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Molecular Architecture of the Helicobacter pylori Cag Type IV Secretion System.
Hu B, Khara P, Song L, Lin AS, Frick-Cheng AE, Harvey ML, Cover TL, Christie PJ
(2019) MBio 10:
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Cryoelectron Microscopy, Genomic Islands, Helicobacter pylori, Humans, Type IV Secretion Systems
Show Abstract · Added July 14, 2019
colonizes about half of humans worldwide, and its presence in the gastric mucosa is associated with an increased risk of gastric adenocarcinoma, gastric lymphoma, and peptic ulcer disease. strains carrying the pathogenicity island (PAI) are associated with increased risk of disease progression. The PAI encodes the Cag type IV secretion system (Cag), which delivers the CagA oncoprotein and other effector molecules into human gastric epithelial cells. We visualized structures of native and mutant Cag machines on the cell envelope by cryoelectron tomography. Individual cells contain multiple Cag nanomachines, each composed of a wheel-shaped outer membrane complex (OMC) with 14-fold symmetry and an inner membrane complex (IMC) with 6-fold symmetry. CagX, CagY, and CagM are required for assembly of the OMC, whereas strains lacking Cag3 and CagT produce outer membrane complexes lacking peripheral components. The IMC, which has never been visualized in detail, is configured as six tiers in cross-section view and three concentric rings surrounding a central channel in end-on view. The IMC contains three T4SS ATPases: (i) VirB4-like CagE, arranged as a hexamer of dimers at the channel entrance; (ii) a hexamer of VirB11-like Cagα, docked at the base of the CagE hexamer; and (iii) VirD4-like Cagβ and other unspecified Cag subunits, associated with the stacked CagE/Cagα complex and forming the outermost rings. The Cag and recently solved Dot/Icm system comprise new structural prototypes for the T4SS superfamily. Bacterial type IV secretion systems (T4SSs) have been phylogenetically grouped into two subfamilies. The T4ASSs, represented by the VirB/VirD4, include "minimized" machines assembled from 12 VirB- and VirD4-like subunits and compositionally larger systems such as the Cag T4BSSs encompass systems closely related in subunit composition to the Dot/Icm Here, we present structures of native and mutant Cag machines determined by cryoelectron tomography. We identify distinct outer and inner membrane complexes and, for the first time, visualize structural contributions of all three "signature" ATPases of T4SSs at the cytoplasmic entrance of the translocation channel. Despite their evolutionary divergence, the Cag aligns structurally much more closely to the Dot/Icm than an available VirB/VirD4 subcomplex. Our findings highlight the diversity of T4SSs and suggest a structural classification scheme in which T4SSs are grouped as minimized VirB/VirD4-like or larger Cag-like and Dot/Icm-like systems.
Copyright © 2019 Hu et al.
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Muscle-specific stress fibers give rise to sarcomeres in cardiomyocytes.
Fenix AM, Neininger AC, Taneja N, Hyde K, Visetsouk MR, Garde RJ, Liu B, Nixon BR, Manalo AE, Becker JR, Crawley SW, Bader DM, Tyska MJ, Liu Q, Gutzman JH, Burnette DT
(2018) Elife 7:
MeSH Terms: Actin Cytoskeleton, Actins, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Microfilament Proteins, Microscopy, Confocal, Molecular Motor Proteins, Muscle Fibers, Skeletal, Myocytes, Cardiac, Myosin Heavy Chains, Nonmuscle Myosin Type IIB, RNA Interference, Sarcomeres, Stress Fibers
Show Abstract · Added March 27, 2019
The sarcomere is the contractile unit within cardiomyocytes driving heart muscle contraction. We sought to test the mechanisms regulating actin and myosin filament assembly during sarcomere formation. Therefore, we developed an assay using human cardiomyocytes to monitor sarcomere assembly. We report a population of muscle stress fibers, similar to actin arcs in non-muscle cells, which are essential sarcomere precursors. We show sarcomeric actin filaments arise directly from muscle stress fibers. This requires formins (e.g., FHOD3), non-muscle myosin IIA and non-muscle myosin IIB. Furthermore, we show short cardiac myosin II filaments grow to form ~1.5 μm long filaments that then 'stitch' together to form the stack of filaments at the core of the sarcomere (i.e., the A-band). A-band assembly is dependent on the proper organization of actin filaments and, as such, is also dependent on FHOD3 and myosin IIB. We use this experimental paradigm to present evidence for a unifying model of sarcomere assembly.
