tbuckley/cabot-search huggingface dataset:
Proliferation of Endogenous Retroviruses in the Early Stages of a Host Germ Line Invasion
Authors: Yasuko Ishida, Kai Zhao, Alex D. Greenwood, Alfred L. Roca
Journal: Molecular Biology and Evolution (2014)

Endogenous retroviruses (ERVs) comprise 8% of the human genome and are common in all vertebrate genomes. The only retrovirus known to be currently transitioning from exogenous to endogenous form is the koala retrovirus (KoRV), making koalas (Phascolarctos cinereus) ideal for examining the early stages of retroviral endogenization. To distinguish endogenous from exogenous KoRV proviruses, we isolated koala genomic regions flanking KoRV integration sites. In three wild southern Australian koalas, there were fewer KoRV loci than in three captive Queensland koalas, consistent with reports that southern Australian koalas carry fewer KoRVs. Of 39 distinct KoRV proviral loci examined in a sire-dam-progeny triad, all proved to be vertically transmitted and endogenous; none was exogenous. Of the 39 endogenous KoRVs (enKoRVs), only one was present in the genomes of both the sire and the dam, suggesting that, at this early stage in the retroviral invasion of a host germ line, very large numbers of ERVs have proliferated at very low frequencies in the koala population. Sequence divergence between the 5'- and 3'-long terminal repeats (LTRs) of a provirus can be used as a molecular clock. Within each of ten enKoRVs, the 5'-LTR sequence was identical to the 3'-LTR sequence, suggesting a maximum age for enKoRV invasion of the koala germ line of approximately 22,200-49,900 years ago, although a much younger age is possible. Across the ten proviruses, seven LTR haplotypes were detected, indicating that at least seven different retroviral sequences had entered the koala germ line.
The effect of variations of pulsed Doppler sampling site on calculation of cardiac output: an experimental study in open-chest dogs.
Authors: D C Fisher, D J Sahn, M J Friedman, D Larson, L M Valdes-Cruz, S Horowitz, S J Goldberg, H D Allen
Journal: Circulation (1983)

We measured aortic flow by two-dimensional Doppler echocardiography in an open-chest dog model to examine how variations in Doppler sample volume length and position influence aortic hemodynamic flow calculations. Fourteen dogs underwent right-heart bypass, in which venous return from the venae cavae drained by gravity to a reservoir. A variable-speed roller pump returned the blood to the pulmonary artery, fixing left-sided cardiac input and output. Echo Doppler measurements were performed using a 3.5 MHz transducer placed directly on the aortic arch to determine internal aortic cross-sectional area. The transducer was then directed to image the aortic arch for Doppler velocity measurements and the various sampling sites were investigated. Doppler cardiac output could then be determined for each of the various sample volumes over a range of known roller pump settings. Doppler velocity was analyzed using fast Fourier transform spectral analysis. Mean velocity over the cardiac cycle was obtained by planimetry of the area under the Doppler velocity curve with a minicomputer. Doppler-derived determinations of cardiac output achieved a correlation of r = 0.98-0.99 to values obtained by the roller pump over a range of cardiac outputs from 0.75-5 l/min. The standard error of the estimate was 0.21/min. In this laminar flow model, there was no difference between the predictive accuracy of any of the sampling sites over the range of roller pump flows. Our study shows that Doppler velocity measurements can be used to quantify aortic flow over a clinically useful range and that variations of sample length and position did not produce significant differences in calculated flows.
An Oncolytic Adenovirus Vector Combining Enhanced Cell-to-Cell Spreading, Mediated by the ADP Cytolytic Protein, with Selective Replication in Cancer Cells with Deregulated <b> <i>Wnt</i> </b> Signaling
Authors: Karoly Toth, Hakim Djeha, Baoling Ying, Ann E. Tollefson, Mohan Kuppuswamy, Konstantin Doronin, Peter Krajcsi, Kai Lipinski, Christopher J. Wrighton, William S. M. Wold
Journal: Cancer Research (2004)

