tbuckley/cabot-search huggingface dataset:
7-Dehydrocholesterol–dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome
Authors: Barbara U. Fitzky, Fabian F. Moebius, Hitoshi Asaoka, Heather Waage-Baudet, Liwen Xu, Guorong Xu, Nobuyo Maeda, Kimberly Kluckman, Sylvia Hiller, Hongwei Yu, Ashok K. Batta, Sarah Shefer, Thomas Chen, Gerald Salen, Kathleen Sulik, Robert D. Simoni, Gene C. Ness, Hartmut Glossmann, Shailendra B. Patel, G.S. Tint
Journal: Journal of Clinical Investigation (2001)

Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. A null mutation in the murine Dhcr7 causes an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol. Prenatal lethality was not noted, but newborn homozygotes breathed with difficulty, did not suckle, and died soon after birth with immature lungs, enlarged bladders, and, frequently, cleft palates. Despite reduced sterol concentrations in Dhcr7–/– mice, mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme for sterol biosynthesis, the LDL receptor, and SREBP-2 appeared neither elevated nor repressed. In contrast to mRNA, protein levels and activities of HMG-CoA reductase were markedly reduced. Consistent with this finding, 7-dehydrocholesterol accelerates proteolysis of HMG-CoA reductase while sparing other key proteins. These results demonstrate that in mice without Dhcr7 activity, accumulated 7-dehydrocholesterol suppresses sterol biosynthesis posttranslationally. This effect might exacerbate abnormal development in SLOS by increasing the fetal cholesterol deficiency.
Image-Based Quantification of Benzoporphyrin Derivative Uptake, Localization, and Photobleaching in 3D Tumor Models, for Optimization of PDT Parameters
Authors: Michael D. Glidden, Jonathan P. Celli, Iqbal Massodi, Imran Rizvi, Brian W. Pogue, Tayyaba Hasan
Journal: Theranostics (2012)

Photodynamic therapy (PDT) is a light-based treatment modality in which wavelength specific activation of a photosensitizer (PS) generates cytotoxic response in the irradiated region.PDT response is critically dependent on several parameters including light dose, PS dose, uptake time, fluence rate, and the mode of light delivery.While the systematic optimization of these treatment parameters can be complex, it also provides multiple avenues for enhancement of PDT efficacy under diverse treatment conditions, provided that a rational framework is established to quantify the impact of parameter selection upon treatment response.Here we present a theranostic technique, combining the inherent ability of the PS to serve simultaneously as a therapeutic and imaging agent, with the use of image-based treatment assessment in three dimensional (3D) in vitro tumor models, to comprise a platform to evaluate the impact of PDT parameters on treatment outcomes.We use this approach to visualize and quantify the uptake, localization, and photobleaching of the PS benzoporphyrin derivative monoacid ring-A (BPD) in a range of treatment conditions with varying uptake times as well as continuous and fractionated light delivery regimens in 3D cultures of AsPC-1 and PANC-1 cells.Informed by photobleaching patterns and correlation with cytotoxic response, asymmetric fractionated light delivery at 4 hours BPD uptake was found to be the most effective regimen assessed.Quantification of the spatial profile of cell killing within multicellular nodules revealed that these conditions also achieve the highest depth of cytotoxicity along the radial axis of 3D nodules.The framework introduced here provides a means for systematic assessment of PDT treatment parameters in biologically relevant 3D tumor models with potential for broader application to other systems.
Hunting down nucleic acid binding factors in the cardiovascular system
Authors: P A Doevendans, P Ruiz-Lozano, M van Bilsen
Journal: Cardiovascular Research (1998)

