tbuckley/cabot-search huggingface dataset:
Molecular evolution of the psi eta-globin gene locus: gibbon phylogeny and the hominoid slowdown.
Authors: W J Bailey, D H Fitch, D A Tagle, J Czelusniak, J L Slightom, M Goodman
Journal: Molecular Biology and Evolution (1991)

An 8.4-kb genomic region spanning both the psi eta-globin gene locus and flanking DNA was sequenced from the common gibbon (Hylobates lar). In addition, sequencing of the entire orthologous region from galago (Galago crassicaudatus) was completed. The gibbon and galago sequences, along with published orthologous sequences from 10 other species, were aligned. These noncoding nucleotide sequences represented four human alleles, four apes (chimpanzee, gorilla, organgutan, and gibbon), an Old World monkey (rhesus monkey), two New World monkeys (spider and owl monkeys), tarsier, two strepsirhines (galago and lemur), and goat. Divergence and maximum parsimony analyses of the psi eta genomic region first groups humans and chimpanzees and then, at progressively more ancient branch points, successively joins gorillas, orangutans, gibbons, Old World monkeys, New World monkeys, tarsiers, and strepsirhines (the lemuriform-lorisiform branch of primates). This cladistic pattern supports the taxonomic grouping of all extant hominoids into family Hominidae, the division of Hominidae into subfamilies Hylobatinae (gibbons) and Homininae, the division of Homininae into tribes Pongini (orangutans) and Hominini, and the division of Hominini into subtribes Gorillina (gorillas) and Hominina (chimpanzees and humans). The additional gibbon and galago sequence data provide further support for the occurrence of a graded evolutionary-rate slowdown in the descent of simian primates, with the slowing rate being more pronounced in the great-ape and human lineages than in the gibbon or monkey lineages. A comparison of global versus local molecular clocks reveals that local clock predictions, when focused on a specific number of species within a narrow time frame, provide a more accurate estimate of divergence dates than do those of global clocks.
Phylogenetic Evidence for Excision of Stowaway Miniature Inverted-Repeat Transposable Elements in Triticeae (Poaceae)
Authors: Gitte Petersen, Ole Seberg
Journal: Molecular Biology and Evolution (2000)

The mode of transposition of miniature inverted-repeat transposable elements (MITEs) is unknown, but it has been suggested that they are duplicated rather than excised at transposition. However, the present investigation demonstrates that a particular family of MITEs, Stowaway:, is excised. Mapped onto a gene tree based on partial sequences of disrupted meiotic cDNA1 (DMC1) from 30 species of the Triticeae grasses, it is evident that at least two excisions have occurred, leaving short footprints. These footprints may subsequently be reduced in length or deleted. Excision of Stowaway: elements lends strong support to the suggestion that MITEs are DNA transposons and should be classified as class II elements. The evolution of Stowaway: elements can also be traced by scrutiny of the gene tree. It appears that base substitutions are as frequent in the conserved terminal inverted repeats (TIRs) as in the core of the element. Neither substitutions nor deletions lead to compensatory changes; hence, the highly stable secondary structure of the elements may gradually be reduced.
Immunologic characterization of the membrane-bound collagen in normal human fibroblasts: identification of a distinct membrane collagen.
Authors: J R Lichtenstein, E A Bauer, R Hoyt, H J Wedner
Journal: The Journal of Experimental Medicine (1976)

Collagen, the major extracellular matrix protein, is also a membrane protein. Two types of collagen are detected on the normal human fibroblast membrane in culture, type I collagen and a new immunologically and chemically distinct collagen, type M (membrane) collagen. Antibodies to type M collagen elicited complement-mediated cytotoxicity, which could be blocked by pretreatment of the cells with bacterial collagenase or the antibody with type M collagen. Pretreatment of the cells with other proteolytic enzymes or the antibody with type I collagen or type III collagen had no effect on this complement-mediated cytotoxicity. Although type I collagen is the major collagen synthesized by normal human fibroblasts type M collagen may be the major cell membrane collagen and may be a major cell membrane component.
Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes
Authors: Nishant M. Bhensdadia, Kelly J. Hunt, Maria F. Lopes-Virella, J. Michael Tucker, Mohammad R. Mataria, Joseph L. Alge, Benjamin A. Neely, Michael G. Janech, John M. Arthur
Journal: Kidney International (2013)
Sputum periostin in patients with different severe asthma phenotypes
Authors: I. Bobolea, P. Barranco, V. Del Pozo, D. Romero, V. Sanz, V. López‐Carrasco, J. Canabal, C. Villasante, S. Quirce
Journal: Allergy (2015)

