tbuckley/cabot-search huggingface dataset:
A transient ischemic environment induces reversible compaction of chromatin
Authors: Ina Kirmes, Aleksander Szczurek, Kirti Prakash, Iryna Charapitsa, Christina Heiser, Michael Musheev, Florian Schock, Karolina Fornalczyk, Dongyu Ma, Udo Birk, Christoph Cremer, George Reid
Journal: Genome biology (2015)

Cells detect and adapt to hypoxic and nutritional stress through immediate transcriptional, translational and metabolic responses. The environmental effects of ischemia on chromatin nanostructure were investigated using single molecule localization microscopy of DNA binding dyes and of acetylated histones, by the sensitivity of chromatin to digestion with DNAseI, and by fluorescence recovery after photobleaching (FRAP) of core and linker histones. Short-term oxygen and nutrient deprivation of the cardiomyocyte cell line HL-1 induces a previously undescribed chromatin architecture, consisting of large, chromatin-sparse voids interspersed between DNA-dense hollow helicoid structures 40–700 nm in dimension. The chromatin compaction is reversible, and upon restitution of normoxia and nutrients, chromatin transiently adopts a more open structure than in untreated cells. The compacted state of chromatin reduces transcription, while the open chromatin structure induced upon recovery provokes a transitory increase in transcription. Digestion of chromatin with DNAseI confirms that oxygen and nutrient deprivation induces compaction of chromatin. Chromatin compaction is associated with depletion of ATP and redistribution of the polyamine pool into the nucleus. FRAP demonstrates that core histones are not displaced from compacted chromatin; however, the mobility of linker histone H1 is considerably reduced, to an extent that far exceeds the difference in histone H1 mobility between heterochromatin and euchromatin. These studies exemplify the dynamic capacity of chromatin architecture to physically respond to environmental conditions, directly link cellular energy status to chromatin compaction and provide insight into the effect ischemia has on the nuclear architecture of cells.
Diagnostic accuracy of clinical tests for the diagnosis of hip femoroacetabular impingement/labral tear: a systematic review with meta-analysis
Authors: M P Reiman, A P Goode, C E Cook, P Hölmich, K Thorborg
Journal: British Journal of Sports Medicine (2014)

Background Surgery for hip femoroacetabular impingement/acetabular labral tear (FAI/ALT) is exponentially increasing despite lacking investigation of the accuracy of various diagnostic measures. Useful clinical utility of these measures is necessary to support diagnostic imaging and subsequent surgical decision-making. Objective Summarise/evaluate the current diagnostic accuracy of various clinical tests germane to hip FAI/ALT pathology. Methods A computer-assisted literature search of MEDLINE, CINAHL and EMBASE databases using keywords related to diagnostic accuracy of the hip joint, as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for the search and reporting phases of the study. Quality assessment of bias and applicability was conducted using the Quality of Diagnostic Accuracy Studies-2 (QUADAS-2). Random effects models were used to summarise sensitivities (SN), specificities (SP), diagnostic odds ratio (DOR) and respective confidence intervals (CI). Results The employed search strategy revealed 21 potential articles, with one demonstrating high quality. Nine articles qualified for meta-analysis. The meta-analysis demonstrated that flexion-adduction-internal rotation (pooled SN ranging from 0.94 (95% CI 0.90 to 0.97) to 0.99 (95% CI 0.98 to 1.00); DOR 5.71 (95% CI 0.84 to 38.86) to 7.82 (95% CI 1.06 to 57.84)) and flexion-internal rotation (pooled SN 0.96 (95% CI 0.81 to 0.99); DOR 8.36 (95% CI 0.41 to 171.3) tests possess only screening accuracy. Conclusions Few hip physical examination tests for diagnosing FAI/ALT have been investigated in enough studies of substantial quality to direct clinical decision-making. Further high-quality studies across a wider spectrum of hip pathology patients are recommended to discern the confirmed clinical utility of these tests. Trials registration number PROSPERO Registration # CRD42014010144.
Comparison of functional efficacy of surfactant protein B analogues in lavaged rats
Authors: M. Gupta, J.M. Hernandez-Juviel, A.J. Waring, R Bruni, F.j Walther
Journal: European Respiratory Journal (2000)