Transcription regulation of genes active in the cardiovascular system is a complex process, involving DNA and RNA binding proteins. Nucleic acid binding proteins bind to the regulatory DNA and interact with other proteins, including RNA polymerase to initiate and control the level of transcription. The RNA binding proteins have a function in spliceosome formation and in stabilising mRNA. In this review the currently available molecular approaches to analyse regulatory DNA in relation to DNA binding proteins are discussed. Similar techniques that have been developed for RNA binding protein studies are included. In addition to an explanation of the various methods, examples are provided from DNA-protein interactions on genes active in the cardiovascular system, together with strategies for identification and characterisation of new nucleic acid binding proteins active in cardiac or vascular cell types.
Effects of Sex and of Gene Variants in Constitutive Nitric Oxide Synthases on Exhaled Nitric Oxide
Authors: Hartmut Grasemann, Karin Storm van's Gravesande, Rainer Büscher, Jeffrey M. Drazen, Felix Ratjen
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Genetic factors may contribute to the variability of exhaled nitric oxide in healthy individuals. We studied exhaled nitric oxide and genetic variants in both neuronal and endothelial nitric oxide synthases in 105 healthy nonsmoking and smoking subjects. Genomic DNA was screened for a repeat polymorphism in intron 20 of the neuronal nitric oxide synthase gene and for the 894G/T mutation of the endothelial nitric oxide synthase gene. Exhaled nitric oxide was significantly higher in males than females among both nonsmokers (p < 0.0001) and smokers (p = 0.003). No association was found between exhaled nitric oxide and the endothelial nitric oxide synthase gene variant. However, healthy nonsmoking females with greater numbers of repeats (i.e., both alleles with 12 or more repeats) in neuronal nitric oxide synthase had significantly lower nitric oxide levels than did females with fewer numbers of repeats (i.e., at least one allele with fewer than 12 repeats) (13.6 +/- 1.6 versus 19.4 +/- 1.6 ppb, p = 0.02). No association was found between exhaled nitric oxide and neuronal nitric oxide synthase genotype in males. These data suggest that variants in the neuronal nitric oxide synthase gene contribute to the variability of airway nitric oxide concentrations in healthy females.
Antiidiotype Antibody against Platelet Anti-Gpiiia Contributes to the Regulation of Thrombocytopenia in HIV-1–Itp Patients
Authors: Michael Nardi, Simon Karpatkin
Journal: The Journal of Experimental Medicine (2000)

Patients with human immunodeficiency virus 1–associated immunological thrombocytopenia (HIV-1–ITP) have markedly elevated platelet-bound immunoglobulin (Ig)G, IgM, and C3C4, as well as serum circulating immune complexes (CICs) composed of the same. Affinity purification of IgGs from their CICs with fixed platelets reveals high-affinity antibody (Ab) against platelet glycoprotein (GP)IIIa 49–66, which correlates inversely with their platelet count. However, sera from these patients have little to no anti-GPIIIa activity. To investigate this, we assayed serum, purified serum IgG, and CIC-Ig from these patients. This revealed ∼150-fold greater Ab activity in purified serum IgG, and ∼4,000-fold greater reactivity in CIC-IgG. This was shown to be associated with the presence of antiidiotype Ab2 (both IgG and IgM) sequestered in the CIC-IgG. The IgM antiidiotype was predominantly blocking Ab, as demonstrated by specificity for F(ab′)2 fragments of anti–GPIIIa 49–66 of HIV-1–ITP patients and inhibition of reactivity with peptide GPIIIa 49–66, not with a control peptide. The IgM antiidiotype was not polyreactive. Similar measurements were made in nonthrombocytopenic HIV-1–infected patients. Their serum reactivity was not measurable, but serum Ig and CIC-IgG against platelet GPIIIa 49–66 was present, although considerably lower than that found in HIV-1–ITP patients (26- and 35-fold lower, respectively). In addition, their IgM antiidiotype reactivity was 12-fold greater than that found in HIV-1–ITP patients. The IgM antiidiotype Ab titer of both cohorts correlated with in vivo platelet count (r = 0.7, P = 0.0001, n = 32). To test the in vivo effectiveness of the IgM antiidiotype, thrombocytopenia was induced in mice with 25 μg of affinity-purified anti–GPIIIa 49–66 (mouse GPIIIa has 83% homology with human GPIIIa and Fc receptors for human IgG1). Maximum effect was obtained at 4–6 h after intraperitoneal injection into Balb/c mice with a platelet count of ∼30% baseline value. Preincubation of the anti-GPIIIa Ab with control IgM at molar ratios of IgM/IgG of 1:7 before intraperitoneal injection had no effect on the in vivo platelet count, whereas preincubation with patient IgM antiidiotype improved the platelet count to 50–80% of normal. Thrombocytopenia could be reversed after addition of IgM antiidiotype 4 h after induction of thrombocytopenia. Thus, CICs of HIV-1–infected patients contain IgM antiidiotype Ab against anti-GPIIIa, which appears to regulate their serum reactivity in vitro and their level of thrombocytopenia in vivo.
Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells
Authors: Andrea L. Wurster, Vikki L. Rodgers, Abhay R. Satoskar, Matthew J. Whitters, Deborah A. Young, Mary Collins, Michael J. Grusby
Journal: The Journal of Experimental Medicine (2002)