Identifying inflammatory phenotypes is relevant in severe uncontrolled asthma. The aim of this study was to identify the different clinical, inflammatory, functional, and molecular phenotypes in patients with severe asthma and to investigate the potential role of sputum periostin as a biomarker of severe asthma phenotypes.Sputum induction was performed in 62 patients diagnosed with severe asthma. Skin prick testing, lung function tests, exhaled nitric oxide, hematimetry, and total serum IgE were performed. Periostin was measured in sputum supernatants.Patients with asthma were phenotyped and 80% had late-onset asthma, 50% had fixed airflow obstruction, and 66% showed a Th2-high phenotype. With respect to inflammatory phenotypes, 71% were eosinophilic and 25% mixed granulocytic. Periostin levels were higher in patients with fixed as compared to variable airflow limitation (69.76 vs 43.84 pg/ml, P < 0.05) and in patients with eosinophilic as compared to mixed granulocytic phenotype (61.58 vs 37.31 pg/ml, P < 0.05). There was an inverse correlation between postbronchodilator FEV1 /FVC and periostin levels (-0.276, P < 0.05).This study demonstrates the utility of periostin in phenotyping severe asthma. Periostin levels in sputum are associated with persistent airflow limitation in asthma patients with airway eosinophilia despite treatment with high-dose inhaled corticosteroids.
Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA)
Authors: Jens Klotsche, Martina Niewerth, Johannes-Peter Haas, Hans-Iko Huppertz, Angela Zink, Gerd Horneff, Kirsten Minden
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Abstract</h3> Chimeric antigen receptor (CAR) T cell therapy is an effective treatment for B cell malignancies, with emerging potential for the treatment of other hematologic cancers and solid tumors. The strength of the promoter within the CAR cassette will alter CAR-polypeptide levels on the cell surface of the T cell – impacting on the kinetics of activation, survival and memory cell formation in T cells. In addition to the CAR, promoters can be used to drive other genes of interest to enhance CAR T cell function. Expressing multiple genes from a single RNA transcript can be effectively achieved by linking the genes via a ribosomal skip site. However, promoters may differ in their ability to transcribe longer RNAs, or could interfere with lentiviral production, or transduction frequencies. In this study we compared the ability of the strong well-characterized promoters CMV, EF-1, hPGK and RPBSA to drive functional expression of a single RNA encoding three products: GFP, CAR, plus an additional cell-survival gene, Mcl-1. Although the four promoters produced similarly high lentiviral titres, EF-1 gave the best transduction efficacy of primary T cells. Major differences were found in the ability of the promoters to drive expression of long RNA encoding GFP, CAR and Mcl-1, highlighting promoter choice as an important consideration for gene therapy applications requiring the expression of long and complex mRNA.
Physical Health Monitoring of Patients With Schizophrenia
Authors: Stephen R. Marder, Susan M. Essock, Alexander L. Miller, Robert W. Buchanan, Daniel E. Casey, John M. Davis, John M. Kane, Jeffrey A. Lieberman, Nina R. Schooler, Nancy Covell, Scott Stroup, Ellen M. Weissman, Donna A. Wirshing, Catherine S. Hall, Leonard Pogach, Xavier Pi-Sunyer, J. Thomas Bigger, Alan Friedman, David Kleinberg, Steven J. Yevich, Bonnie Davis, Steven Shon
Journal: American Journal of Psychiatry (2004)

Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings.A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached.Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations.The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.
Effects of calcium on vasopressin-mediated cyclic adenosine monophosphate formation in cultured rat inner medullary collecting tubule cells. Evidence for the role of intracellular calcium.
Authors: I Teitelbaum, T Berl
Journal: Journal of Clinical Investigation (1986)

We explored the effects of alterations in extracellular and intracellular calcium concentration on arginine vasopressin (AVP)-stimulated cAMP formation in cultured rat inner medullary collecting tubule cells. cAMP formation remains constant at extracellular calcium concentrations between 0.5 and 4.0 mM, which did not change intracellular calcium. Maneuvers that alter intracellular calcium concentration are associated with marked changes in cAMP generation. EGTA decreases intracellular calcium and enhances AVP-stimulated cAMP formation, while increasing cellular calcium with 2 microM A23187 decreases AVP-stimulated cAMP formation in the presence, but not in the absence, of extracellular calcium. The changes in cAMP formation observed when intracellular calcium is altered are associated with reciprocal changes in prostaglandin E2 (PGE2) synthesis. Despite greater than 95% inhibition of PGE2 synthesis with 5 microM meclofenamic acid, the changes in cAMP formation accompanying alterations in intracellular calcium concentration are still evident. These studies suggest that intracellular calcium critically influences AVP-stimulated cAMP formation. It does so by a mechanism independent of PG that is probably mediated by a direct effect of the cation on the adenylate cyclase complex.
Dihydropyridine agonist Bay K 8644 inhibits platelet activation by competitive antagonism of thromboxane A2-prostaglandin H2 receptor.
Authors: G J Johnson, P C Dunlop, L A Leis, A H From
Journal: Circulation Research (1988)

