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Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice.
Ou-Yang MH, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, Contractor A, Chetkovich DM, Tourtellotte WG, Vassar R
(2018) Sci Transl Med 10:
MeSH Terms: Aging, Amyloid Precursor Protein Secretases, Animals, Animals, Newborn, Apoptosis, Aspartic Acid Endopeptidases, Axons, Cognition, Epilepsy, Gene Deletion, Hippocampus, Long-Term Potentiation, Memory Disorders, Mice, Inbred C57BL, Mice, Knockout, Myelin Sheath, Neurogenesis, Phenotype, Substrate Specificity
Show Abstract · Added April 2, 2019
β-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the β-secretase enzyme that initiates production of the toxic amyloid-β peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear. Germline BACE1 knockout mice have multiple neurological phenotypes, although these could arise from BACE1 deficiency during development. To address this question, we report that tamoxifen-inducible conditional BACE1 knockout mice in which the gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced BACE1-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that BACE1 inhibition in the adult mouse brain may avoid phenotypes associated with BACE1 deficiency during embryonic and postnatal development, they also suggest that BACE1 inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.
Copyright © 2018 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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19 MeSH Terms
Differential proteomic and behavioral effects of long-term voluntary exercise in wild-type and APP-overexpressing transgenics.
Rao SK, Ross JM, Harrison FE, Bernardo A, Reiserer RS, Reiserer RS, Mobley JA, McDonald MP
(2015) Neurobiol Dis 78: 45-55
MeSH Terms: Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Animals, Aspartic Acid Endopeptidases, Behavior, Animal, Hippocampus, Mice, Mice, Transgenic, Motor Activity, Presenilin-1, Proteomics, Spatial Memory
Show Abstract · Added May 11, 2015
Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer's disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r(2)=.959), but uncorrelated in transgenics (r(2)=.013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics' deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Aβ40 and Aβ42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. β-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Aβ. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways.
Copyright © 2015 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours.
Fadare O, Zhao C, Khabele D, Parkash V, Quick CM, Gwin K, Desouki MM
(2015) Pathology 47: 105-11
MeSH Terms: Adenocarcinoma, Clear Cell, Aspartic Acid Endopeptidases, Biomarkers, Tumor, Diagnosis, Differential, Female, Hepatocyte Nuclear Factor 1-beta, Humans, Immunohistochemistry, Neoplasm Grading, Ovarian Neoplasms, Racemases and Epimerases, Sensitivity and Specificity
Show Abstract · Added February 19, 2015
Napsin A and α-methylacyl-coenzyme A racemase (AMACR, P504S) have recently been described as being frequently expressed in clear cell carcinomas (CCC) of the gynecological tract. The present study was conducted to assess the test performance of these newer markers relative to the more traditional marker, hepatocyte nuclear factor 1β (HNF1β), in a large and histotypically diverse dataset. A total of 279 ovarian tumours in tissue microarrays were immunohistochemically assessed for the expression of Napsin A, AMACR and HNF1β. HNF1β, Napsin A and AMACR were expressed in 92%, 82% and 63% of 65 CCC, 7%, 1% and 1% of 101 serous carcinomas, 37%, 5.3% and 0% of 19 endometrioid carcinomas, 60%, 0% and 0% of 45 mucinous tumours, 100%, 0% and 0% of seven yolk sac tumours, and 0%, 16.7% and 16.7% of six steroid cell tumours NOS, respectively. All other tumours, including 18 adult-type granulosa cell tumours, eight dysgerminomas and nine other miscellaneous tumour types were negative for all three markers. Using a benchmark of ≥1% of tumour cells for positivity and CCC as the diagnostic end-point, the sensitivity, specificity, negative predictive value and positive predictive value of Napsin A expression were 0.82, 0.99, 0.94, and 0.98, respectively (odds ratio 439, p < 0.0001). Respective parameters were 0.92, 0.79, 0.97, and 0.58 (odds ratio 44, p < 0.0001) for HNF1β and 0.63, 0.99, 0.89, and 0.5 (odds ratio 112, p < 0.0001) for AMACR. The combination of any two positive markers, irrespective of the staining pattern of the third, significantly predicted the CCC histotype in every analytic scenario. In summary, HNF1β is highly sensitive but is suboptimally specific in isolation, whereas AMACR is highly specific but is suboptimally sensitive. Napsin A is specific but of intermediate sensitivity. Napsin A, AMACR and HNF1β are all viable markers of CCC that can be deployed as components of larger panels when CCC is a diagnostic consideration.
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12 MeSH Terms
Identification of HKDC1 and BACE2 as genes influencing glycemic traits during pregnancy through genome-wide association studies.
Hayes MG, Urbanek M, Hivert MF, Armstrong LL, Morrison J, Guo C, Lowe LP, Scheftner DA, Pluzhnikov A, Levine DM, McHugh CP, Ackerman CM, Bouchard L, Brisson D, Layden BT, Mirel D, Doheny KF, Leya MV, Lown-Hecht RN, Dyer AR, Metzger BE, Reddy TE, Cox NJ, Lowe WL, HAPO Study Cooperative Research Group
(2013) Diabetes 62: 3282-91
MeSH Terms: Adolescent, Adult, Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Blood Glucose, C-Peptide, Fasting, Female, Genome-Wide Association Study, Genotype, Glucose Tolerance Test, Humans, Pregnancy, Young Adult
Show Abstract · Added February 22, 2016
Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.
