binding proteins that can bind Zn, Mn, and other transition metals with high affinity at two sites in the dimer interface. Certain S100 proteins, including S100A7, S100A12, S100A8, and S100A9, play key roles in the innate immune response to pathogens. These proteins function via a "nutritional immunity" mechanism by depleting essential transition metals in the infection that are required for the invading organism to grow and thrive. They also act as damage-associated molecular pattern ligands, which activate pattern recognition receptors (e.g., Toll-like receptor 4, RAGE) that mediate inflammation. Here we present protocols for these S100 proteins for high-level production of recombinant protein, measurement of binding affinities using isothermal titration calorimetry, and an assay of antimicrobial activity.
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10 MeSH Terms
Glucose-mediated inhibition of calcium-activated potassium channels limits α-cell calcium influx and glucagon secretion.
Dickerson MT, Dadi PK, Altman MK, Verlage KR, Thorson AS, Jordan KL, Vierra NC, Amarnath G, Jacobson DA
(2019) Am J Physiol Endocrinol Metab 316: E646-E659
MeSH Terms: Alkanes, Animals, Apamin, Calcium, Calcium Channels, Calcium Channels, L-Type, Calcium Channels, P-Type, Calcium Channels, Q-Type, Endoplasmic Reticulum, Glucagon, Glucagon-Secreting Cells, Glucose, Mice, Mice, Transgenic, Patch-Clamp Techniques, Peptides, Potassium Channel Blockers, Potassium Channels, Calcium-Activated, Pyrazoles, Quinolinium Compounds
Show Abstract · Added February 13, 2019
Pancreatic α-cells exhibit oscillations in cytosolic Ca (Ca), which control pulsatile glucagon (GCG) secretion. However, the mechanisms that modulate α-cell Ca oscillations have not been elucidated. As β-cell Ca oscillations are regulated in part by Ca-activated K (K) currents, this work investigated the role of K in α-cell Ca handling and GCG secretion. α-Cells displayed K currents that were dependent on Ca influx through L- and P/Q-type voltage-dependent Ca channels (VDCCs) as well as Ca released from endoplasmic reticulum stores. α-Cell K was decreased by small-conductance Ca-activated K (SK) channel inhibitors apamin and UCL 1684, large-conductance Ca-activated K (BK) channel inhibitor iberiotoxin (IbTx), and intermediate-conductance Ca-activated K (IK) channel inhibitor TRAM 34. Moreover, partial inhibition of α-cell K with apamin depolarized membrane potential ( V) (3.8 ± 0.7 mV) and reduced action potential (AP) amplitude (10.4 ± 1.9 mV). Although apamin transiently increased Ca influx into α-cells at low glucose (42.9 ± 10.6%), sustained SK (38.5 ± 10.4%) or BK channel inhibition (31.0 ± 11.7%) decreased α-cell Ca influx. Total α-cell Ca was similarly reduced (28.3 ± 11.1%) following prolonged treatment with high glucose, but it was not decreased further by SK or BK channel inhibition. Consistent with reduced α-cell Ca following prolonged K inhibition, apamin decreased GCG secretion from mouse (20.4 ± 4.2%) and human (27.7 ± 13.1%) islets at low glucose. These data demonstrate that K activation provides a hyperpolarizing influence on α-cell V that sustains Ca entry during hypoglycemic conditions, presumably by preventing voltage-dependent inactivation of P/Q-type VDCCs. Thus, when α-cell Ca is elevated during secretagogue stimulation, K activation helps to preserve GCG secretion.
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20 MeSH Terms
Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension.
Dikalov S, Itani H, Richmond B, Vergeade A, Rahman SMJ, Boutaud O, Blackwell T, Massion PP, Harrison DG, Dikalova A
(2019) Am J Physiol Heart Circ Physiol 316: H639-H646
MeSH Terms: Angiotensin II, Animals, Blood Pressure, Calcium Channels, Endothelium, Vascular, Hydrogen Peroxide, Hypertension, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Heart, Oxidative Stress, Superoxide Dismutase, TRPV Cation Channels, Tobacco Smoking, Vasoconstrictor Agents
Show Abstract · Added March 26, 2019
Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial HO in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg·day), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial HO in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases.