The cytokine potential of developing T helper (Th) cells is directly shaped both positively and negatively by the cytokines expressed by the effector Th cell subsets. Here we find that the recently identified cytokine, interleukin (IL)-21, is preferentially expressed by Th2 cells when compared with Th1 cells generated in vitro and in vivo. Exposure of naive Th precursors to IL-21 inhibits interferon (IFN)-γ production from developing Th1 cells. The repression of IFN-γ production is specific in that the expression of other Th1 and Th2 cytokines is unaffected. IL-21 decreases the IL-12 responsiveness of developing Th cells by specifically reducing both signal transducer and activator of transcription 4 protein and mRNA expression. These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-γ–producing Th1 cells which could serve to amplify a Th2 response.
What Is the Outcome of Targeted Tuberculosis Screening Based on Universal Genotyping and Location?
Authors: Patrick K. Moonan, Joseph Oppong, Behzad Sahbazian, Karan P. Singh, Raghbir Sandhu, Gerry Drewyer, Terry LaFon, Marco Marruffo, Teresa N. Quitugua, Charles Wallace, Stephen E. Weis
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Identifying and treating persons with latent tuberculosis (TB) infection (LTBI) at high risk for developing TB is part of the current TB elimination strategy. There are no specific criteria, other than medical risks, to designate groups as high risk for developing TB. We hypothesized that, if location-based screenings were done in communities where persons with genotypically clustered Mycobacterium tuberculosis resided, then persons with LTBI from recent transmission and with undiagnosed TB could be identified.Location-based TB screenings were done in partnership with multiple community-based organizations using resources previously used for other types of screening.Location-based screenings identified one person with TB for every 83 screened, and one person with LTBI for every five screened. The yield of this targeted screening program for discovering persons with TB and LTBI exceeded what would be expected from nontargeted screening in a county with a TB incidence of 5.7 per 100,000 population.Genotyping combined with geographic information systems analysis can potentially be used to define high-risk status and to define areas for location-based TB screenings.
Impact of aerobic exercise capacity and procedure-related factors in lung cancer surgery
Authors: M. Licker, J-M. Schnyder, J-G. Frey, J. Diaper, V. Cartier, C. Inan, J. Robert, P-O. Bridevaux, J-M. Tschopp
Journal: European Respiratory Journal (2010)

Over the past decades, major progress in patient selection, surgical techniques and anaesthetic management have largely contributed to improved outcome in lung cancer surgery. The purpose of this study was to identify predictors of post-operative cardiopulmonary morbidity in patients with a forced expiratory volume in 1 s &lt;80% predicted, who underwent cardiopulmonary exercise testing (CPET). In this observational study, 210 consecutive patients with lung cancer underwent CPET with completed data over a 9-yr period (2001–2009). Cardiopulmonary complications occurred in 46 (22%) patients, including four (1.9%) deaths. On logistic regression analysis, peak oxygen uptake (peak V′ O 2 ) and anaesthesia duration were independent risk factors of both cardiovascular and pulmonary complications; age and the extent of lung resection were additional predictors of cardiovascular complications, whereas tidal volume during one-lung ventilation was a predictor of pulmonary complications. Compared with patients with peak V′ O 2 &gt;17 mL·kg −1 ·min −1 , those with a peak V′ O 2 &lt;10 mL·kg −1 ·min −1 had a four-fold higher incidence of cardiac and pulmonary morbidity. Our data support the use of pre-operative CPET and the application of an intra-operative protective ventilation strategy. Further studies should evaluate whether pre-operative physical training can improve post-operative outcome.
Mechanisms of Seizures and Coma in Hypoglycemia EVIDENCE FOR A DIRECT EFFECT OF INSULIN ON ELECTROLYTE TRANSPORT IN BRAIN
Authors: Allen I. Arieff, Tom Doerner, Harry Zelig, Shaul G. Massry
Journal: Journal of Clinical Investigation (1974)

The mechanisms involved in the production of hypoglycemic coma were studied in rabbits. Measurements were made in brain, cerebrospinal fluid (CSF), and plasma of osmolality, Na(+), K(+), Cl(-), water content, exogenous insulin, glucose, lactate, and glutamate, while pH, Pco(2), Po(2), and bicarbonate were evaluated in arterial blood, 35 min after i.v. injection of insulin (50 U/kg), plasma glucose did not change, but brain K(+) content increased significantly. Grand mal seizures were observed in unanesthetized animals (+/-SD) 133+/-37 min after administration of insulin, at a time when brain glucose was normal, but brain tissue content of Na(+), K(+), osmoles, and water was significantly greater than normal. Coma supervened 212+/-54 min after insulin injection, at which time brain glucose, lactate, and glutamate were significantly decreased. At both 35 and 146 min after insulin administration, exogenous insulin was present in brain, but not in the CSF. After 208 min of insulin administration, animals were given i.v. glucose and sacrificed 35 min later. Most changes in the brain produced by hypoglycemia were reversed by the administration of glucose. Hypoxia (Po(2) = 23 mm Hg) was produced and maintained for 35 min in another group of animals. Hypoxia caused brain edema but did not affect brain electrolyte content. However, brain lactate concentration was significantly greater than normal. The data indicate that the seizures noted early in the course of insulin-induced hypoglycemia are temporally related to a rise in brain osmolality secondary to an increased net transport into brain of Na(+) and K(+), probably caused by insulin, per se. As hypoglycemia persists, there is also depletion of energy-supplying substrates (glucose, lactate, glutamate) in the brain, an event which coincides with the onset of coma. The brain edema observed during hypoxia is largely due to an increase in brain osmolality secondary to accumulation of lactate.
Functional Unresponsiveness and Replicative Senescence of Myeloid Leukemia Antigen–specific CD8+ T Cells After Allogeneic Stem Cell Transplantation
Authors: Gregory L. Beatty, Jasmine S. Smith, Ran Reshef, Kunal P. Patel, Theresa A. Colligon, Barbara A. Vance, Noelle V. Frey, F. Brad Johnson, David L. Porter, Robert H. Vonderheide
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myeloid malignancies has been attributed in part to a graft-versus-leukemia effect that is dependent on donor T lymphocytes. CD8+ T-cell responses to MHC class I–restricted tumor epitopes, not just allogeneic antigens, may help mediate antileukemia effects after HSCT, but the specificity and function of such cells are not completely understood. Experimental Design: We examined the diversity, phenotype, and functional potential of leukemia-associated antigen-specific CD8+ T cells in patients with myeloid leukemia following allogeneic HSCT. Screening for antigen-specific T cells was accomplished with a peptide/MHC tetramer library. Results: Patients with acute myelogenous leukemia or chronic myelogenous leukemia in remission following HSCT exhibited significant numbers of peripheral blood CD8+ T cells that recognized varying combinations of epitopes derived from leukemia-associated antigens. However, these cells failed to proliferate, release cytokines, or degranulate in response to antigen-specific stimuli. As early as 2 months after HSCT, CD8+ T cells from patients were predominantly CD28− CD57+ and had relatively short telomeres, consistent with cellular senescence. Conclusions: Circulating leukemia-specific CD8+ T cells are prominent in myeloid leukemia patients after HSCT, but such cells are largely functionally unresponsive, most likely due to replicative senescence. These findings carry important implications for the understanding of the graft-versus-leukemia effect and for the rational design of immunotherapeutic strategies for patients with myeloid leukemias.
A Stochastic Simulator of Birth-Death Master Equations with Application to Phylodynamics
Authors: T. G. Vaughan, A. J. Drummond
Journal: Molecular Biology and Evolution (2013)