Abstract We have constructed a novel oncolytic adenovirus (Ad) vector named VRX-009 that combines enhanced cell spread with tumor-specific replication. Enhanced spread, which could significantly increase antitumor efficacy, is mediated by overexpression of the Ad cytolytic protein named ADP (also known as E3–11.6K). Replication of VRX-009 is restricted to cells with a deregulated wnt signal transduction pathway by replacement of the wild-type Ad E4 promoter with a synthetic promoter consisting of five consensus binding sites for the T-cell factor transcription factor. Tumor-selective replication is indicated by several lines of evidence. VRX-009 expresses E4ORF3, a representative Ad E4 protein, only in colon cancer cell lines. Furthermore, VRX-009 replicates preferentially in colon cancer cell lines as evidenced by virus productivity 2 orders of magnitude higher in SW480 colon cancer cells than in A549 lung cancer cells. Replication in primary human bronchial epithelial cells and human umbilical vein endothelial cells was also significantly lower than in SW480 cells. When tested in human tumor xenografts in nude mice, VRX-009 effectively suppressed the growth of SW480 colon tumors but not of A549 lung tumors. VRX-009 may provide greater level of antitumor efficacy than standard oncolytic Ad vectors in tumors in which a defect in wnt signaling increases the level of nuclear β-catenin.
Variability of Spontaneous Ca <sup>2+</sup> Release Between Different Rat Ventricular Myocytes Is Correlated With Na <sup>+</sup> -Ca <sup>2+</sup> Exchange and [Na <sup>+</sup> ] <sub>i</sub>
Authors: M.E. Díaz, S.J. Cook, J.P. Chamunorwa, A.W. Trafford, M.K. Lancaster, S.C. O’Neill, D.A. Eisner
Journal: Circulation Research (1996)

Abstract We have studied the factors responsible for the variation of the frequency of “waves” caused by spontaneous Ca 2+ release in rat ventricular myocytes. The experiments were performed in isolated myocytes using the fluorescent indicators Indo-1 (to measure [Ca 2+ ] i ) and SBFI (to measure [Na + ] i ). After electrical stimulation (either with action potentials or voltage-clamp pulses), some cells showed spontaneous Ca 2+ release. The frequency of this release, where present, was variable. The Ca 2+ content of the sarcoplasmic reticulum (SR) was measured by applying caffeine (10 mmol/L). The resulting increase of [Ca 2+ ] i activated the electrogenic Na + -Ca 2+ exchange, and the integral of this current was used to estimate the Ca 2+ content of the SR. The SR Ca 2+ content was significantly higher in cells that oscillated at high rates (&gt;10·min −1 ) than in those that were quiescent. The rate of removal of Ca 2+ from the cytoplasm by non-SR mechanisms was measured by adding caffeine (10 mmol/L) and measuring the rate constant of decay of the resulting increase of [Ca 2+ ] i . Cells that had a high rate constant of decay of [Ca 2+ ] i had a low frequency of oscillations. Measurements of [Na + ] i showed a positive correlation between the frequency of spontaneous SR Ca 2+ release and [Na + ] i . After cessation of stimulation, there was a gradual decrease of [Na + ] i , which was correlated with a parallel decrease of the frequency of oscillation rate. We conclude that the variability of frequency of spontaneous SR Ca 2+ release is due to variations of the rate of Ca 2+ removal from the cell, which are probably due to Na + -Ca 2+ exchange. The variability of Na + -Ca 2+ exchange rate, in turn, is likely to result from variations of [Na + ] i .
Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway by Inositol Pentakisphosphate Results in Antiangiogenic and Antitumor Effects
Authors: Tania Maffucci, Enza Piccolo, Albana Cumashi, Manuela Iezzi, Andrew M. Riley, Adolfo Saiardi, H. Yasmin Godage, Cosmo Rossi, Massimo Broggini, Stefano Iacobelli, Barry V.L. Potter, Paolo Innocenti, Marco Falasca
Journal: Cancer Research (2005)