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16 MeSH Terms
Estradiol Treatment Initiated Early After Ovariectomy Regulates Myocardial Gene Expression and Inhibits Diastolic Dysfunction in Female Cynomolgus Monkeys: Potential Roles for Calcium Homeostasis and Extracellular Matrix Remodeling.
Michalson KT, Groban L, Howard TD, Shively CA, Sophonsritsuk A, Appt SE, Cline JM, Clarkson TB, Carr JJ, Kitzman DW, Register TC
(2018) J Am Heart Assoc 7: e009769
MeSH Terms: Animals, Calcium, Diastole, Estradiol, Extracellular Matrix, Female, Gene Expression, Heart, Homeostasis, Macaca fascicularis, Myocardium, Ovariectomy, Postoperative Period, Random Allocation, Time Factors
Show Abstract · Added January 10, 2020
Background Left ventricular ( LV ) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on LV function and myocardial gene expression in female cynomolgus macaques. Methods and Results Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a human-equivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of LV myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all P<0.05), despite similar estimated LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals ( P<0.05). Microarray analysis revealed differential myocardial expression of 40 genes (>1.2-fold change; false discovery rate, P<0.05) in estradiol animals relative to controls, which implicated pathways associated with better calcium ion homeostasis and muscle contraction and lower extracellular matrix deposition ( P<0.05). Conclusions Estradiol treatment initiated soon after ovariectomy resulted in enhanced LV diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function.
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Poly(Thioketal Urethane) Autograft Extenders in an Intertransverse Process Model of Bone Formation.
McGough MAP, Shiels SM, Boller LA, Zienkiewicz KJ, Duvall CL, Wenke JC, Guelcher SA
(2019) Tissue Eng Part A 25: 949-963
MeSH Terms: Animals, Autografts, Bone Transplantation, Calcium Phosphates, Catalysis, Cell Line, Mice, Models, Biological, Osteogenesis, Polyurethanes, Rabbits, Rats, Nude, Sheep, X-Ray Microtomography
Show Abstract · Added April 10, 2019
IMPACT STATEMENT - The development of autograft extenders is a significant clinical need in bone tissue engineering. We report new settable poly(thioketal urethane)-based autograft extenders that have bone-like mechanical properties and handling properties comparable to calcium phosphate bone cements. These settable autograft extenders remodeled to form new bone in a biologically stringent intertransverse process model of bone formation that does not heal when treated with calcium phosphate bone void fillers or cements alone. This is the first study to report settable autograft extenders with bone-like strength and handling properties comparable to ceramic bone cements, which have the potential to improve treatment of bone fractures and other orthopedic conditions.
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14 MeSH Terms
Activated CaMKII Binds to the mGlu Metabotropic Glutamate Receptor and Modulates Calcium Mobilization.
Marks CR, Shonesy BC, Wang X, Stephenson JR, Niswender CM, Colbran RJ
(2018) Mol Pharmacol 94: 1352-1362
MeSH Terms: Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Cell Line, Cell Membrane, Female, HEK293 Cells, Humans, Immunoprecipitation, Male, Mice, Mice, Knockout, Protein Binding, Receptor, Metabotropic Glutamate 5, Signal Transduction
Show Abstract · Added November 8, 2018
Ca/calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu is present in CaMKII complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu directly interacts with purified Thr286-autophosphorylated (activated) CaMKII However, the binding of CaMKII to this CTD fragment is reduced by the addition of excess Ca/calmodulin or by additional CaMKII autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKII is dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866-868 of the mGlu-CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKII with full-length mGlu expressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKII with mGlu in heterologous cells. First, cell-surface biotinylation studies showed that CaMKII increases the surface expression of mGlu Second, using Ca fluorimetry and single-cell Ca imaging, we found that CaMKII reduces the initial peak of mGlu-mediated Ca mobilization by about 25% while doubling the relative duration of the Ca signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
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16 MeSH Terms