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14 MeSH Terms
Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease.
Shi J, Wang Q, Johansson JU, Liang X, Woodling NS, Priyam P, Loui TM, Merchant M, Breyer RM, Montine TJ, Andreasson K
(2012) Ann Neurol 72: 788-98
MeSH Terms: Age Factors, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Animals, Newborn, Aspartic Acid Endopeptidases, Brain, Calcium-Binding Proteins, Cells, Cultured, Cognitive Dysfunction, DNA-Binding Proteins, Dinoprostone, Disease Models, Animal, Encephalitis, Female, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Microtubule-Associated Proteins, Mutation, Neurons, Oxidative Stress, Peptide Fragments, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, Receptors, Prostaglandin E, EP3 Subtype, Signal Transduction, Synaptosomal-Associated Protein 25, Vesicle-Associated Membrane Protein 2
Show Abstract · Added December 21, 2013
OBJECTIVE - There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide.
METHODS - The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of Aβ(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1ΔE9 transgenic mice.
RESULTS - Deletion of the PGE(2) EP3 receptor in a model of Aβ(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1ΔE9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were β-secretase and β C-terminal fragment levels, suggesting that generation of Aβ peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1ΔE9 mice.
INTERPRETATION - Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.
Copyright © 2012 American Neurological Association.
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37 MeSH Terms
Diagnostic utility of PAX8, TTF-1 and napsin A for discriminating metastatic carcinoma from primary adenocarcinoma of the lung.
Ye J, Hameed O, Findeis-Hosey JJ, Fan L, Li F, McMahon LA, Yang Q, Wang HL, Xu H
(2012) Biotech Histochem 87: 30-4
MeSH Terms: Adenocarcinoma, Aspartic Acid Endopeptidases, Biomarkers, Tumor, DNA-Binding Proteins, Diagnosis, Differential, Humans, Immunohistochemistry, Lung Neoplasms, PAX8 Transcription Factor, Paired Box Transcription Factors, Transcription Factors
Show Abstract · Added March 21, 2014
TTF-1 and napsin A are useful biomarkers for differentiating primary lung adenocarcinoma from metastatic tumors. Studies have shown, however, that TTF-1 and napsin A also can be expressed in extrapulmonary carcinomas, and that a small fraction of primary lung adenocarcinomas do not co-express these two markers. We attempted to determine whether a tissue-specific transcriptional factor, PAX8, can help determine primary sites of lung carcinomas. Immunohistochemical stains for PAX8, TTF-1 and napsin A were performed on 103 cases of metastatic lung carcinomas from a variety of origins and 120 cases of primary lung adenocarcinomas. Our data demonstrated that all 103 metastatic carcinomas were negative for napsin A, while 14 (13.6%; four thyroid, two endometrium, three colon, one prostate, one salivary adenoid cystic, two renal cell carcinomas, and one ovary) showed weak to strong TTF-1 nuclear staining in 5-60% of the tumor cells. All primary lung adenocarcinomas were negative for PAX8, whereas 46 (44.7%) metastatic carcinomas from the kidney (29/33), ovary (6/8), endometrium (5/5), endocervix (1/1), thyroid (4/5) and urinary tract (1/3) were positive for PAX8. Our data demonstrate that of combined use of PAX8, TTF-1 and napsin A is reliable to separate reliably lung primary from metastatic tumors.
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11 MeSH Terms
BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension.
Talati M, West J, Blackwell TR, Loyd JE, Meyrick B
(2010) Am J Physiol Lung Cell Mol Physiol 299: L363-73
MeSH Terms: Adolescent, Adult, Aged, Animals, Aspartic Acid Endopeptidases, Bone Morphogenetic Protein Receptors, Type II, Endothelin-1, Endothelin-Converting Enzymes, Female, Gene Expression, Humans, Hypertension, Pulmonary, Macrophages, Macrophages, Alveolar, Male, Metalloendopeptidases, Mice, Mice, Mutant Strains, Microscopy, Confocal, Middle Aged, Mutation, Receptor, Endothelin A, Receptor, Endothelin B, Tissue Distribution, Young Adult
Show Abstract · Added March 5, 2014
Macrophage derived-endothelin-1 (ET-1) has been suggested to contribute to a number of chronic lung diseases. Whether the ET-1 cascade from non-vascular sources (inflammatory cells) also contributes to pulmonary artery hypertension (PAH) and in particular to heritable PAH (HPAH) with known bone morphogenetic protein type 2 receptor (BMPR2) mutations is not known. We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH). At baseline ET(A) and ET(B) receptors and endothelin converting enzyme (ECE) gene expression was reduced in BMPR2 mutant BMDM compared with controls. In control BMDM, LPS resulted in increased ppET-1 gene expression and ET-1 in culture media, whereas ET(A) and ET(B) receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ET(B) receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ET(B) receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ET(A) and ET(B) expression was decreased in the HPAH, but not IPAH, patients compared with controls. We conclude that reduced expression of macrophage ET-1 receptors in HPAH increases lung ET-1 and may contribute to the pathogenesis and maintenance of HPAH. This is the first description of protein expression that distinguishes HPAH from IPAH in patients.
