tbuckley/cabot-search huggingface dataset:
General Heterotachy and Distance Method Adjustments
Authors: J. Wu, E. Susko
Journal: Molecular Biology and Evolution (2009)

Heterotachy is a general term to describe positions in a sequence that evolve at different rates in different lineages. Kolaczkowski and Thornton (2004. Performance of maximum parsimony and likelihood phylogenetics when evolution is heterogeneous. Nature 431:980–984.) recently described an intriguing heterotachy model that leads to topological bias for likelihood-based methods and parsimony methods. In this article, we show that heterotachy can generally be viewed as multivariate rates-across-sites variation, which can be described as randomly drawing rates (or branch lengths) from a multivariate distribution for each branch at each site. Motivated by this idea, we propose a pairwise alpha heterotachy adjustment model, which gives us much improved topological estimation in the settings by Kolaczkowski and Thornton (2004).
Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain
Authors: Jeffrey C Lee, Igor Vivanco, Rameen Beroukhim, Julie H. Y Huang, Whei L Feng, Ralph M DeBiasi, Koji Yoshimoto, Jennifer C King, Phioanh Nghiemphu, Yuki Yuza, Qing Xu, Heidi Greulich, Roman K Thomas, J. Guillermo Paez, Timothy C Peck, David J Linhart, Karen A Glatt, Gad Getz, Robert Onofrio, Liuda Ziaugra, Ross L Levine, Stacey Gabriel, Tomohiro Kawaguchi, Keith O'Neill, Haumith Khan, Linda M Liau, Stanley F Nelson, P. Nagesh Rao, Paul Mischel, Russell O Pieper, Tim Cloughesy, Daniel J Leahy, William R Sellers, Charles L Sawyers, Matthew Meyerson, Ingo K Mellinghoff
Journal: PLoS Medicine (2006)

Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy.Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors.Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
Hypersensitivity of BK <sub>Ca</sub> to Ca <sup>2+</sup> Sparks Underlies Hyporeactivity of Arterial Smooth Muscle in Shock
Authors: Guiling Zhao, Yan Zhao, Bingxing Pan, Jie Liu, Xuliang Huang, Xiuqin Zhang, Chunmei Cao, Ning Hou, Caihong Wu, Ke-seng Zhao, Heping Cheng
Journal: Circulation Research (2007)

Large conductance Ca(2+)-activated K(+) channels (BK(Ca)) play a critical role in blood pressure regulation by tuning the vascular smooth muscle tone, and hyposensitivity of BK(Ca) to Ca(2+) sparks resulting from its altered beta1 subunit stoichiometry underlies vasoconstriction in animal models of hypertension. Here we demonstrate hypersensitivity of BK(Ca) to Ca(2+) sparks that contributes to hypotension and blunted vasoreactivity in acute hemorrhagic shock. In arterial smooth muscle cells under voltage-clamp conditions (0 mV), the amplitude and duration, but not the frequency, of spontaneous transient outward currents of BK(Ca) origin were markedly enhanced in hemorrhagic shock, resulting in a 265% greater hyperpolarizing current. Concomitantly, subsurface Ca(2+) spark frequency was either unaltered (at 0 mV) or decreased in hyperpolarized resting cells. Examining the relationship between spark and spontaneous transient outward current amplitudes revealed a hypersensitive BK(Ca) activity to Ca(2+) spark in hemorrhagic shock, whereas the spark-spontaneous transient outward current coupling fidelity was near unity in both groups. Importantly, we found an acute upregulation of the beta1 subunit of the channel, and single-channel recording substantiated BK(Ca) hypersensitivity at micromolar Ca(2+), which promotes the alpha and beta1 subunit interaction. Treatment of shock animals with the BK(Ca) inhibitors iberiotoxin and charybdotoxin partially restored vascular membrane potential and vasoreactivity to norepinephrine and blood reinfusion. Thus, the results underscore a dynamic regulation of the BK(Ca)-Ca(2+) spark coupling and its therapeutic potential in hemorrhagic shock-associated vascular disorders.
Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice
Authors: Youchun Jiang, Corey Reynolds, Chang Xiao, Wenke Feng, Zhanxiang Zhou, Walter Rodriguez, Suresh C. Tyagi, John W. Eaton, Jack T. Saari, Y. James Kang
Journal: The Journal of Experimental Medicine (2007)

Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses preestablished hypertrophic cardiomyopathy caused by pressure overload induced by ascending aortic constriction in a mouse model. The reversal occurs in the continued presence of pressure overload. Sustained pressure overload leads to decreases in cardiac Cu and vascular endothelial growth factor (VEGF) levels along with suppression of myocardial angiogenesis. Cu supplementation replenishes cardiac Cu, increases VEGF, and promotes angiogenesis. Systemic administration of anti-VEGF antibody blunts Cu regression of hypertrophic cardiomyopathy. In cultured human cardiomyocytes, Cu chelation blocks insulin-like growth factor (IGF)-1- or Cu-stimulated VEGF expression, which is relieved by addition of excess Cu. Both IGF-1 and Cu activate hypoxia-inducible factor (HIF)-1alpha and HIF-1alpha gene silencing blocks IGF-1- or Cu-stimulated VEGF expression. HIF-1alpha coimmunoprecipitates with a Cu chaperone for superoxide dismutase-1 (CCS), and gene silencing of CCS, but not superoxide dismutase-1, prevents IGF-1- or Cu-induced HIF-1alpha activation and VEGF expression. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1alpha activation of VEGF expression and angiogenesis.
Subjective and objective measures of physical activity in relationship to bone mineral content during late childhood: the Iowa Bone Development Study
Authors: K F Janz, H C Medema-Johnson, E M Letuchy, T L Burns, J M Eichenberger Gilmore, J C Torner, M Willing, S M Levy
Journal: British Journal of Sports Medicine (2008)

This study compared accelerometry to self-report for the assessment of physical activity (PA) in relation to bone mineral content (BMC). In addition, we compared the ability of these measures to assess PA in boys versus girls.Participants in this cross-sectional study included 449 children (mean age 11 years) from the Iowa Bone Development Study. PA was measured via 3-5 days of accelerometry using the Actigraph and 7 day self-report questionnaire using the Physical Activity Questionnaire for Children (PAQ-C). Hip, spine, and whole body BMC were measured via dual energy x ray absorptiometry (DXA).Partial correlation analysis (controlling for height, weight, and maturity) showed the Actigraph was significantly associated with hip (r = 0.40), spine (r = 0.20), and whole body (r = 0.33) BMC in boys, as was the PAQ-C (r = 0.28 hip, r = 0.19 spine, and r = 0.22 whole body). Among girls, only the Actigraph was significantly associated with hip (r = 0.18) and whole body (r = 0.16) BMC. Both the Actigraph and PAQ-C were significant in hip, spine, and whole body multivariable linear regression models (after controlling for body size and maturity) in boys. Only the Actigraph entered hip BMC regression model in girls.Our study supports previous work showing associations between everyday PA and BMC in older children. These associations are more likely to be detected with an objective versus subjective measure of PA, particularly in girls.
An Economic Evaluation of Screening for Chlamydia trachomatis in Adolescent Males
Authors: Mehmet Genç
Journal: JAMA (1993)

<h3>Objective.</h3> —To assess the cost-effectiveness of identifying asymptomatic carriers of<i>Chlamydia trachomatis</i>among adolescent males. <h3>Design.</h3> —Cost-effectiveness analysis based on cohort analytic studies previously reported and average salaries and costs of medical care in Sweden. <h3>Setting.</h3> —Adolescent males attending a primary care center for routine health checks. <h3>Participants.</h3> —Estimates of costs and benefits are based on a cohort of 1000 adolescent males and their female contacts. <h3>Intervention.</h3> —Screening with enzyme immunoassay (EIA), either on leukocyte esterase (LE)—positive urine samples (LE-EIA screening) or on all urine samples (EIA screening), was compared with no screening (no treatment or contact tracing). The effects of confirming positive EIA results with a blocking assay and alternative antibiotic regimens on the outcome of the screening strategies were also evaluated. <h3>Results.</h3> —Compared with no screening, the LE-EIA and EIA screening strategies reduced the overall costs when the prevalence of chlamydial infection in males exceeded 2% and 10%, respectively. Enzyme immunoassay screening achieved an overall cure rate that was 12.2% to 12.6% (95% confidence interval) better, but reduced the incremental savings by at least $2144 per cured male, in comparison with LE-EIA screening. Confirmation of positive EIA results reduced the overall cost of the LE-EIA screening strategy when the prevalence of<i>C trachomatis</i>among males was less than 8%. Compared with a 7-day course of doxycycline, a single oral dose of azithromycin administered under supervision in the clinic improved the cure rates of both EIA and LE-EIA screening strategies by 15.1% to 16.3% and 11.2% to 12.0%, respectively, while reducing the corresponding overall costs by 5% and 9%, respectively, regardless of the prevalence of chlamydial infection in males. <h3>Conclusion.</h3> —The use of LE-EIA screening combined with treatment of positive cases with azithromycin was the most cost-effective intervention strategy focusing on asymptomatic male carriers of<i>C trachomatis</i>. Positive EIA results should be confirmed when screening low-risk populations. (<i>JAMA</i>. 1993;270:2057-2067)
Factors contributing to low back pain in rowers
Authors: Duncan A Reid, Peter J Mcnair
Journal: British Journal of Sports Medicine (2000)