© 2018, Fenix et al.
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16 MeSH Terms
Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality.
Benjamin JT, Moore DJ, Bennett C, van der Meer R, Royce A, Loveland R, Wynn JL
(2018) J Immunol 201: 2873-2878
MeSH Terms: Animals, Animals, Newborn, Female, Humans, Infant, Newborn, Inflammation, Interleukin-1alpha, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Receptors, Interleukin-1 Type I, Sepsis, Signal Transduction
Show Abstract · Added October 12, 2018
Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.
Copyright © 2018 by The American Association of Immunologists, Inc.
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14 MeSH Terms
Pulmonary Vascular Platform Models the Effects of Flow and Pressure on Endothelial Dysfunction in Associated Pulmonary Arterial Hypertension.
D'Amico RW, Faley S, Shim HN, Prosser JR, Agrawal V, Bellan LM, West JD
(2018) Int J Mol Sci 19:
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, Cell Line, Disease Models, Animal, Endothelial Cells, Hypertension, Pulmonary, Mice, Sequence Analysis, RNA
Show Abstract · Added April 2, 2019
Endothelial dysfunction is a known consequence of bone morphogenetic protein type II receptor () mutations seen in pulmonary arterial hypertension (PAH). However, standard 2D cell culture models fail to mimic the mechanical environment seen in the pulmonary vasculature. Hydrogels have emerged as promising platforms for 3D disease modeling due to their tunable physical and biochemical properties. In order to recreate the mechanical stimuli seen in the pulmonary vasculature, we have created a novel 3D hydrogel-based pulmonary vasculature model ("artificial arteriole") that reproduces the pulsatile flow rates and pressures seen in the human lung. Using this platform, we studied both and WT endothelial cells to better understand how the addition of oscillatory flow and physiological pressure influenced gene expression, cell morphology, and cell permeability. The addition of oscillatory flow and pressure resulted in several gene expression changes in both WT and cells. However, for many pathways with relevance to PAH etiology, cells responded differently when compared to the WT cells. cells were also found not to elongate in the direction of flow, and instead remained stagnant in morphology despite mechanical stimuli. The increased permeability of the layer was successfully reproduced in our artificial arteriole, with the addition of flow and pressure not leading to significant changes in permeability. Our artificial arteriole is the first to model many mechanical properties seen in the lung. Its tunability enables several new opportunities to study the endothelium in pulmonary vascular disease with increased control over environmental parameters.
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Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
Phelps HM, Al-Jadiry MF, Corbitt NM, Pierce JM, Li B, Wei Q, Flores RR, Correa H, Uccini S, Frangoul H, Alsaadawi AR, Al-Badri SAF, Al-Darraji AF, Al-Saeed RM, Al-Hadad SA, Lovvorn Iii HN
(2018) World J Pediatr 14: 585-593
MeSH Terms: Adaptor Proteins, Signal Transducing, Child, Preschool, DNA Topoisomerases, Type II, Female, Homeodomain Proteins, Humans, Immunohistochemistry, Infant, Insulin-Like Growth Factor II, Iraq, Kidney Neoplasms, Male, Multiplex Polymerase Chain Reaction, Mutation, N-Myc Proto-Oncogene Protein, Nerve Tissue Proteins, Neural Cell Adhesion Molecules, Nuclear Proteins, Poly-ADP-Ribose Binding Proteins, Receptors, Retinoic Acid, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, WT1 Proteins, Wilms Tumor, beta Catenin
Show Abstract · Added January 28, 2019
BACKGROUND - Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS - Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS - Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS - These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
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Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes.