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25 MeSH Terms
Analysis of transmembrane domain mutants is consistent with sequential cleavage of Notch by gamma-secretase.
Chandu D, Huppert SS, Kopan R
(2006) J Neurochem 96: 228-35
MeSH Terms: Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Cell Line, Cell Membrane, Cytosol, Endopeptidases, Humans, Hydrolysis, Immunoprecipitation, Isoenzymes, Leucine, Methionine, Mutation, Peptide Hydrolases, Protease Inhibitors, Receptor, Notch1
Show Abstract · Added January 11, 2011
gamma-Secretase is a lipid-embedded, intramembrane-cleaving aspartyl protease that cleaves its substrates twice within their transmembrane domains (TMD): once near the cytosolic leaflet (at S3/epsilon) and again in the middle of the TMD (at S4/gamma). To address whether this unusual process occurs in two independent or interdependent steps, we investigated how mutations at the S3/epsilon site in Notch1-based substrates impact proteolysis. We demonstrate that such mutations greatly inhibit not only gamma-secretase-mediated cleavage at S3 but also at S4, independent of their impact on NICD stability. These results, together with our previous observations, suggest that hydrolysis at the center of the Notch transmembrane domain (S4/gamma) is dependent on the S3/epsilon cleavage. Notch (and perhaps all gamma-secretase substrates) may be cleaved by sequential proteolysis starting at S3.
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16 MeSH Terms
Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation.
Huppert SS, Ilagan MX, De Strooper B, Kopan R
(2005) Dev Cell 8: 677-88
MeSH Terms: Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Body Patterning, Cell Differentiation, Endopeptidases, In Situ Hybridization, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Microscopy, Electron, Scanning, Phenotype, Presenilin-1, Presenilin-2, Receptor, Notch1, Receptor, Notch2, Receptors, Cell Surface, Somites, Transcription Factors
Show Abstract · Added January 11, 2011
The role of Notch signaling in general and presenilin in particular was analyzed during mouse somitogenesis. We visualize cyclical production of activated Notch (NICD) and establish that somitogenesis requires less NICD than any other tissue in early mouse embryos. Indeed, formation of cervical somites proceeds in Notch1; Notch2-deficient embryos. This is in contrast to mice lacking all presenilin alleles, which have no somites. Since Nicastrin-, Pen-2-, and APH-1a-deficient embryos have anterior somites without gamma-secretase, presenilin may have a gamma-secretase-independent role in somitogenesis. Embryos triple homozygous for both presenilin null alleles and a Notch allele that is a poor substrate for presenilin (N1(V-->G)) experience fortuitous cleavage of N1(V-->G) by another protease. This restores NICD, anterior segmentation, and bilateral symmetry but does not rescue rostral/caudal identities. These data clarify multiple roles for Notch signaling during segmentation and suggest that the earliest stages of somitogenesis are regulated by both Notch-dependent and Notch-independent functions of presenilin.
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21 MeSH Terms
Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling.
Rufo PA, Lin PW, Andrade A, Jiang L, Rameh L, Flexner C, Alper SL, Lencer WI
(2004) Am J Physiol Cell Physiol 286: C998-C1008
MeSH Terms: Adult, Aspartic Acid Endopeptidases, Calcium Signaling, Carbachol, Cell Line, Cell Membrane, Chlorides, Cytosol, Diarrhea, Drug Synergism, Electric Conductivity, HIV Infections, HIV-1, Humans, Intestinal Mucosa, Intracellular Membranes, Middle Aged, Muscarinic Agonists, Nelfinavir, Protease Inhibitors, Time Factors
Show Abstract · Added December 10, 2018
Aspartyl protease inhibitors (APIs) effectively extend the length and quality of life in human immunodeficiency virus (HIV)-infected patients, but dose-limiting side effects such as lipodystrophy, insulin resistance, and diarrhea have limited their clinical utility. Here, we show that the API nelfinavir induces a secretory form of diarrhea in HIV-infected patients. In vitro studies demonstrate that nelfinavir potentiates muscarinic stimulation of Cl(-) secretion by T84 human intestinal cell monolayers through amplification and prolongation of an apical membrane Ca(2+)-dependent Cl(-) conductance. This stimulated ion secretion is associated with increased magnitude and duration of muscarinically induced intracellular Ca(2+) transients via activation of a long-lived, store-operated Ca(2+) entry pathway. The enhanced intracellular Ca(2+) signal is associated with uncoupling of the Cl(-) conductance from downregulatory intracellular mediators generated normally by muscarinic activation. These data show that APIs modulate Ca(2+) signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects.
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21 MeSH Terms