Abstract The purpose of this study was to investigate the antiangiogenic and in vivo properties of the recently identified phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor Inositol(1,3,4,5,6) pentakisphosphate [Ins(1,3,4,5,6)P5]. Because activation of the PI3K/Akt pathway is a crucial step in some of the events leading to angiogenesis, the effect of Ins(1,3,4,5,6)P5 on basic fibroblast growth factor (FGF-2)–induced Akt phosphorylation, cell survival, motility, and tubulogenesis in vitro was tested in human umbilical vein endothelial cells (HUVEC). The effect of Ins(1,3,4,5,6)P5 on FGF-2-induced angiogenesis in vivo was evaluated using s.c. implanted Matrigel in mice. In addition, the effect of Ins(1,3,4,5,6)P5 on growth of ovarian carcinoma SKOV-3 xenograft was tested. Here, we show that FGF-2 induces Akt phosphorylation in HUVEC resulting in antiapoptotic effect in serum-deprived cells and increase in cellular motility. Ins(1,3,4,5,6)P5 blocks FGF-2-mediated Akt phosphorylation and inhibits both survival and migration in HUVEC. Moreover, Ins(1,3,4,5,6)P5 inhibits the FGF-2-mediated capillary tube formation of HUVEC plated on Matrigel and the FGF-2-induced angiogenic reaction in BALB/c mice. Finally, Ins(1,3,4,5,6)P5 blocks the s.c. growth of SKOV-3 xenografted in nude mice to the same extent than cisplatin and it completely inhibits Akt phosphorylation in vivo. These data definitively identify the Akt inhibitor Ins(1,3,4,5,6)P5 as a specific antiangiogenic and antitumor factor. Inappropriate activation of the PI3K/Akt pathway has been linked to the development of several diseases, including cancer, making this pathway an attractive target for therapeutic strategies. In this respect, Ins(1,3,4,5,6)P5, a water-soluble, natural compound with specific proapoptotic and antiangiogenic properties, might result in successful anticancer therapeutic strategies.
Endothelin modulates the pressor actions of acute systemic nitric oxide blockade.
Authors: C Qiu, K Engels, C Baylis
Journal: Journal of the American Society of Nephrology (1995)

Acute nitric oxide blockade not only potentiates the vasoconstrictor actions of endothelin but also enhances the synthesis and release of endothelin. To investigate whether the vasoconstrictor actions of acute nitric oxide blockade are modulated by endothelin, studies were conducted in the conscious, chronically catheterized rat. Renal function was measured before and during acute nitric oxide blockade with nitro-L-arginine methylester (L-NAME), L-NAME + endothelin blockade with the endothelin-converting enzyme inhibitor phosphoramidon, or L-NAME + the nonpeptide ETA and ETB receptor antagonist Bosentan. The increases in blood pressure and RVR seen with acute nitric oxide blockade were attenuated by either method of concomitant endothelin blockade. The falls in RPF and GFR were not blunted because endothelin blockade produced parallel reductions of both pressor and renal vasoconstrictor responses to acute nitric oxide blockade. Endothelin blockade alone with either endothelin-converting enzyme inhibitor or the nonpeptide ETA and ETB receptor antagonist had little effect on blood pressure, RPF, or RVR, but increases in urinary sodium excretion and a small decline in GFR were observed with Bosentan. These observations indicate that endogenous endothelin exerts a tonic antinatriuretic action in the normal conscious rat and partially mediates the pressor actions of acute nitric oxide blockade.
The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study
Authors: Wouter Hoefsloot, Jakko van Ingen, Claire Andrejak, Kristian Ängeby, Rosine Bauriaud, Pascale Bemer, Natalie Beylis, Martin J. Boeree, Juana Cacho, Violet Chihota, Erica Chimara, Gavin Churchyard, Raquel Cias, Rosa Daza, Charles L. Daley, P.N. Richard Dekhuijzen, Diego Domingo, Francis Drobniewski, Jaime Esteban, Maryse Fauville-Dufaux, Dorte Bek Folkvardsen, Noel Gibbons, Enrique Gómez-Mampaso, Rosa Gonzalez, Harald Hoffmann, Po-Ren Hsueh, Alexander Indra, Tomasz Jagielski, Frances Jamieson, Mateja Jankovic, Eefje Jong, Joseph Keane, Wo-Jung Koh, Berit Lange, Sylvia Leao, Rita Macedo, Turid Mannsåker, Theodore K. Marras, Jeannette Maugein, Heather J. Milburn, Tamas Mlinkó, Nora Morcillo, Kozo Morimoto, Dimitrios Papaventsis, Elia Palenque, Mar Paez-Peña, Claudio Piersimoni, Monika Polanová, Nalin Rastogi, Elvira Richter, Maria Jesus Ruiz-Serrano, Anabela Silva, M. Pedro da Silva, Hulya Simsek, Dick van Soolingen, Nora Szabó, Rachel Thomson, Teresa Tórtola Fernandez, Enrico Tortoli, Sarah E. Totten, Greg Tyrrell, Tuula Vasankari, Miguel Villar, Renata Walkiewicz, Kevin L. Winthrop, Dirk Wagner
Journal: European Respiratory Journal (2013)

A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework ( www.ntm-net.org ), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi . Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location.
Tranexamic acid for traumatic brain injury
Authors: Y. B. W. E. M. Roos
Journal: BMJ (2011)

New data justify a re-evaluation in other types of intracranial haemorrhage

In July 2010 the results of the CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2) study were published.1 CRASH-2 was a large placebo controlled trial that investigated the effects of early administration of a short course of the antifibrinolytic agent tranexamic acid (TXA) in 20 211 adult patients with trauma. TXA significantly reduced all cause mortality (relative risk 0.91, 95% CI 0.85 to 0.97) and the risk of death as a result of bleeding (0.85, 0.76 to 0.96). The authors concluded that TXA safely reduced the risk of death and suggested that TXA should be used in trauma patients with bleeding. However, it was unclear whether TXA could also benefit patients with traumatic brain injury because in the past TXA had been associated with cerebral ischaemia and poor outcome in patients with aneurysmal subarachnoid haemorrhage.2 

In the linked study (doi:10.1136/bmj.d3795),3 the CRASH-2 collaborators present the results …
Evolution and Biochemistry of Family 4 Glycosidases: Implications for Assigning Enzyme Function in Sequence Annotations
Authors: Barry G. Hall, Andreas Pikis, John Thompson
Journal: Molecular Biology and Evolution (2009)

Glycosyl hydrolase Family 4 (GH4) is exceptional among the 114 families in this enzyme superfamily.Members of GH4 exhibit unusual cofactor requirements for activity, and an essential cysteine residue is present at the active site.Of greatest significance is the fact that members of GH4 employ a unique catalytic mechanism for cleavage of the glycosidic bond.By phylogenetic analysis, and from available substrate specificities, we have assigned a majority of the enzymes of GH4 to five subgroups.Our classification revealed an unexpected relationship between substrate specificity and the presence, in each subgroup, of a motif of four amino acids that includes the active-site Cys residue: a-glucosidase, CHE(I/V); a-galactosidase, CHSV; a-glucuronidase, CHGx; 6-phospho-a-glucosidase, CDMP; and 6-phosphob-glucosidase, CN(V/I)P.The question arises: Does the presence of a particular motif sufficiently predict the catalytic function of an unassigned GH4 protein?To test this hypothesis, we have purified and characterized the a-glucoside -specific GH4 enzyme (PalH) from the phytopathogen, Erwinia rhapontici.The CHEI motif in this protein has been changed by site-directed mutagenesis, and the effects upon substrate specificity have been determined.The change to CHSV caused the loss of all a-glucosidase activity, but the mutant protein exhibited none of the anticipated a-galactosidase activity.The Cys-containing motif may be suggestive of enzyme specificity, but phylogenetic placement is required for confidence in that specificity.The Acholeplasma laidlawii GH4 protein is phylogenetically a phosphob-glucosidase but has a unique SSSP motif.Lacking the initial Cys in that motif it cannot hydrolyze glycosides by the normal GH4 mechanism because the Cys is required to position the metal ion for hydrolysis, nor can it use the more common single or double-displacement mechanism of Koshland.Several considerations suggest that the protein has acquired a new function as the consequence of positive selection.This study emphasizes the importance of automatic annotation systems that by integrating phylogenetic analysis, functional motifs, and bioinformatics data, may lead to innovative experiments that further our understanding of biological systems.
Safety and feasibility of dobutamine-atropine stress echocardiography for the diagnosis of coronary artery disease in diabetic patients unable to perform an exercise stress test.
Authors: A Elhendy, R T van Domburg, D Poldermans, J J Bax, P R Nierop, M L Geleijnse, J R Roelandt
Journal: Diabetes Care (1998)

OBJECTIVE: Dobutamine stress testing is increasingly used for the diagnosis and functional evaluation of coronary artery disease. However, little is known about the safety and feasibility of this stress modality in diabetic patients. RESEARCH DESIGN AND METHODS: We studied the impact of diabetes on hemodynamic profile and on the safety and feasibility of dobutamine (up to 40 microg x kg(-1) x min(-1)) and atropine (up to 1 mg) stress echocardiography for the diagnosis of coronary artery disease in 1,446 consecutive patients (aged 60+/-12 years, 962 men) with limited exercise capacity and suspected myocardial ischemia. Of these, 184 patients were known to have IDDM or NIDDM. The test was considered feasible when 85% of the maximal heart rate and/or an ischemic end point (new or worsened wall motion abnormalities, ST segment depression, or angina) was achieved. RESULTS: No myocardial infarction or death occurred during the test. There was no significant difference between diabetic and nondiabetic patients with regard to heart rate increase during dobutamine stress echocardiography (58+/-25 vs. 61+/-24 beats/min), peak rate pressure product (18,400+/-3,135 vs. 18,048+/-4454), or the prevalence of hypotension (systolic blood pressure drop of &amp;gt;40 mmHg) (7 vs. 5%), ventricular tachycardia (5.4 vs. 4.5%), and supraventricular tachycardia (3 vs. 4%) during the test. Dobutamine stress echocardiography was feasible in 92% of the diabetic patients and in 90% of the nondiabetic patients. Coronary angiography was performed in 55 diabetic and 240 nondiabetic patients. Sensitivity, specificity, and accuracy of dobutamine stress echocardiography for the diagnosis of coronary artery disease in diabetic patients were 81, 85, and 82%. Those in nondiabetic patients were 74, 87, and 77%, respectively (NS). CONCLUSIONS: Dobutamine stress echocardiography is a feasible method for the diagnosis of coronary artery disease in patients with limited exercise capacity with a comparable safety, feasibility, and accuracy in diabetic and nondiabetic patients.
How much is too much breast screening?
Authors: I. Torjesen
Journal: BMJ (2015)

Ingrid Torjesen describes how the government is pushing on with a giant trial of extended breast screening, despite serious concerns that women are not being fully informed of the risks

Since 2009 women in their late 40s and early 70s across England have been receiving letters inviting them to come for NHS breast screening and giving them an appointment time. The letter explains that screening for breast cancer is usually for women aged 50-70 years but that some women aged 47 to 49 and over 70 up to 73 are now also being invited, as part of a study.

Along with the letter comes the standard pink leaflet on breast screening produced for women aged 50-70, who have been offered regular breast scans under the national screening programme since 2004. Also included is a question and answer sheet explaining that the recipient lives in an area where the age range for breast screening is being widened. Randomly phasing in the extension by area will allow the net benefit of extending the age range to be “scientifically evaluated” by researchers at Oxford University, it explains. The letter does not explicitly ask for consent from the invited women to be entered into the study; instead consent is assumed when women turn up at the given appointment time.

The government decided to extend the age range for screening in 2007.1 The phased extension will offer mammography to 1.5 million women in the new age groups, whose breast cancer incidence and mortality will then be compared with another 1.5 million women not offered the screening.2 3

What the letter doesn’t explain, however, is that debate has been growing in recent years about whether the benefits of screening outweigh the harms, particularly to women under 50.

The government did not provide evidence in …
A translational rheostat for RFLAT-1 regulates RANTES expression in T lymphocytes
Authors: Tania Nikolcheva, Stephane Pyronnet, Szu-yi Chou, Nahum Sonenberg, An Song, Carol Clayberger, Alan M. Krensky
Journal: Journal of Clinical Investigation (2002)

Activation of T lymphocytes by specific antigen triggers a 3- to 7-day maturation process. Terminal differentiation begins late after T cell activation and involves expression of effector genes, including the chemokine RANTES and its major transcriptional regulator, RANTES factor of late-activated T lymphocytes-1 (RFLAT-1). In this article we demonstrate that RFLAT-1 expression is translationally regulated through its 5′-UTR and in a cell type–specific manner. Overexpression of the translation initiation factor eIF4E increases RFLAT-1 protein, while inhibition of Mnk1, which phosphorylates eIF4E, reduces RFLAT-1 production, indicating cap-dependent translational regulation. These events are regulated by ERK-1/2 and p38 MAP kinases and allow T cells to rapidly adjust RANTES expression in response to changes in the cellular environment, such as stress and/or growth factors. These findings provide a molecular mechanism for a rheostat effect of increasing or decreasing RANTES expression at sites of inflammation. Memory T cells, already poised to make RANTES, are finely regulated by translational control of the major transcription factor regulating RANTES expression. This is the first example of such a mechanism regulating a chemokine, but it seems likely that this will prove to be a general way for cells to rapidly respond to stress, cytokines, and other proinflammatory factors in their local environment.