The dihydropyridine calcium channel antagonists, such as nifedipine, inhibit platelet aggregation in vitro and ex vivo, but the mechanism by which this occurs is uncertain. Bay K 8644 (BAY) is a substituted dihydropyridine that has effects on voltage-dependent calcium channels in cardiac and smooth muscle that are opposite the effects of nifedipine. To evaluate the mechanism responsible for dihydropyridine-induced inhibition of platelet function, we studied the in vitro effects of BAY on human platelet aggregation and secretion plus several related biochemical parameters, including cytoplasmic ionized calcium ([Ca2+]i). BAY exerted concentration-dependent effects on platelet aggregation and secretion of [14C]serotonin. BAY (1-10 microns) inhibited the second wave of platelet aggregation and secretion stimulated by adenosine diphosphate or epinephrine and blocked shape change, aggregation, and secretion induced by the thromboxane A2 (TXA2) mimic, U46619. BAY also inhibited U46619-induced phosphorylation of the approximately 40,000-dalton cytoplasmic protein substrate of protein kinase C (40K protein), formation of TXA2, and rise in [Ca2+]i, all biochemical consequences of platelet activation. The (+)-(R) enantiomer of BAY [BAY(+)] was predominantly responsible for the inhibitory effects of racemic BAY. Nifedipine had the same inhibitory effects on platelet function and biochemistry, except it was approximately 10 times less potent than BAY. Since these results suggested inhibition of the TXA2-prostaglandin H2 (PGH2) receptor, we measured binding of [3H]U46619 to intact platelets. BAY, BAY(+), and nifedipine all functioned as competitive antagonists of [3H]U46619 binding (BAY Ki = 1.47 microM). They did not inhibit binding of [3H]yohimbine to platelet alpha 2-adrenergic receptors. At 1-10 nM BAY, BAY(+) and the (-)-(S) enantiomer of BAY [BAY(-)] all resulted in slight stimulation of platelet function and biochemical events. No significant increase in [3H]U46619 binding was demonstrable, however. Therefore, dihydropyridines that function as either calcium channel agonists or antagonists in cardiac or smooth muscle exert concentration-dependent effects on platelet function. In nanomolar concentrations, they augment, and in micromolar concentrations, they inhibit platelet activation induced by TXA2 or U46619. These data indicate that dihydropyridines do not inhibit TXA2-induced platelet activation by an effect on voltage-dependent calcium channels; they define the mechanism of inhibition as competitive antagonism of the TXA2-PGH2 receptor. The mechanism responsible for augmentation of platelet activation is uncertain.(ABSTRACT TRUNCATED AT 400 WORDS)
Drugging the Cancer Stem Cell Compartment: Lessons Learned from the Hedgehog and Wnt Signal Transduction Pathways
Authors: Michael E. Dodge, Lawrence Lum
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Cell-cell communication mediated by the secreted Hedgehog (Hh) and Wnt signaling molecules is essential to the coordination of cell fate decision making throughout the metazoan lifespan. From decades of genetically based interrogation, core components constituting the Hh and Wnt signal transduction pathways have been assembled, and a deep appreciation of how these signals elaborate distinct bodily tissues during development has been established. On the other hand, our incapacity to leverage similar genetic approaches to study adult organ systems has limited our understanding of how these molecules promote tissue renewal and regeneration through stem cell regulation. We discuss recent progress in the use of chemically based approaches to achieve control of these pathway activities in a broad range of biological studies and therapeutic contexts. In particular, we discuss the unique experimental opportunities that chemical modulators of these pathways afford in exploring the cancer stem cell hypothesis.
Diagnostic Inaccuracy of Smartphone Applications for Melanoma Detection
Authors: Joel A. Wolf, Jacqueline F. Moreau, Oleg Akilov, Timothy Patton, Joseph C. English, Jonhan Ho, Laura K. Ferris
Journal: JAMA Dermatology (2013)