Competitive rowing is a highly aerobic sport requiring technical skills, motor coordination, adequate strength, and endurance.1,2 A number of authors13–6 have reported a significant incidence of low back pain among the rowing population. This paper identifies the factors that may influence the onset of low back pain.

During the rowing stroke, the magnitude of the forces on the lumbar spine is high. Hosea et al 7 reported average compressive loads of 3919 N for men and 3330 N for women, while anterior shear forces were found to be 848 N and 717 N for men and women respectively. Peak compressive loads during the stroke were 6066 N and 5031 N for men and women respectively. Furthermore, for 70% of the stroke cycle, rowers are in a flexed posture.7 Hosea et al 7 recorded flexion ranges averaging 28–30° which equates to 55% of maximum range of spinal flexion. Tensile stresses on the outer annulus of the intervertebral disc have been found to increase considerably above 50% flexion.8 The combination of flexion with compressive loading has been identified as a mechanism for injury to the lumbar spine structures.9 In addition to flexion and compression, sweep rowers also rotate their trunks. This combination can place considerably more stress through the facet joint capsules and ligaments and may facilitate damage to discs, although the evidence for the latter is inconclusive.9 For rowers, the time of day will also influence the magnitude of the forces on their lumbar spines. In order to have calm …
An Anatomical Study of the Bronchial Vascular System and its Variations in Disease
Authors: P. Marchand, J. C. Gilroy, V. H. Wilson
Journal: Thorax (1950)

During the course of an anatomical study of specimens of emphysematous lungs evidence was found to suggest that the bronchial circulation might play a more important part in producing the disease picture than has been appreciated hitherto.Consequently we undertook a detailed investigation of the bronchial arteries and veins in both normal and diseased lungs.In some respects our findings differ from presently accepted views of the anatomy of these vessels.MATERIAL AND METHODS OF INVESTIGATION The material us.d in our experiments is set out in Tables I andII.The specimens have varied from very fresh lungs obtained at operation to necropsy material injected at least 24 hours after death and after rigor mortis had passed off.In all, a total of 63 lung specimens were injected.The following injection techniques were employed:The Vinylite Corrosion Technique (Puckett and Newman, 1940).-Inthis pro- cedure coloured plastic was injected into the vessels under a positive pressure which varied from 2 to 5 lb.per sq.in.The organic material was digested off the cast by immersion in either concentrated hydrochloric acid or a 40% solution of caustic potash.After digestion a careful dissection was necessary to remove the finer radicles of the pulmonary vessels in order to visualize for study the bronchial circu- lation.The lungs, in the majority of instances, were inflated with air before the injection of the blood vessels; in other cases vinylite was formed into the bronchi as an alternative to inflation with air.In preparing demonstration specimens, casts of the bronchi were made by pouring Wood's metal into the trachea before opening the chest.When injecting complete lungs obtained at necropsy the pulmonary artery was filled through a cannula tied into the main stem; the pulmonary veins were filled through a cannula in the left auricular appendix, the aorta being ligated at its origin to prevent the escape of vinylite into the systemic vessels.The bronchial arteries were injected through a cannula tied into the divided descending aorta, the arch of the aorta being clamped at the origin of the left subclavian artery and the intercostal vessels being tied or clamped before or during the injection.The veins which enter the azygos and hemiazygos veins were injected through these veins in a retrograde manner.
Gut lavage IgG and interleukin 1 receptor antagonist:interleukin 1 beta ratio as markers of intestinal inflammation in children with inflammatory bowel disease.
Authors: R Troncone, N Caputo, A Campanozzi, M Cucciardi, V Esposito, R Russo, B De Vizia, L Greco, S Cucchiara
Journal: Gut (1997)

BACKGROUND: Whole gut lavage is currently used as preparation before radiological or endoscopic examination of the large bowel. AIM: To validate the gut lavage technique for the assessment of mucosal inflammation, by measuring intestinal IgG and interleukin 1 beta (IL-1 beta) in the fluid obtained. PATIENTS: Sixteen children with Crohn9s disease (CD), 14 with ulcerative colitis (UC), and 22 age matched controls. METHODS: Isotonic, non-absorbable polyethylene glycol based lavage solution was given orally or by nasogastric tube. Clear fluid was collected, filtered, and treated with protease inhibitors. IgG, IL-1 beta and IL-1-receptor antagonist (IL-1-ra) were measured by sandwich enzyme linked immunosorbent assay (ELISA). RESULTS: In patients with UC and CD, IgG and IL-1 beta levels were significantly (p &lt; 0.001) higher than in controls. A positive correlation (p &lt; 0.05) was found with disease activity scores. IL-1-ra levels were not significantly different in UC and CD, when compared with controls, but the IL-1-ra:IL-1 beta ratio was significantly (p &lt; 0.01) lower in patients with UC and CD, and negatively (p &lt; 0.001) correlated with IgG levels in lavage fluid. CONCLUSIONS: Gut lavage fluid IgG and IL-1 beta levels and IL-1-ra:IL-1 beta ratio may provide objective discrimination between active and inactive disease in children with inflammatory bowel disease.
Arsenic Induced Mitochondrial DNA Damage and Altered Mitochondrial Oxidative Function: Implications for Genotoxic Mechanisms in Mammalian Cells
Authors: Michael A. Partridge, Sarah X.L. Huang, Evelyn Hernandez-Rosa, Mercy M. Davidson, Tom K. Hei
Journal: Cancer Research (2007)

Abstract Arsenic is a well-established human carcinogen that is chronically consumed in drinking water by millions of people worldwide. Recent evidence has suggested that arsenic is a genotoxic carcinogen. Furthermore, we have shown that mitochondria mediate the mutagenic effects of arsenic in mammalian cells, as arsenic did not induce nuclear mutations in mitochondrial DNA (mtDNA)–depleted cells. Using the human-hamster hybrid AL cells, we show here that arsenic alters mitochondrial function by decreasing cytochrome c oxidase function and oxygen consumption but increasing citrate synthase function. These alterations correlated with depletion in mtDNA copy number and increase in large heteroplasmic mtDNA deletions. In addition, mtDNA isolated periodically from cultures treated continuously with arsenic did not consistently display the same deletion pattern, indicating that the mitochondrial genome was subjected to repeated and continuous damage. These data support the theory that the mitochondria, and particularly mtDNA, are important targets of the mutagenic effects of arsenic in mammalian cells. [Cancer Res 2007;67(11):5239–47]
Trauma and seronegative spondyloarthropathy: rapid joint destruction in peripheral arthritis triggered by physical injury.
Authors: I Olivieri, S Gherardi, C Bini, D Trippi, M L Ciompi, G Pasero
Journal: Annals of the Rheumatic Diseases (1988)

Two B27 positive patients developed peripheral arthritis immediately after a significant musculoskeletal injury. Unlike previously reported peripheral arthritis precipitated by trauma in B27 positive subjects the arthritis was rapidly destructive.
Clusterin promotes the aggregation and adhesion of renal porcine epithelial cells.
Authors: J R Silkensen, K M Skubitz, A P Skubitz, D H Chmielewski, J C Manivel, J A Dvergsten, M E Rosenberg
Journal: Journal of Clinical Investigation (1995)

The function of clusterin, a heterodimeric glycoprotein markedly induced in renal and other organ injuries, is unclear. Since renal injury is accompanied by alterations in cell attachment, it is possible that clusterin functions to promote cell-cell and cell-substratum interactions. In this study, a single cell suspension of renal epithelial (LLC-PK1) cells was treated with purified human clusterin, resulting in time- and dose-dependent cell aggregation. Electron microscopy of the cell aggregates demonstrated cell junction and lumen formation. To determine the effect of clusterin on cell adhesion, tissue culture plates were coated with clusterin, fibronectin, PBS, or albumin. Clusterin and fibronectin promoted cell adhesion to the same extent. The adhesion to clusterin was dose dependent and specific, as a monoclonal antibody against clusterin inhibited cell adhesion to clusterin but not fibronectin. Perterbations of the cytoskeleton may underlie the alterations in cell attachment which occur in renal injury. Induction of clusterin mRNA was seen after disruption of both microtubules and microfilaments and after inhibition of cell-substratum interactions. In conclusion, clusterin is a potent renal epithelial cell aggregation and adhesion molecule. We speculate that clusterin functions to promote cell-cell and cell-substratum interactions which are perturbed in the setting of renal injury, thereby preserving the integrity of the renal epithelial barrier.
Does the incremental shuttle walking test (ISWT) require maximal effort in healthy subjects of different ages
Authors: Cristiane Golias Gonçalves, Rafael Mesquita, Daniela Hayashi, Josiane Marques Felcar, Fábio Pitta, Karen Barros Parron Fernandes, Vanessa Suziane Probst
Journal: European Respiratory Journal (2012)

Background: It is unknown whether the ISWT requires maximal effort in subjects of different ages. Objective: To evaluate if the ISWT requires maximal effort in healthy subjects of different ages. Methods: 331 individuals (158 men) performed two ISWT, allowing more than 12 levels of the test, if necessary. The participants were separated into six groups according to their age (G1: 18-28, G2: 29-39, G3: 40-50, G4: 51-61, G5: 62-72 and G6: 73-83 years). Heart rate (HR) and symptoms of dyspnea and fatigue were recorded. HR achieved at the end of the test was expressed as a percentage of the maximum heart rate (HRmax). Results: 31% of the subjects achieved more than 12 speed levels. The majority of subjects reached HR values greater than 90% of HRmax at the end of the test with a median [interquartile range] of: G1: 100[95-104]; G2: 100[96-105]; G3: 102[97-107]; G4: 99[91-105]; G5: 95[87-106] and G6: 95[90-109]%HRmax. Regarding symptoms, all groups showed higher values of dyspnea and fatigue at the end of the test (p < 0.05). A multivariate analysis (logistic regression) identified that female gender (odds ratio: 3.3 [95% confidence interval:1.4-8.1], worse performance in the ISWT (low: 4.2 [1.7-10.2]; normal: 2.6 [1.3-5.4] versus high performance) and older age (4.7 [1.7-12.9]) increased the chance for not achieving 90% of HRmax at the end of the ISWT. Conclusion: The Incremental Shuttle Walking Test is a field test that requires maximum effort for most healthy individuals, and for that it is necessary to extend the test beyond twelve speed levels. Female gender, older age and worse performance in the test are the determinants for not reaching maximal effort during the ISWT.
Potential Clinical Uses of CDK Inhibitors: Lessons from Synthetic Lethality Screens
Authors: Ladislava Vymětalová, Vladimír Kryštof
Journal: Medicinal Research Reviews (2015)

Abstract Developments in genetic and genomic technology have produced vast quantities of data that are gradually yielding new insights into fundamental cellular and molecular processes. In particular, they have revealed some differences between normal and transformed cells that could potentially be exploited to develop targeted, personalized cancer therapies with unprecedented efficiencies. This review summarizes recent findings from synthetic lethality (SL) screens against cyclin‐dependent kinases (CDKs) that can be targeted with small molecule kinase inhibitors. SL screens can be used to identify cancers sensitive to CDK inhibitors. Several SL partners of specific CDKs have been identified, including MYC, K‐Ras, VHL, PI3K, and PARP, all of which are discussed in the review. CDK inhibitors have been in clinical trials for nearly 20 years and it has become clear that effective therapy using these compounds will require careful selection of patients with respect to the specific molecular phenotype of their disease.