Li Z, Li Y, Overstreet JM, Chung S, Niu A, Fan X, Wang S, Wang Y, Zhang MZ, Harris RC
(2018) Diabetes 67: 1847-1857
MeSH Terms: Albuminuria, Animals, Biomarkers, Crosses, Genetic, Cytokines, Diabetes Mellitus, Type 2, Diabetic Nephropathies, ErbB Receptors, Erlotinib Hydrochloride, Fibrosis, Glomerulonephritis, Hypoglycemic Agents, Insulin Resistance, Kidney, Macrophages, Membrane Transport Modulators, Mice, Knockout, Mice, Mutant Strains, Nitric Oxide Synthase Type III, Oxidative Stress, Protein Kinase Inhibitors, T-Lymphocytes, Transforming Growth Factor alpha
Show Abstract · Added November 9, 2018
Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and that inhibition of EGFR activity protects against progressive DN in type 1 diabetes. In this study we examined whether inhibition of EGFR activation would affect the development of DN in a mouse model of accelerated type 2 diabetes (BKS with endothelial nitric oxide knockout [eNOS]). eNOS mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity, beginning at 8 weeks of age and were sacrificed at 20 weeks of age. In addition, genetic models inhibiting EGFR activity () and transforming growth factor-α () were studied in this model of DN in type 2 diabetes. Compared with vehicle-treated mice, erlotinib-treated animals had less albuminuria and glomerulosclerosis, less podocyte loss, and smaller amounts of renal profibrotic and fibrotic components. Erlotinib treatment decreased renal oxidative stress, macrophage and T-lymphocyte infiltration, and the production of proinflammatory cytokines. Erlotinib treatment also preserved pancreas function, and these mice had higher blood insulin levels at 20 weeks, decreased basal blood glucose levels, increased glucose tolerance and insulin sensitivity, and increased blood levels of adiponectin compared with vehicle-treated mice. Similar to the aforementioned results, both and diabetic mice also had attenuated DN, preserved pancreas function, and decreased basal blood glucose levels. In this mouse model of accelerated DN, inhibition of EGFR signaling led to increased longevity.
© 2018 by the American Diabetes Association.
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23 MeSH Terms
Imaging mass spectrometry reveals direct albumin fragmentation within the diabetic kidney.
Grove KJ, Lareau NM, Voziyan PA, Zeng F, Harris RC, Hudson BG, Caprioli RM
(2018) Kidney Int 94: 292-302
MeSH Terms: Albumins, Albuminuria, Animals, Cathepsin D, Diabetic Nephropathies, Disease Models, Animal, Frozen Sections, Humans, Kidney Glomerulus, Kidney Tubules, Mice, Mice, Inbred C57BL, Molecular Imaging, Nitric Oxide Synthase Type III, Proteolysis, Renal Elimination, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added May 29, 2018
Albumin degradation in the renal tubules is impaired in diabetic nephropathy such that levels of the resulting albumin fragments increase with the degree of renal injury. However, the mechanism of albumin degradation is unknown. In particular, fragmentation of the endogenous native albumin has not been demonstrated in the kidney and the enzymes that may contribute to fragmentation have not been identified. To explore this we utilized matrix-assisted laser desorption/ionization imaging mass spectrometry for molecular profiling of specific renal regions without disturbing distinct tissue morphology. Changes in protein expression were measured in kidney sections of eNOSdb/db mice, a model of diabetic nephropathy, by high spatial resolution imaging allowing molecular localizations at the level of single glomeruli and tubules. Significant increases were found in the relative abundances of several albumin fragments in the kidney of the mice with diabetic nephropathy compared with control nondiabetic mice. The relative abundance of fragments detected correlated positively with the degree of nephropathy. Furthermore, specific albumin fragments accumulating in the lumen of diabetic renal tubules were identified and predicted the enzymatic action of cathepsin D based on cleavage specificity and in vitro digestions. Importantly, this was demonstrated directly in the renal tissue with the endogenous nonlabeled murine albumin. Thus, our results provide molecular insights into the mechanism of albumin degradation in diabetic nephropathy.
Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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17 MeSH Terms
Modification by isolevuglandins, highly reactive γ-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function.