Leakage of plasma proteins into the alveoli inhibits pulmonary surfactant function and worsens respiratory failure. Surfactant protein B (SP-B), is essential for surfactant function, but the N-terminal domain of human SP-B (residues 1.25, SP-B1-25) can mimic the biophysical properties of full length SP-B1-78 in vitro. The authors compared the function and inhibition resistance of synthetic surfactant preparations containing SP-B analogues to a natural bovine surfactant preparation "Survanta". Eight groups of eight rats were lavaged to induce surfactant deficiency, fibrinogen was instilled as a surfactant inhibitor, and then they were rescued with exogenous surfactant. Five experimental surfactants were formulated by mixing 3% SP-B1-78, or an equimolar amount of SP-B1-25 and/or 1% palmitoylated surfactant protein C (SP-C)1-35, into a standard phospholipid (PL) mixture: B1-78, B1-25, C1-35, B1-78+C1-35, and B1-25+C1-35 surfactant preparations. Survanta was used as a positive control and PL and no treatment as a negative control. Lung function was assessed during a 2-h period using arterial blood gas and lung compliance measurements. Rats treated with B1-25+C1-35 surfactant and Survanta maintained the highest oxygenation and lung compliance values throughout the experiments. The surfactants could be ranked as B1-25+C1-35 surfactant and Survanta &gt;B1-25 and B1-78+C1-35 surfactants &gt;others. Because the N-terminal domain of surfactant protein B1-25 can improve inhibition resistance, it may be able to substitute for surfactant protein B in exogenous surfactant preparations.
Cellular Mechanism of Calcium-Mediated Triggered Activity in the Heart
Authors: Rodolphe P. Katra, Kenneth R. Laurita
Journal: Circulation Research (2005)

Calcium overload due to enhanced calcium entry is a mechanism for spontaneous calcium release (SCR) from the sarcoplasmic reticulum, delayed-afterdepolarizations (DAD), and triggered activity. However, the exact mechanistic relationship between elevated intracellular calcium levels and triggered activity originating from a specific location remains unclear. We hypothesize that under conditions of enhanced calcium entry, elevation of intracellular calcium will result in multiple calcium release events of which only one is more likely to initiate a triggered beat. We used optical mapping of action potentials and ratiometric calcium transients in an electromechanically-uncoupled canine wedge model of enhanced calcium entry, using I Ks blockade with β-adrenergic stimulation. Under conditions of enhanced calcium entry, the rate of calcium uptake was faster compared with control conditions; however, during rapid pacing, cytoplasmic calcium elevation at the endocardium was significantly increased (15±4%) compared with control (10±3, P &lt;0.04). Rapid pacing induced multiple simultaneous SCR events with largest amplitude and earliest onset near the endocardium compared with the epicardium. Furthermore, SCR events with largest amplitude and earliest onset served as a focus for DAD-mediated triggered activity. Interestingly, polymorphic VT occurred in some experiments when multiple SCR events occurred. In conclusion, multiple, simultaneous SCR events occur over a broad region of relatively slower calcium uptake and elevated diastolic calcium levels. However, SCR events closer to the endocardium have the largest amplitude and earliest onset and are, thereby, more likely to initiate DAD-mediated triggered activity. Finally, multiple SCR events may be a mechanism of polymorphic VT under calcium overload conditions.
Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism
Authors: Timothy A. Brighton, John W. Eikelboom, Kristy Mann, Rebecca Mister, Alexander Gallus, Paul Ockelford, Harry Gibbs, Wendy Hague, Denis Xavier, Rafael Diaz, Adrienne Kirby, John Simes
Journal: New England Journal of Medicine (2012)

Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism.We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism.During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P=0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P=0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P=0.22) or serious adverse events.In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.).
Mononuclear phagocytes egress from an in vitro model of the vascular wall by migrating across endothelium in the basal to apical direction: role of intercellular adhesion molecule 1 and the CD11/CD18 integrins.
Authors: G J Randolph, M B Furie
Journal: The Journal of Experimental Medicine (1996)

Little is known about how mononuclear phagocytes (MP) are cleared from sites of inflammation as inflammatory lesions resolve. In this study, the possibility that MP could be cleared from tissues by migrating across endothelium in the basal to apical direction was investigated. In an in vitro model of a blood vessel wall consisting of human umbilical vein endothelial cells (HUVEC) grown on amniotic tissue, a majority of MP that initially transmigrated into the amnion later exited by migrating back across the endothelium in the basal to apical direction. MP that egressed from these cultures adhered to the apical surface of the endothelium or were found nonadherent in the medium above the endothelium. Egression of MP continued throughout the 4-d period examined, displaying higher than first order kinetics and a t(1/2) of approximately 24 h. These kinetics were decreased by increasing the volume of medium bathing the cultures, suggesting that a soluble factor(s) regulates the rate of egression. In contrast, the kinetics were accelerated by pretreating the endothelium with IL-1. The initial phase of this increased rate of egression was inhibited by antibodies to inter- cellular adhesion molecule 1 (ICAM-1) or CD18 by 100 and 71%, respectively. Immunostaining revealed that ICAM-1 was present on the apical and basal surfaces of umbilical vein endothelium in vitro and in situ. These data demonstrate that MP can traverse endothelium in the basal to apical direction, and lend insight into the mechanisms by which this process occurs.
Predicting the pathogenesis of influenza from genomic response: a step toward early diagnosis
Authors: Eric Bortz, Adolfo García-Sastre
Journal: Genome Medicine (2011)

Infection with influenza virus does not always lead to symptomatic illness, but it is not currently possible to predict who will be severely affected and who will have mild or no symptoms. Gene expression profiling of biofluids might unlock the complex dynamics of response to acute respiratory virus infections such as influenza. A recent article by Alfred Hero and colleagues used transcriptional microarray analyses to follow the response to symptomatic and asymptomatic influenza infection over time, and revealed a role for type I IFN (IFNβ and IFNα) signaling and the NLRP3 inflammasome in determining the outcome in human infections.
IgG subclass antibodies against <i>Parietaria judaica</i> in normal and allergic subjects
Authors: S. Palumbo, G. Di Felice, A. Mari, S. Bonini, G. Bruno, R. Tinghino, C. Afferni, F. Sallusto, C. Pini
Journal: Allergy (1994)

IgG antibody response to the inhalant allergen Parietaria judaica (Pj) and IgG subclass distribution were studied in 82 normal subjects, divided into three groups according to age (0-1, 1-20, and 20-60 years) and in 32 allergic subjects aged 20-60 years. Both normal and allergic subjects showed an IgG response, and all had IgG1 antibodies specific for PjE. Serum IgG2, IgG3, and IgG4 against PjE were detectable in 36%, 46%, and 22% of normal subjects, and in 58%, 31%, and 65% of allergic subjects, respectively. A significant difference in class distribution between allergic and age-matched normal subjects was found only for IgG4 antibodies against PjE (65% and 17%; P < 0.01). The ELISA results were also analyzed quantitatively, taking into account the relative proportion of specific antibodies. Thus, in normal subjects IgG1 antibodies showed a decreasing trend as the age rose, while no differences according to the age of the subject were found for IgG2 and IgG4. When data from allergic subjects (20-60 years) and the age-matched normal group were compared, they were different for the relative percentage of IgG2 only, showing for this a significantly lower value (P < 0.001). The present data indicate that normal and allergic subjects show differences in the IgG isotype distribution depending on their sensitivity and duration of allergen exposure.
Alcohol Consumption Raises HDL Cholesterol Levels by Increasing the Transport Rate of Apolipoproteins A-I and A-II
Authors: Elizabeth R. De Oliveira e Silva, David Foster, Monnie McGee Harper, Cynthia E. Seidman, Jonathan D. Smith, Jan L. Breslow, Eliot A. Brinton
Journal: Circulation (2000)