In this article, we present a versatile new software tool for the simulation and analysis of stochastic models of population phylodynamics and chemical kinetics. Models are specified via an expressive and human-readable XML format and can be used as the basis for generating either single population histories or large ensembles of such histories. Importantly, phylogenetic trees or networks can be generated alongside the histories they correspond to, enabling investigations into the interplay between genealogies and population dynamics. Summary statistics such as means and variances can be recorded in place of the full ensemble, allowing for a reduction in the amount of memory used—an important consideration for models including large numbers of individual subpopulations or demes. In the case of population size histories, the resulting simulation output is written to disk in the flexible JSON format, which is easily read into numerical analysis environments such as R for visualization or further processing. Simulated phylogenetic trees can be recorded using the standard Newick or NEXUS formats, with extensions to these formats used for non-tree-like inheritance relationships.
The role of the membrane cytoskeleton cross-linker ezrin in medulloblastoma cells
Authors: Hirokatsu Osawa, Christian A. Smith, Young Shin Ra, Paul Kongkham, James T. Rutka
Journal: Neuro-Oncology (2008)

Medulloblastoma is a highly malignant brain tumor that occurs predominantly in children. The molecular pathogenesis of medulloblastoma is under investigation. Previously, we used complementary DNA microarray analysis to compare patterns of gene expression in medulloblastoma samples versus normal cerebellum. The cytoskeletal protein ezrin was found to be overexpressed in medulloblastoma compared with normal cerebellum, an observation that was further validated by immunohistochemistry and real-time PCR analysis. To assess the role of ezrin in medulloblastoma, we studied ezrin's role in medulloblastoma migration, invasion, and adhesion. Western blotting and immunofluorescence showed high expression of ezrin in four medulloblastoma cell lines, and ezrin was primarily localized to filopodia. Ezrin-specific small interfering RNA suppressed the formation of filopodia and in vitro migration, invasion, and adhesion. We also used a stably transfected medulloblastoma cell line to study the effect of ezrin overexpression. We showed that high expression of ezrin promotes filopodia formation and in vitro invasion. Finally, athymic mice implanted with ezrin-overexpressing DAOY medullo-blastoma cell clones in the cerebellum showed shortened survival compared with controls. These findings suggest that, in addition to other cytoskeletal proteins, ezrin plays an important role in medulloblastoma adhesion, migration, and invasion.
Blood volume changes and water appearance in the circulation from water and 3% and 6% carbohydrate drinks
Authors: S M Shirreffs, R J Maughan
Journal: British Journal of Sports Medicine (2010)

This study investigated water absorption and blood volume changes after drinking water and 3% and 6% carbohydrate drinks. Nine healthy male volunteers completed this crossover study after giving informed consent to participate. On three separate occasions they consumed 500 ml of Evian water (W), a 3% carbohydrate drink (3% CHO) or a 6% carbohydrate drink (6% CHO) to which had been added 10.00±0.01 g of deuterium oxide. Blood samples were collected 10 and 5 min before drink ingestion and at 2, 5, 10, 15, 20, 30, 45 and 60 min after drink ingestion. In addition, subjective feeling questionnaires were completed at intervals throughout and subjects urinated before and after the study period. Blood samples were analysed for haematocrit and haemoglobin, glucose and deuterium concentrations. There was a significant increase in blood glucose concentration after consumption of both the 3% CHO and 6% CHO drinks, with the increase being greater after consumption of the 6% CHO drink. Both the 3% CHO and 6% CHO drinks promoted a significant blood and plasma volume expansion after their consumption whereas there was no change in blood and plasma volumes when water was consumed. Blood deuterium enrichment increased after consumption of all three drinks, but there was no significant difference between drinks. The results suggest that when a significant expansion of blood volume is desired, this can be achieved by consumption of the 3% CHO or 6% CHO drink rather than with plain water consumption. This is likely to be due to the sodium and carbohydrate content of these drinks.