May-Zhang LS, Yermalitsky V, Huang J, Pleasent T, Borja MS, Oda MN, Jerome WG, Yancey PG, Linton MF, Davies SS
(2018) J Biol Chem 293: 9176-9187
MeSH Terms: Aldehydes, Animals, Apolipoprotein A-I, Apolipoprotein A-II, Cells, Cultured, Cholesterol, Female, Humans, Hyperlipoproteinemia Type II, Ketones, Lipid Metabolism, Lipids, Lipoproteins, HDL, Macrophages, Male, Mice, Mice, Inbred C57BL, Phosphatidylethanolamines
Show Abstract · Added August 3, 2018
Cardiovascular disease risk depends on high-density lipoprotein (HDL) function, not HDL-cholesterol. Isolevuglandins (IsoLGs) are lipid dicarbonyls that react with lysine residues of proteins and phosphatidylethanolamine. IsoLG adducts are elevated in atherosclerosis. The consequences of IsoLG modification of HDL have not been studied. We hypothesized that IsoLG modification of apoA-I deleteriously alters HDL function. We determined the effect of IsoLG on HDL structure-function and whether pentylpyridoxamine (PPM), a dicarbonyl scavenger, can preserve HDL function. IsoLG adducts in HDL derived from patients with familial hypercholesterolemia ( = 10, 233.4 ± 158.3 ng/mg) were found to be significantly higher than in healthy controls ( = 7, 90.1 ± 33.4 pg/mg protein). Further, HDL exposed to myeloperoxidase had elevated IsoLG-lysine adducts (5.7 ng/mg protein) compared with unexposed HDL (0.5 ng/mg protein). Preincubation with PPM reduced IsoLG-lysine adducts by 67%, whereas its inactive analogue pentylpyridoxine did not. The addition of IsoLG produced apoA-I and apoA-II cross-links beginning at 0.3 molar eq of IsoLG/mol of apoA-I (0.3 eq), whereas succinylaldehyde and 4-hydroxynonenal required 10 and 30 eq. IsoLG increased HDL size, generating a subpopulation of 16-23 nm. 1 eq of IsoLG decreased HDL-mediated [H]cholesterol efflux from macrophages via ABCA1, which corresponded to a decrease in HDL-apoA-I exchange from 47.4% to only 24.8%. This suggests that IsoLG inhibits apoA-I from disassociating from HDL to interact with ABCA1. The addition of 0.3 eq of IsoLG ablated HDL's ability to inhibit LPS-stimulated cytokine expression by macrophages and increased IL-1β expression by 3.5-fold. The structural-functional effects were partially rescued with PPM scavenging.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
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The Role of Matrix Composition in the Mechanical Behavior of Bone.
Unal M, Creecy A, Nyman JS
(2018) Curr Osteoporos Rep 16: 205-215
MeSH Terms: Biomechanical Phenomena, Bone Density, Bone Matrix, Bone and Bones, Cancellous Bone, Collagen Type I, Fractures, Bone, Glycation End Products, Advanced, Humans, Minerals, Protein Processing, Post-Translational, Tropocollagen, Water
Show Abstract · Added April 9, 2018
PURPOSE OF REVIEW - While thinning of the cortices or trabeculae weakens bone, age-related changes in matrix composition also lower fracture resistance. This review summarizes how the organic matrix, mineral phase, and water compartments influence the mechanical behavior of bone, thereby identifying characteristics important to fracture risk.
RECENT FINDINGS - In the synthesis of the organic matrix, tropocollagen experiences various post-translational modifications that facilitate a highly organized fibril of collagen I with a preferred orientation giving bone extensibility and several toughening mechanisms. Being a ceramic, mineral is brittle but increases the strength of bone as its content within the organic matrix increases. With time, hydroxyapatite-like crystals experience carbonate substitutions, the consequence of which remains to be understood. Water participates in hydrogen bonding with organic matrix and in electrostatic attractions with mineral phase, thereby providing stability to collagen-mineral interface and ductility to bone. Clinical tools sensitive to age- and disease-related changes in matrix composition that the affect mechanical behavior of bone could potentially improve fracture risk assessment.
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Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA.
Wauchope OR, Mitchener MM, Beavers WN, Galligan JJ, Camarillo JM, Sanders WD, Kingsley PJ, Shim HN, Blackwell T, Luong T, deCaestecker M, Fessel JP, Marnett LJ
(2018) Nucleic Acids Res 46: 3458-3467
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, DNA Adducts, DNA, Mitochondrial, Electron Transport, Endothelial Cells, Gene Expression Regulation, Humans, Hypertension, Pulmonary, Lipid Peroxidation, Mice, Mice, Transgenic, Mitochondria, Mutagenesis, Oxidants, Oxidative Stress, Purine Nucleosides, Reactive Oxygen Species, Superoxides
Show Abstract · Added March 14, 2018
Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.
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19 MeSH Terms