Moderate alcohol intake is associated with lower atherosclerosis risk, presumably due to increased HDL cholesterol (HDL-C) concentrations; however, the metabolic mechanisms of this increase are poorly understood.We tested the hypothesis that ethanol increases HDL-C by raising transport rates (TRs) of the major HDL apolipoproteins apoA-I and -II. We measured the turnover of these apolipoproteins in vivo in paired studies with and without alcohol consumption in 14 subjects. The fractional catabolic rate (FCR) and TR of radiolabeled apoA-I and -II were determined in the last 2 weeks of a 4-week Western-type metabolic diet, without (control) or with alcohol in isocaloric exchange for carbohydrates. Alcohol was given as vodka in fixed amounts ranging from 0.20 to 0.81 g. kg(-1). d(-1) (mean+/-SD 0.45+/-0.19) to reflect the usual daily intake of each subject. HDL-C concentrations increased 18% with alcohol compared with the control (Wilcoxon matched-pairs test, P=0.002). The apoA-I concentrations increased by 10% (P=0.048) and apoA-II concentrations increased by 17% (P=0.005) due to higher apoA-I and -II TRs, respectively, whereas the FCR of both apoA-I and -II did not change. The amount of alcohol consumed correlated with the degree of increase in HDL-C (Pearson's r=0.66, P=0.01) and apoA-I TR (r=0.57, P=0.03). The increase in HDL-C also correlated with the increase in apoA-I TR (r=0.61, P=0.02).Alcohol intake increases HDL-C in a dose-dependent fashion, associated with and possibly caused by an increase in the TR of HDL apolipoproteins apoA-I and -II.
Rebuttal: ‘Obesity hypoventilation syndrome (OHS): does the current definition need revisiting?’
Authors: Nicholas Hart, Swapna Mandal, Ari Manuel, Babak Mokhlesi, Jean-Louis Pepin, Amanda Piper, John Stradling
Journal: Thorax (2014)

Rebuttal: 'Obesity hypoventilation syndrome (OHS): does the current definition need revisiting?'In response to the comments by Tulaimat and Littleton, 1 we will clarify our original statement on 'Obesity hypoventilation syndrome (OHS): does the current definition need revisiting? 2 The two issues that these authors raise are curious and indeed re-enforce the statement we made previously, and we wholly appreciate this.We highlighted that the use of 'calculated arterial standard bicarbonate (HCO 3 -) level from a conventional blood gas machine, in the absence of another influence on metabolic acid-base status' should be considered, and this is supported by Tulaimat and Littleton's comments.Additionally, we did not suggest removing obstructive sleep apnoea (OSA) from the definition of OHS, but rather, we wished to extend the definition, with a PaCO2 ≥45 mm Hg (6 kPa) OR an arterial base excess >3 mmol/L OR a standard HCO 3 ->27 mmol/L (in the absence of another cause for a metabolic alkalosis).We agree that the phenotyping of such patients into OSA, combined OSA-OHS, and lone OHS, would be clinically useful and enhance the long-term management, but
Metabolic Depletion of Atp by Fructose Inversely Controls Cd95- and Tumor Necrosis Factor Receptor 1–Mediated Hepatic Apoptosis
Authors: Markus Latta, Gerald Künstle, Marcel Leist, Albrecht Wendel
Journal: The Journal of Experimental Medicine (1999)

