tbuckley/cabot-search huggingface dataset:
Limitations of the evolutionary parsimony method of phylogenetic analysis.
Authors: L Jin, M Nei
Journal: Molecular Biology and Evolution (1990)

Lake's evolutionary parsimony (EP) method of constructing a phylogenetic tree is primarily applied to four DNA sequences. In this method, three quantities--X, Y, and Z--that correspond to three possible unrooted trees are computed, and an invariance property of these quantities is used for choosing the best tree. However, Lake's method depends on a number of unrealistic assumptions. We therefore examined the theoretical basis of his method and reached the following conclusions: (1) When the rates of two transversional changes from a nucleotide are unequal, his invariance property breaks down. (2) Even if the rates of two transversional changes are equal, the invariance property requires some additional conditions. (3) When Kimura's two-parameter model of nucleotide substitution applies and the rate of nucleotide substitution varies greatly with branch, the EP method is generally better than the standard maximum-parsimony (MP) method in recovering the correct tree but is inferior to the neighbor-joining (NJ) and a few other distance matrix methods. (4) When the rate of nucleotide substitution is the same or nearly the same for all branches, the EP method is inferior to the MP method even if the proportion of transitional changes is high. (5) When Lake's assumptions fail, his chi2 test may identify an erroneous tree as the correct tree. This happens because the test is not for comparing different trees. (6) As long as a proper distance measure is used, the NJ method is better than the EP and MP methods whether there is a transition/transversion bias or whether there is variation in substitution rate among different nucleotide sites.
The operational analysis of psychological terms
Authors: B. F. Skinner
Journal: Behavioral and Brain Sciences (1984)

Abstract The major contributions of operationism have been negative, largely because operationists failed to distinguish logical theories of reference from empirical accounts of language. Behaviorism never finished an adequate formulation of verbal reports and therefore could not convincingly embrace subjective terms. But verbal responses to private stimuli can arise as social products through the contingencies of reinforcement arranged by verbal communities. In analyzing traditional psychological terms, we need to know their stimulus conditions (“finding the referent”), and why each response is controlled by that condition. Consistent reinforcement of verbal responses in the presence of stimuli presupposes stimuli acting upon both the speaker and the reinforcing community, but subjective terms, which apparently are responses to private stimuli, lack this characteristic. Private stimuli are physical, but we cannot account for these verbal responses by pointing to controlling stimuli, and we have not shown how verbal communities can establish and maintain the necessary consistency of reinforcement contingencies. Verbal responses to private stimuli may be maintained through appropriate reinforcement based on public accompaniments, or through reinforcements accorded responses made to public stimuli, with private cases then occurring by generalization. These contingencies help us understand why private terms have never formed a stable and uniform vocabulary: It is impossible to establish rigorous vocabularies of private stimuli for public use, because differential reinforcement cannot be made contingent upon the property of privacy. The language of private events is anchored in the public practices of the verbal community, which make individuals aware only by differentially reinforcing their verbal responses with respect to their own bodies. The treatment of verbal behavior in terms of such functional relations between verbal responses and stimuli provides a radical behaviorist alternative to the operationism of methodological behaviorists.
Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests
Authors: Armando Tripodi, Francesco Salerno, Veena Chantarangkul, Marigrazia Clerici, Massimo Cazzaniga, Massimo Primignani, Pier Mannuccio Mannucci
Journal: Hepatology (2005)

The role played by coagulation defects in the occurrence of bleeding in cirrhosis is still unclear. This is partly due to the lack of tests that truly reflect the balance of procoagulant and anticoagulant factors in vivo. Conventional coagulation tests such as prothrombin time and activated partial thromboplastin time are inadequate to explore the physiological mechanism regulating thrombin, because they do not allow full activation of the main anticoagulant factor, protein C, whose levels are considerably reduced in cirrhosis. We used a thrombin generation test to investigate the coagulation function in patients with cirrhosis. Thrombin generation measured without thrombomodulin was impaired, which is consistent with the reduced levels of procoagulant factors typically found in cirrhosis. However, when the test was modified by adding thrombomodulin (i.e., the protein C activator operating in vivo), patients generated as much thrombin as controls. Hence, the reduction of procoagulant factors in patients with cirrhosis is compensated by the reduction of anticoagulant factors, thus leaving the coagulation balance unaltered. These findings help clarify the pathophysiology of hemostasis in cirrhosis, suggesting that bleeding is mainly due to the presence of hemodynamic alterations and that conventional coagulation tests are unlikely to reflect the coagulation status of these patients. In conclusion, generation of thrombin is normal in cirrhosis. For a clinical validation of these findings, a prospective clinical trial is warranted where the results of thrombin generation in the presence of thrombomodulin are related to the occurrence of bleeding.
Hypertrophy and Dilatation of the Heart
Authors: J. M. Fothergill
Journal: BMJ (1872)

MIarch 2, I872. of cornea pellucida.He was admitted as an in-door patient to the in - stitution on November iith, when I broke up some of the adhesions with a needle, and next day I made a large iridectomy and extracted the lens.On November 14th, he had good sight ; and on the i8th, he was dismissed cured.The left eye is still improving ; but, owing to its extensive opacity, he will depend almost exclusively upon his right eye, which was considered hopeless. List of Cases.No.
Control of Human Viral Infections by Natural Killer Cells
Authors: Stephanie Jost, Marcus Altfeld
Journal: Annual Review of Immunology (2013)

Natural killer (NK) cells are effector cells of the innate immune system and are important in the control of viral infections. Their relevance is reflected by the multiple mechanisms evolved by viruses to evade NK cell–mediated immune responses. Over recent years, our understanding of the interplay between NK cell immunity and viral pathogenesis has improved significantly. Here, we review the role of NK cells in the control of four important viral infections in humans: cytomegalovirus, influenza virus, HIV-1, and hepatitis C virus.
Decreased macrophage release of TGF- and TIMP-1 in chronic obstructive pulmonary disease
Authors: A. R. Pons, J. Sauleda, A. Noguera, J. Pons, B. Barceló, A. Fuster, A. G. N. Agustí
Journal: European Respiratory Journal (2005)

The present study tested the hypothesis that alveolar macrophages (AM) from patients with chronic obstructive pulmonary disease (COPD) release more pro-inflammatory and/or less anti-inflammatory mediators than those from smokers with normal lung function and never-smokers. AM were sorted by flow cytometry from bronchoalveolar lavage fluid in 13 patients with COPD (mean± SEM 67±2 yrs, forced expiratory volume in one second (FEV 1 ) 61±4% reference), 16 smokers with normal lung function (55±2 yrs, FEV 1 97±4% reference) and seven never-smokers (67±7 yrs, FEV 1 94±4% reference). After sorting, AM were cultured (with and without lipopolysaccharide stimulation) after 4 h and 24 h, and the concentrations of leukotriene B 4 (LTB 4 ), transforming growth factor (TGF)-β 1 and tissue inhibitor of metalloproteinase (TIMP)-1 were quantified in the supernatant by ELISA. The production of reactive oxygen intermediates (ROI) in freshly isolated AM was determined by flow cytometry. LTB 4 secretion and ROI production were not different between groups. In contrast, AM from COPD patients released significantly less TGF-β 1 and TIMP-1 than those from smokers with normal lung function and nonsmokers. In conclusion, these observations are compatible with reduced anti-inflammatory and anti-elastolytic capacity in chronic obstructive pulmonary disease, which is likely to contribute to the pathogenesis of the disease.
Even an “epistemic triangle” has three sides
Authors: John Barresi, Chris Moore
Journal: Behavioral and Brain Sciences (2004)

By focusing primarily on communication between adult and child and on adult-set criteria for appropriate action, Carpendale &amp; Lewis's (C&amp;L's) account of the development of social understanding in the epistemic triangle tends toward an enculturation view, while diminishing the role of individuals. What their proposed mechanism fails to acknowledge is that the two agents in the epistemic triangle necessarily have independent perspectives of the object and of each other.
Ecologically and Evolutionarily Important SNPs Identified in Natural Populations
Authors: L. M. Williams, M. F. Oleksiak
Journal: Molecular Biology and Evolution (2011)

Evolution by natural selection acts on natural populations amidst migration, gene-by-environmental interactions, constraints, and tradeoffs, which affect the rate and frequency of adaptive change. We asked how many and how rapidly loci change in populations subject to severe, recent environmental changes. To address these questions, we used genomic approaches to identify randomly selected single nucleotide polymorphisms (SNPs) with evolutionarily significant patterns in three natural populations of Fundulus heteroclitus that inhabit and have adapted to highly polluted Superfund sites. Three statistical tests identified 1.4–2.5% of SNPs that were significantly different from the neutral model in each polluted population. These nonneutral patterns in populations adapted to highly polluted environments suggest that these loci or closely linked loci are evolving by natural selection. One SNP identified in all polluted populations using all tests is in the gene for the xenobiotic metabolizing enzyme, cytochrome P4501A (CYP1A), which has been identified previously as being refractory to induction in the three highly polluted populations. Extrapolating across the genome, these data suggest that rapid evolutionary change in natural populations can involve hundreds of loci, a few of which will be shared in independent events.
Multiple adverse pregnancy outcomes before symptom onset are associated with a worse disease outcome in women with recent-onset inflammatory polyarthritis
Authors: EM Camacho, SMM Verstappen, M Lunt, DK Bunn, DPM Symmons
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> Previous evidence suggests that women with a history of adverse pregnancy outcomes (APOs) may be at greater risk of developing rheumatoid arthritis. Additionally, one study reported that female patients with rheumatoid arthritis with a history of preonset APOs showed a worse 2-year radiographic outcome than did patients with no APOs. The authors9 aim was to investigate the relationship between preonset APOs (spontaneous abortion or stillbirth) and disease outcome in women with inflammatory polyarthritis (IP). <h3>Methods</h3> The Norfolk Arthritis Register (NOAR) is a primary-care-based cohort of patients with recent-onset IP; 1586 gravid women who joined NOAR during 1990–2004 were included in this analysis. The authors examined the relationship between patient-reported preonset APOs and disease outcome, measured using the Health Assessment Questionnaire (HAQ) and disease activity score in 28 joints (DAS28<sub>CRP</sub>) (for a subgroup of patients), using linear random effects analysis, adjusted for age and other factors. <h3>Results</h3> In a predominantly parous cohort (99%), 397 (25%) women reported ≥1 APO before symptom onset. The rates of APOs in NOAR were comparable to the general population. On average, women with a history of ≥2 APOs had significantly higher HAQ and DAS28 scores over time than women with no APOs (mean difference in HAQ 0.13 (95% CI 0.002 to 0.26); DAS28, 0.56 (95% CI 0.01 to 1.11)). This relationship was more pronounced in women with ≥3 APOs (mean difference in HAQ 0.23 (95% CI 0.02 to 0.43); DAS28, 0.98 (95% CI 0.23 to 1.74)). <h3>Conclusion</h3> Women with two or more APOs before IP onset had a worse disease outcome than women with no APOs.
Expiratory and inspiratory chest computed tomography and pulmonary function tests in cigarette smokers
Authors: K. Kubo, S Eda, H Yamamoto, K Fujimoto, Y Matsuzawa, Y Murayama, M Hasegawa, S Sone, F Sakai
Journal: European Respiratory Journal (1999)

This study evaluated small airway dysfunction and emphysematous destruction of lung parenchyma in cigarette smokers, using chest expiratory high-resolution computed tomography (HRCT) and pulmonary function tests (PFT). The degree of emphysematous destruction was classified by visual scoring (VS) and the average HRCT number at full expiration/full inspiration (E/I ratio) calculated in 63 male smokers and 10 male nonsmokers (group A). The Brinkman smoking index (BI), defined as cigarettes x day(-1) x yrs, was estimated. Sixty-three smokers were divided into three groups by PFT: group B1 (n=7), with normal PFT; group B2 (n=21), with diffusing capacity of the lung for carbon monoxide (DL,CO) &gt; or = 80% predicted, forced expiratory volume in one second (FEV1) &lt; 80% pred and/or residual volume (RV) &gt; 120% pred; and group B3 (n=35), with DL,CO &lt; 80% pred, FEV1 &lt; 80% pred and/or RV &gt; 120% pred. Heavy smokers (BI &gt; or = 600) (n=48) showed a significant increase in emphysema by both VS and E/I. E/I was significantly elevated in both group B2 (mean+/-SD 0.95+/-0.05) and B3 (0.96+/-0.06) compared with group B1 (0.89+/-0.03). VS could not differentiate group B2 (3.9+/-5.0) from B1 (1.1+/-1.6). These findings suggest that the expiration/inspiration ratio reflects hyperinflation and airway obstruction, regardless of the functional characteristics of emphysema, in cigarette smokers.
Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice.
Authors: L C Wood, S M Jackson, P M Elias, C Grunfeld, K R Feingold
Journal: Journal of Clinical Investigation (1992)

The disruption of the cutaneous permeability barrier results in metabolic events that ultimately restore barrier function. These include increased epidermal sterol, fatty acid, and sphingolipid synthesis, as well as increased epidermal DNA synthesis. Because tumor necrosis factor (TNF) and other cytokines are known products of keratinocytes and have been shown to modulate lipid and DNA synthesis in other systems, their levels were examined in two acute models and one chronic model of barrier perturbation in hairless mice. Acute barrier disruption with acetone results in a 72% increase in epidermal TNF 2.5 h after treatment, as determined by Western blotting. Furthermore, epidermal TNF mRNA was elevated ninefold over controls 2.5 h after acetone treatment. This elevation in TNF mRNA was maximal at 1 h after acetone, and decreased to control levels by 8 h. After tape stripping, a second acute model of barrier disruption that avoids application of potentially toxic chemicals, TNF mRNA was elevated fivefold over controls at 2.5 h. Moreover, the mRNA levels for epidermal IL-1 alpha, IL-1 beta, and granulocyte macrophage-colony-stimulating factor (GM-CSF) also were elevated several-fold over controls, after either acetone treatment or tape stripping, but their kinetics differed. GM-CSF mRNA reached a maximal level at 1 h after acetone, while IL-1 alpha and IL-1 beta were maximal at 4 h after treatment. In contrast, mRNAs encoding IL-6 and IFN gamma were not detected either in control murine epidermis or in samples obtained at various times after tape stripping or acetone treatment. The relationship of the cytokine response to barrier function is further strengthened by results obtained in essential fatty acid deficient mice. In this chronic model of barrier perturbation mRNA levels for epidermal TNF, IL-1 alpha, IL-1 beta, and GM-CSF were each elevated several-fold over controls. These results suggest that epidermal cytokine production is increased after barrier disruption and may play a role in restoring the cutaneous permeability barrier.
5-lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor α-induced hepatocyte damage in hyperlipidemia-prone ApoE-null mice
Authors: Marcos Martínez-Clemente, Natàlia Ferré, Ana González-Périz, Marta López-Parra, Raquel Horrillo, Esther Titos, Eva Morán-Salvador, Rosa Miquel, Vicente Arroyo, Colin D. Funk, Joan Clària
Journal: Hepatology (2009)

The actual risk factors that drive hepatic inflammation during the transition from steatosis to steatohepatitis are unknown. We recently demonstrated that hyperlipidemia-prone apolipoprotein E-deficient (ApoE(-/-)) mice exhibit hepatic steatosis and increased susceptibility to hepatic inflammation and advanced fibrosis. Because the proinflammatory 5-lipoxygenase (5-LO) pathway was found to be up-regulated in these mice and given that 5-LO deficiency confers cardiovascular protection to ApoE(-/-) mice, we determined the extent to which the absence of 5-LO would alter liver injury in these mice. Compared with ApoE(-/-) mice, which showed expected hepatic steatosis and inflammation, ApoE/5-LO double-deficient (ApoE(-/-)/5-LO(-/-)) mice exhibited reduced hepatic inflammation, macrophage infiltration, tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-18 expression, caspase-3 and nuclear factor-kappaB (NF-kappaB) activities, and serum alanine aminotransferase levels in the absence of changes in hepatic steatosis. The lack of 5-LO produced a remarkable insulin-sensitizing effect in the adipose tissue because peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and adiponectin were up-regulated, whereas c-Jun amino-terminal kinase phosphorylation and MCP-1 and IL-6 expression were down-regulated. On the other hand, hepatocytes isolated from ApoE(-/-)/5-LO(-/-) mice were more resistant to TNF-alpha-induced apoptosis. The 5-LO products leukotriene (LT) B(4), LTD(4), and 5-HETE consistently triggered TNF-alpha-induced apoptosis and compromised hepatocyte survival by suppressing NF-kappaB activity in the presence of actinomycin D. Moreover, ApoE(-/-)/5-LO(-/-) mice were protected against sustained high-fat diet (HFD)-induced liver injury and hepatic inflammation, macrophage infiltration and insulin resistance were significantly milder than those of ApoE(-/-) mice. Finally, pharmacological inhibition of 5-LO significantly reduced hepatic inflammatory infiltrate in the HFD and ob/ob models of fatty liver disease.These combined data indicate that hyperlipidemic mice lacking 5-LO are protected against hepatic inflammatory injury, suggesting that 5-LO is involved in mounting hepatic inflammation in metabolic disease.
Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer
Authors: Ju-Won Roh, Jie Huang, Wei Hu, XiaoYun Yang, Nicholas B. Jennings, Vasudha Sehgal, Bo Hwa Sohn, Hee Dong Han, Sun Joo Lee, Duangmani Thanapprapasr, Justin Bottsford-Miller, Behrouz Zand, Heather J. Dalton, Rebecca A. Previs, Ashley N. Davis, Koji Matsuo, Ju-Seog Lee, Prahlad Ram, Robert L. Coleman, Anil K. Sood
Journal: Clinical Cancer Research (2014)

Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.
Phase II Clinical Trial of Intratumoral Application of TG1042 (Adenovirus-interferon-γ) in Patients With Advanced Cutaneous T-cell Lymphomas and Multilesional Cutaneous B-cell Lymphomas
Authors: Reinhard Dummer, Stefan Eichmüller, Sylke Gellrich, Chalid Assaf, Brigitte Dreno, Meinhard Schiller, Olivier Dereure, Marion Baudard, Martine Bagot, Amir Khammari, Pascal Bleuzen, Vincent Bataille, Anna Derbij, Nicole Wiedemann, Tim Waterboer, Monika Lusky, Bruce Acres, Mirjana Urosevic-Maiwald
Journal: Molecular Therapy (2010)

Cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative disorders that are manageable by immunotherapy. Twenty-one patients were enrolled in a prospective open-label, dose-escalation multicenter study evaluating the effects of repeated TG1042 [adenovirus-interferon (IFN)-γ] intralesional injections in patients with primary CLs, of which 18 were of T-cell and 3 of B-cell type. Repeated intralesional therapy using TG1042 consistently results in local tumor regressions in about half of treated patients and one-third of patients also in regressions in noninjected distant lesions, likely reflecting the systemic immune activation after intralesional therapy. Treatment was well tolerated with few adverse events including injection site reactions, chills, lymphopenia, and fever. Immune monitoring in the peripheral blood demonstrated systemic immune activation and the induction of antibodies against tumor antigens in some patients without clear association with clinical responses. CLs, in particular B-cell lymphomas with high objective response rates, seem to be excellent targets for this type of immunotherapy. Cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative disorders that are manageable by immunotherapy. Twenty-one patients were enrolled in a prospective open-label, dose-escalation multicenter study evaluating the effects of repeated TG1042 [adenovirus-interferon (IFN)-γ] intralesional injections in patients with primary CLs, of which 18 were of T-cell and 3 of B-cell type. Repeated intralesional therapy using TG1042 consistently results in local tumor regressions in about half of treated patients and one-third of patients also in regressions in noninjected distant lesions, likely reflecting the systemic immune activation after intralesional therapy. Treatment was well tolerated with few adverse events including injection site reactions, chills, lymphopenia, and fever. Immune monitoring in the peripheral blood demonstrated systemic immune activation and the induction of antibodies against tumor antigens in some patients without clear association with clinical responses. CLs, in particular B-cell lymphomas with high objective response rates, seem to be excellent targets for this type of immunotherapy.
Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma
Authors: J.B. Bachet, R. Maréchal, P. Demetter, F. Bonnetain, A. Couvelard, M. Svrcek, A. Bardier-Dupas, P. Hammel, A. Sauvanet, C. Louvet, F. Paye, P. Rougier, C. Penna, J.C. Vaillant, T. André, J. Closset, I. Salmon, J.F. Emile, J.L. Van Laethem
Journal: Annals of Oncology (2012)