To measure the performance of smartphone applications that evaluate photographs of skin lesions and provide the user with feedback about the likelihood of malignancy.Case-control diagnostic accuracy study.Academic dermatology department. PARTICIPANTS AND MATERIALS: Digital clinical images of pigmented cutaneous lesions (60 melanoma and 128 benign control lesions) with a histologic diagnosis rendered by a board-certified dermatopathologist, obtained before biopsy from patients undergoing lesion removal as a part of routine care.Sensitivity, specificity, and positive and negative predictive values of 4 smartphone applications designed to aid nonclinician users in determining whether their skin lesion is benign or malignant.Sensitivity of the 4 tested applications ranged from 6.8% to 98.1%; specificity, 30.4% to 93.7%; positive predictive value, 33.3% to 42.1%; and negative predictive value, 65.4% to 97.0%. The highest sensitivity for melanoma diagnosis was observed for an application that sends the image directly to a board-certified dermatologist for analysis; the lowest, for applications that use automated algorithms to analyze images.The performance of smartphone applications in assessing melanoma risk is highly variable, and 3 of 4 smartphone applications incorrectly classified 30% or more of melanomas as unconcerning. Reliance on these applications, which are not subject to regulatory oversight, in lieu of medical consultation can delay the diagnosis of melanoma and harm users.
Design and synthesis of sialyl Lewis<sup>x</sup> mimics as E‐ and P‐selectin inhibitors
Authors: Neelu Kaila, Bert E. Thomas IV
Journal: Medicinal Research Reviews (2002)

Abstract The selectins are a family of cell‐adhesion proteins that mediate the rolling of leukocytes on activated endothelial cells through the recognition of the carbohydrate epitope sialyl Lewis x (sLe x ). Control of the leukocyte‐endothelial cell adhesion process may prove useful in cases where excess recruitment of leukocytes can contribute to acute diseases such as stroke and reperfusion injury and chronic diseases such as psoriasis and rheumatoid arthritis. The development of molecules that block the interactions between sLe x and the selectins has become an active area of research. In this review, we will highlight the various approaches taken toward the development of sLe x mimetics as antagonists of E‐ and P‐selectin, including the use of structural information about the selectins and their interactions with sLe x that have been revealed through the use of NMR, protein crystallography and molecular modeling. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 6, 566–601, 2002; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10018
Physiological Roles of the Permeability Transition Pore
Authors: Catherine Brenner, Maryline Moulin
Journal: Circulation Research (2012)

Mitochondria are implicated in many important cellular functions covering the whole life cycle from mitochondrial biogenesis to cell death. Mitochondrial homeostasis is tightly regulated, and mitochondrial dysfunction is frequently associated with severe human pathologies (eg, cardiovascular diseases, cancer, and neurodegeneration). The permeability transition pore (PTP) is an unselective voltage-dependent mitochondrial channel. Despite the extensive use of electrophysiology, biochemistry, pharmacology, and genetic invalidation in mice, the molecular identity of PTP is still unknown. Nevertheless, PTP is central to mitochondrial vital functions and can play a lethal role in many pathophysiological conditions. This review recapitulates the current knowledge of the various modes of conductance of the PTP channel and discusses their implication in the physiological roles of PTP and their regulation. Based on its involvement in normal physiology and human pathology, a better understanding of this channel and its roles remains a major goal for basic scientists and clinicians.
The US7 score is sensitive to change in a large cohort of patients with rheumatoid arthritis over 12 months of therapy
Authors: Tina M Backhaus, Sarah Ohrndorf, Herbert Kellner, Johannes Strunk, Wolfgang Hartung, Horst Sattler, Christof Iking-Konert, Gerd R Burmester, Wolfgang A Schmidt, Marina Backhaus
Journal: Annals of the Rheumatic Diseases (2012)

Purpose To determine the sensitivity to change of the US7 score among RA patients under various therapies and to analyze the effect of each therapeutic option over 1 year. To estimate predictors for development of destructive bone changes. Methods Musculoskeletal ultrasound (US7 score), DAS28, CRP and ESR were performed in 432 RA patients at baseline and after 3, 6 and 12 months. The cohort was divided into four sub-groups: first-line DMARDs (Group 1; 27.3%), therapy switch: DMARDs to second DMARDs (Group 2; 25.0%), first-line biologic after DMARDs therapy (Group 3; 35.4%) and therapy change from biologic to second biologic (Group 4; 12.3%). Results The US7 synovitis and tenosynovitis sum scores in grey-scale (GSUS) and power Doppler ultrasound (PDUS) as well as ESR, CRP decreased significantly (p&lt;0.05) after 12 months in group 1 to 3. Group 1+2 also illustrated a significant change of DAS28 after 1 year (p&lt;0.001). Only in Group 4, the US7 erosion sum score decreased significantly from 4.3 to 3.6 (p=0.008) after 1 year. Predictors capable of forecasting US erosions after one year were: higher score of US7 synovitis (p&lt;0.001), of US7 erosions in GSUS (p&lt;0.001), as well as of DAS28 (p&lt;0.001) at baseline. Conclusions The comparable developments of the US7 score with clinical and laboratory data illustrates its potential to reflect therapeutic response. Therefore, the novel US7 score is sensitive to change. Patients who switched from one biologic to another exhibited a significant decline in erosions after 12 months, while the erosions scores in the other groups were stable.