Hepatocyte apoptosis is crucial in several forms of liver disease. Here, we examined in different models of murine liver injury whether and how metabolically induced alterations of hepatocyte ATP levels control receptor-mediated apoptosis. ATP was depleted either in primary hepatocytes or in vivo by various phosphate-trapping carbohydrates such as fructose. After the activation of the tumor necrosis factor (TNF) receptor or CD95, the extent of hepatocyte apoptosis and liver damage was quantified. TNF-induced cell death was completely blocked in ATP-depleted hepatocyte cultures, whereas apoptosis mediated by CD95 was enhanced. Similarly, acute TNF-induced liver injury in mice was entirely inhibited by ATP depletion with ketohexoses, whereas CD95-mediated hepatotoxicity was enhanced. ATP depletion prevented mitochondrial cytochrome c release, loss of mitochondrial membrane potential, activation of type II caspases, DNA fragmentation, and cell lysis after exposure to TNF. The extent of apoptosis inhibition correlated with the severity of ATP depletion, and TNF-induced apoptosis was restored when ATP was repleted by increasing the extracellular phosphate concentration. Our study demonstrates that TNF-induced hepatic apoptosis can be selectively and reversibly blocked upstream of mitochondrial dysfunction by ketohexose-mediated ATP depletion.
Indirect Induction of Vascular Damage by X-Irradiation
Authors: CHARLES K. LEVY
Journal: Circulation Research (1960)

The changes in petechial susceptibility of the vessels of hamster cheek to the moccasin venom test have been compared in shielded and irradiated pouches of the same animal which had received median lethal doses of x-irradiation. There was no statistically significant difference demonstrable between the irradiated and controlled cheek pouches, but both showed a greater hemorrhagic response than was found in the cheek pouches of unirradiated control animals. Similar results were found when the diffusion of intradermally injected Evans blue was used as an indication of x-irradiation damage. The shielded and the exposed areas both showed enhanced permeability to the dye when compared with the unirradiated control animals. These results suggest that some indirect factor or factors are involved in the vascular and permeability changes following exposure to ionizing radiation.
Towards defining the nuclear proteome
Authors: J Lynn Fink, Seetha Karunaratne, Amit Mittal, Donald M Gardiner, Nicholas Hamilton, Donna Mahony, Chikatoshi Kai, Harukazu Suzuki, Yosihide Hayashizaki, Rohan D Teasdale
Journal: Genome biology (2008)

Abstract Background The nucleus is a complex cellular organelle and accurately defining its protein content is essential before any systematic characterization can be considered. Results We report direct evidence for 2,568 mammalian proteins within the nuclear proteome: the nuclear subcellular localization of 1,529 proteins based on a high-throughput subcellular localization protocol of full-length proteins and an additional 1,039 proteins for which clear experimental evidence is documented in published literature. This is direct evidence that the nuclear proteome consists of at least 14% of the entire proteome. This dataset was used to evaluate computational approaches designed to identify additional nuclear proteins. Conclusion This represents direct experimental evidence that the nuclear proteome consists of at least 14% of the entire proteome. This high-quality nuclear proteome dataset was used to evaluate computational approaches designed to identify additional nuclear proteins. Based on this analysis, researchers can determine the stringency and types of lines of evidence they consider to infer the size and complement of the nuclear proteome.
An open-label trial of rituximab therapy in pulmonary alveolar proteinosis
Authors: M.S. Kavuru, A. Malur, I. Marshall, B.P. Barna, M. Meziane, I. Huizar, H. Dalrymple, R. Karnekar, M.J. Thomassen
Journal: European Respiratory Journal (2011)

Rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20, has shown promise in several autoimmune disorders. Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterised by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF). An open-label, proof-of-concept phase II clinical trial was conducted in 10 PAP patients. The intervention consisted of two intravenous infusions of rituximab (1,000 mg) 15 days apart. Bronchoalveolar lavage (BAL) fluid and peripheral blood samples were collected. The primary outcome was improvement in arterial blood oxygenation. Both arterial oxygen tension and alveolar–arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study. Lung function and high-resolution computed tomography scans, which were secondary outcomes, also improved. Peripheral blood CD19+ B-lymphocytes decreased from mean± sem 15±2% to &lt;0.05% (n=10) 15 days post-therapy. This decrease persisted for 3 months in all patients; at 6 months, CD19+ B-cells were detected in four out of seven patients (5±2%). Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids (n=8) but unchanged in sera (n=9). In this PAP cohort: 1) rituximab was well-tolerated and effectively ameliorated lung disease; and 2) reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ.