tbuckley/cabot-search huggingface dataset:
Estimation of Amino Acid Residue Substitution Rates at Local Spatial Regions and Application in Protein Function Inference: A Bayesian Monte Carlo Approach
Authors: Yan Y. Tseng, Jie Liang
Journal: Molecular Biology and Evolution (2005)

The amino acid sequences of proteins provide rich information for inferring distant phylogenetic relationships and for predicting protein functions. Estimating the rate matrix of residue substitutions from amino acid sequences is also important because the rate matrix can be used to develop scoring matrices for sequence alignment. Here we use a continuous time Markov process to model the substitution rates of residues and develop a Bayesian Markov chain Monte Carlo method for rate estimation. We validate our method using simulated artificial protein sequences. Because different local regions such as binding surfaces and the protein interior core experience different selection pressures due to functional or stability constraints, we use our method to estimate the substitution rates of local regions. Our results show that the substitution rates are very different for residues in the buried core and residues on the solvent-exposed surfaces. In addition, the rest of the proteins on the binding surfaces also have very different substitution rates from residues. Based on these findings, we further develop a method for protein function prediction by surface matching using scoring matrices derived from estimated substitution rates for residues located on the binding surfaces. We show with examples that our method is effective in identifying functionally related proteins that have overall low sequence identity, a task known to be very challenging.
Crosslinkage of B lymphocyte surface immunoglobulin by anti-Ig or antigen induces prolonged oscillation of intracellular ionized calcium.
Authors: H A Wilson, D Greenblatt, M Poenie, F D Finkelman, R Y Tsien
Journal: The Journal of Experimental Medicine (1987)

Our results indicate that B lymphocytes stimulated with anti-Ig or antigen exhibit repetitive [Ca2+]i transients which persist for hours. The magnitude of these transients favors an important and ongoing role for [Ca2+]i elevation in antigen driven B cell activation. Repetitive Ca2+ transients may prove to be a prevalent mechanism of Ca2+ signaling. In preliminary experiments (with L. E. Samelson and R. D. Klausner), we have observed Ca2+ transients in cloned T cells stimulated with antigen. Woods et al. have described repetitive free Ca2+ transients in hepatocytes stimulated with extracellular ligands promoting glycogenolysis, and suggest that the intervals of base-line [Ca2+]i levels explain the absence of mitochondrial overload in chronically stimulated cells. These considerations apply equally to B lymphocytes and recommend caution in delineating the range of Ca2+-mediated functions by prolonged coculture of cells with Ca2+ ionophores. Our experiments were done in a simple recording chamber with one cell type. No cell interactions were observed. Given the variety of indicator dyes now available, the technical approach we present, augmented by a more sophisticated recording chamber, is a potentially powerful tool for examining the intrinsic, and T- or accessory cell-dependent, physiology of B cell differentiation.
A Randomized, Double-Blind Evaluation of <scp>d</scp>-Cycloserine or Alprazolam Combined With Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder in Iraq and Afghanistan War Veterans
Authors: Barbara Olasov Rothbaum, Matthew Price, Tanja Jovanovic, Seth D. Norrholm, Maryrose Gerardi, Boadie Dunlop, Michael Davis, Bekh Bradley, Erica J. Duncan, Albert Rizzo, Kerry J. Ressler
Journal: American Journal of Psychiatry (2014)

The authors examined the effectiveness of virtual reality exposure augmented with D-cycloserine or alprazolam, compared with placebo, in reducing posttraumatic stress disorder (PTSD) due to military trauma.After an introductory session, five sessions of virtual reality exposure were augmented with D-cycloserine (50 mg) or alprazolam (0.25 mg) in a double-blind, placebo-controlled randomized clinical trial for 156 Iraq and Afghanistan war veterans with PTSD.PTSD symptoms significantly improved from pre- to posttreatment across all conditions and were maintained at 3, 6, and 12 months. There were no overall differences in symptoms between D-cycloserine and placebo at any time. Alprazolam and placebo differed significantly on the Clinician-Administered PTSD Scale score at posttreatment and PTSD diagnosis at 3 months posttreatment; the alprazolam group showed a higher rate of PTSD (82.8%) than the placebo group (47.8%). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only. At posttreatment, the D-cycloserine group had the lowest cortisol reactivity and smallest startle response during virtual reality scenes.A six-session virtual reality treatment was associated with reduction in PTSD diagnoses and symptoms in Iraq and Afghanistan veterans, although there was no control condition for the virtual reality exposure. There was no advantage of D-cycloserine for PTSD symptoms in primary analyses. In secondary analyses, alprazolam impaired recovery and D-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning. D-cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo, findings that are consistent with those in the animal literature.
Physiologic mechanisms in aortic insufficiency. I. The effect of changing heart rate on flow dynamics. II. Determinants of Austin Flint murmur.
Authors: S Laniado, E L Yellin, C Yoran, J Strom, M Hori, S Gabbay, R Terdiman, R W Frater
Journal: Circulation (1982)

We studied the dynamic changes in mitral flow patterns and in mitral valve motion before and after producing acute, reversible aortic insufficiency (AI) in nine open-chest dogs. Phasic mitral flow, the mitral valve echocardiogram, and intracardiac phonocardiogram and other hemodynamic variables were measured. During moderate AI (mean regurgitant fraction 52 +/- 5%) (+/- SD), the antegrade filling volume decreased from 31 +/- 7 to 24 +/- 6 ml (p less than 0.01), but the peak protodiastolic mitral flow rate increased from 139 +/- 37 to 157 +/- 42 ml/sec (p less than 0.01), reflecting the shift of a larger fraction of total mitral filling volume to early diastole. In six dogs, atrial pacing was used to examine the hemodynamic effects of tachycardia. Increasing the heart rate from 90 to 120 beats/min increased cardiac output from 2.64 +/- 0.56 to 3.3 +/- 0.831/min (p less than 0.05) and decreased left atrial pressure from 24 +/- 8 to 17 +/- 7 mm Hg (p less than 0.05). Increasing heart rate to 150 beats/min compromised mitral filling, reduced cardiac output and increased left atrial pressure. Moderate tachycardia improves cardiac performance in AI by reducing regurgitant volume, without significantly reducing transmitral filling volume. The mitral valve echocardiogram showed only a small decrease in cusp opening amplitude during AI. A low-pitched left ventricular inflow tract murmur was recorded in protodiastole and corresponded in time to the rapidly increasing mitral flow. We conclude that the major determinant of the turbulence responsible for the creation of the austin flint murmur is the antegrade mitral flow stream and its mixing with the retrograde aortic flow.
Interleukin-1β Inhibits Phospholamban Gene Expression in Cultured Cardiomyocytes
Authors: Charles F. McTiernan, Bonnie H. Lemster, Carole Frye, Steven Brooks, Alain Combes, Arthur M. Feldman
Journal: Circulation Research (1997)

Phospholamban is a key regulatory protein that defines diastolic function. Proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) can depress contractility and intracellular Ca2+ currents and transients. An alteration in phospholamban expression is a possible pathway by which these cytokines modulate cardiac function. To test this hypothesis, primary cultures of neonatal rat cardiomyocytes were incubated with IL-1 beta, TNF-alpha, or both, and the level of phospholamban transcripts was examined by Northern blot analyses. Phospholamban transcript levels were decreased approximately equal to 50% (P < .0001) in cells exposed to 2 ng/mL IL-1 beta (20 hours), whereas TNF-alpha had no effect. Western blot analyses showed that IL-1 beta also reduced phospholamban protein levels (60% of control, P < .0001). The effects on transcript levels were gene specific; IL-1 beta induced transcripts for inducible NO synthase (iNOS), did not alter GAPDH transcripts, and reduced sarcoplasmic reticulum Ca(2+)-ATPase (65% of control, P < .001) transcripts. Cardiomyocytes treated with IL-1 beta showed no alterations in basal contractile parameters (maximum velocity of contraction and relaxation and maximal amplitude of contraction) but were unresponsive to beta-adrenergic stimulation. Studies performed in the presence of second-messenger inhibitors showed that the effect of IL-1 beta on phospholamban transcript levels was blocked by dexamethasone, was insensitive to inhibitors of iNOS, cyclooxygenase, or tyrosine kinases, but was enhanced by the addition of the protein kinase inhibitor staurosporine. These data demonstrate that IL-1 beta alters the expression of phospholamban, a key regulator of cardiac contractility, at both the transcript and protein levels. The results suggest novel mechanisms by which IL-1 beta may modify cardiac function.
The effectiveness of helmet wear in skiers and snowboarders: a systematic review
Authors: Michael D Cusimano, Judith Kwok
Journal: British Journal of Sports Medicine (2010)

Objective To summarise the best available evidence to determine the impact of helmet use on head injuries, neck injuries and cervical spine injuries in skiers and snowboarders. Data sources Relevant publications were identified through electronic searches of MEDLINE, PubMed, EMBASE, CINAHL and the Cochrane Library databases (1966–2009) in addition to manual reference checks of all included articles. Review methods 45 articles were identified through our systematic literature search. Of these, 10 studies met the inclusion criteria after two levels of screening. Two independent reviewers critically appraised the studies. Data were extracted on the primary outcomes of interest: head injury, neck injury and cervical spine injury. Studies were assessed for quality by the criteria of Downs and Black. Results Studies reviewed indicate that helmet wear reduces the risk of head injuries in skiing and snowboarding. Four case-control studies reported a reduction in the risk of head injury with helmet use ranging from 15% to 60%. Another cohort study found a significantly lower incidence of head injuries involving loss of consciousness in helmet users (p&lt;0.05). The five remaining studies suggested a major protective effect of helmets by indicating that none or few of the head-injured and deceased participants wore a helmet. Conclusions There is strong evidence to support the protective value of helmets in reducing the risk of head injuries in skiing and snowboarding. There is no good evidence to support the claim that the use of helmets leads to an increase risk of cervical spine injuries or neck injuries.
First-Order Correct Bootstrap Support Adjustments for Splits that Allow Hypothesis Testing When Using Maximum Likelihood Estimation
Authors: E. Susko
Journal: Molecular Biology and Evolution (2010)

The most frequent measure of phylogenetic uncertainty for splits is bootstrap support. Although large bootstrap support intuitively suggests that a split in a tree is well supported, it has not been clear how large bootstrap support needs to be to conclude that there is significant evidence that a hypothesized split is present. Indeed, recent work has shown that bootstrap support is not first-order correct and thus cannot be directly used for hypothesis testing. We present methods that adjust bootstrap support values in a maximum likelihood (ML) setting so that they have an interpretation corresponding to P values in conventional hypothesis testing; for instance, adjusted bootstrap support larger than 95% occurs only 5% of the time if the split is not present. Through examples and simulation settings, it is found that adjustments always increase the level of support. We also find that the nature of the adjustment is fairly constant across parameter settings. Finally, we consider adjustments that take into account the data-dependent nature of many hypotheses about splits: the hypothesis that they are present is being tested because they are in the tree estimated through ML. Here, in contrast, we find that bootstrap probability often needs to be adjusted downwards.
The quantitative relationship of urinary peptide hydroxyproline excretion to collagen degradation
Authors: Phillip H. Weiss, LeRoy Klein
Journal: Journal of Clinical Investigation (1969)

To determine the quantitative relationship of urinary hydroxyproline peptide excretion to collagen breakdown, known quantities of radioactive hydroxyproline peptides were administered to unlabeled animals and excertion of radioactivity in respiratory carbon dioxide, urine, and feces was measured. The major routes of excretion of collagen peptide metabolites were respiratory carbon dioxide (75%) and urine, as hydroxyproline-containing peptides (25%). Since the predominant urine hydroxyproline peptide linkage is proly-hydroxyproline, L-prolyl-L-hydroxyproline-(3)H was administered to unlabeled animals. Greater than 80% of the administered dipeptide was excreted in urine, suggesting that this peptide linkage is not hydrolyzed to a significant extent in vivo. These data suggest that urinary hydroxyproline excretion is a "fairly" sensitive indicator of collagen breakdown and can be used at the clinical level to quantitate changes in collagen breakdown.
Neuromuscular responses to hydration in moderate to warm ambient conditions during self-paced high-intensity exercise
Authors: F E Marino, J Cannon, D Kay
Journal: British Journal of Sports Medicine (2010)

To examine the neuromuscular responses to 60 minutes of self-paced high-intensity exercise punctuated with 6 × 1-minute "all-out" sprints at 10-minute intervals in moderate (19.8°C, SEM 0.3) and warm (33.2, SEM 0.1), humid (∼64% relative humidity) conditions with either complete hydration (CH) or without hydration (NF).Seven subjects (mean age 20.6 years (SE 1.1), mass 73.8 kg (SE 4.5), peak power 288 W (SE 11.3)) performed the time trial on four separate occasions, which were differentiated by ambient temperature and fluid ingestion. For each sprint interval, distance, power output and electromyographic (EMG) data from the rectus femoris and vastus lateralis muscles were recorded.The NF trials resulted in a reduction in body mass for the moderate and warm conditions of 1.7% and 2.1%, respectively. Final rectal temperatures were not different among conditions (∼38.7°C). Total body sweating was higher in the warm condition (19.1-21.3 ml/kg per hour) compared with the moderate condition (16.1-16.5 ml/kg per hour; p<0.05). Neither fluid ingestion nor ambient temperature altered total distance cycled for any of the trials (range 30.1-32.6 km). The normalised integrated EMG (as percentage of maximal voluntary contraction) when compared with the first sprint increased from sprint three for the rectus femoris muscle in both no and complete hydration but decreased for the vastus lateralis muscle. The mean percentile frequency shift increased for both the vastus lateralis and rectus femoris muscles in both no and complete hydration.These results suggest that the integrity of the neuromuscular system is adjusted according to hydration status and ambient temperatures during intense self-paced cycling.
The effect of hyperglycemia on renal dysfunction associated with altered gene expression profiles in a rat model of mechanical ventilation
Authors: Wonil Choi
Journal: European Respiratory Journal (2013)

Background:  High blood glucose caused an increase in morbidity and mortality in intensive care unit. The molecular mechanisms of this hyperglycemia effect on kidney are poorly understood. Therefore, we used gene microarrays to profile gene expression patterns involved in hyperglycemia related renal dysfunction.   Methods:  Serum creatinine was evaluated in control group, hyperglycemia group (HG), euglycemia group (EG) and hyperglycemia with a-lipoic acid (LA) group (HGLA). Dextrose water (D/W) was injected to increase blood glucose above 200 mg/dl in HG group and D/W with insulin was injected in EG group. Control and hyperglycemic rats were studied for microarray (n= 3 each group). The RatRef-12 expression Beadchip (22,226 gene probes per array) was used to analyze the pattern of gene expression in all groups.   Results:  Microarray analysis showed that 71 genes were differentially expressed in hyperglycemia and control group. The profile revealed that hyperglycemia induced significant alterations of expression of many genes encoding oxidation and antioxidant molecules, apoptosis regulatory protein, metabolic enzyme.  Serum creatinine was significantly increased in the HG group compared to EG group (0.96 ± 0.2 vs 0.62 ± 0.1 mg/dl) (P    Conclusions:  High glucose caused a renal dysfunction during mechanical ventilation. Either insulin or LA attenuated renal dysfunction. Hyperglycemia also affects gene expression profiles in the kidney tissue mainly through oxidative stress.
Tubal Gestation: Rupture into Peritoneal Cavity: Abdominal Section: Recovery
Authors: W. G. Nash
Journal: BMJ (1892)

MKWUCAL JOUaMALfirst two died within thirty-six hours, but the third lived five days.In his case the distension disappeared, the tube was re- moved, and he was taking nourishment; but the bases of his lungs had given out during the previous collapse, and lhe died drom congestive pneumonia.In these cases, as soon as the glass tube is tied into the bowel, the latter is returned to the abdomen, and fixed to the wound with fine catgut sutures, in order that a f&ecal fistula and not an artificial anus should be
In Vitro Study of beta-Adrenergic Receptors
Authors: B B Wolfe, T K Harden, P B Molinoff
Journal: The Annual Review of Pharmacology and Toxicology (1977)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling
Authors: Ismail Adeniran, Aziza El Harchi, Jules C. Hancox, Henggui Zhang
Journal: Cardiovascular Research (2012)

One form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K(+) current (I(K1)). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias.The ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to I(K1) based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N 'mutant' I(K1) led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 'mutant' I(K1) also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry.Increased I(K1) due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.
Coeliac disease with severe hypogammaglobulinaemia.
Authors: A D Webster, G Slavin, M Shiner, T A Platts-Mills, G L Asherson
Journal: Gut (1981)

A patient with severe late onset primary hypogammaglobulinaemia developed coeliac disease. The case illustrates that coeliac disease can occur in the virtual absence of local antibody production by plasma cells in the mucosa of the small bowel. Furthermore, our inability to demonstrate specific cellular immunity to a subfraction of gluten raises doubts about the relevance of immunological reactions in the pathogenesis of coeliac disease.
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Interfere With Angiogenesis by Inhibiting the Geranylgeranylation of RhoA
Authors: Ho-Jin Park, Dequan Kong, Luisa Iruela-Arispe, Ulrike Begley, Dongjiang Tang, Jonas B. Galper
Journal: Circulation Research (2002)

Angiogenesis is implicated in the pathogenesis of cancer, rheumatoid arthritis, and atherosclerosis and in the treatment of coronary artery and peripheral vascular disease. Here, cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are shown to interfere with angiogenesis. In vivo, the HMG-CoA reductase inhibitor simvastatin dose-dependently inhibited capillary growth in both vascular endothelial growth factor–stimulated chick chorioallantoic membranes and basic fibroblast growth factor–stimulated mouse corneas. In vitro, the development of tubelike structures by human microvascular endothelial cells cultured on 3D collagen gels was inhibited at simvastatin concentrations similar to those found in the serum of patients on therapeutic doses of this agent. HMG-CoA reductase inhibitors interfered with angiogenesis via inhibition of the geranylgeranylation and membrane localization of RhoA. Simvastatin inhibited membrane localization of RhoA with a concentration dependence similar to that for the inhibition of tube formation, whereas geranylgeranyl pyrophosphate, the substrate for the geranylgeranylation of Rho, reversed the effect of simvastatin on tube formation and on the membrane localization of RhoA. Furthermore, tube formation was inhibited by GGTI, a specific inhibitor of the geranylgeranylation of Rho; by C3 exotoxin, which inactivates Rho; and by the adenoviral expression of a dominant-negative RhoA mutant. The expression of a dominant-activating RhoA mutant reversed the effect of simvastatin on tube formation. Finally, HMG-CoA reductase inhibitors inhibited signaling by vascular endothelial growth factor, Akt, and focal adhesion kinase, three RhoA-dependent pathways known to be involved in angiogenesis. This study demonstrates a new relationship between lipid metabolism and angiogenesis and an antiangiogenic effect of HMG-CoA reductase inhibitors with possible important therapeutic implications.