tbuckley/cabot-search huggingface dataset:
Epidermal Growth Factor–Like Domain 7 Is a Novel Inhibitor of Neutrophil Adhesion to Coronary Artery Endothelial Cells Injured by Calcineurin Inhibition
Authors: Mitesh V. Badiwala, Daipayan Guha, Laura Tumiati, Jemy Joseph, Arash Ghashghai, Heather J. Ross, Diego H. Delgado, Vivek Rao
Journal: Circulation (2011)

Background— We investigated the effect of epidermal growth factor–like domain 7 (Egfl7) on nuclear factor-κB activation, intercellular adhesion molecule-1 expression, and neutrophil adhesion to human coronary artery endothelial cells after calcineurin-inhibition–induced injury. Methods and Results— Human coronary endothelial cells were incubated with cyclosporine (CyA) 10 μg/mL with or without Egfl7 (100 ng/mL) or the Notch receptor activator Jagged1 (200 ng/mL) for 6 to 48 hours. CyA upregulated nuclear factor-κB (p65) activity (128±2% of control, P &lt;0.001) in nuclear extracts, as determined with a DNA-binding activity ELISA. This activity was inhibited by Egfl7 (86±3% of control; P &lt;0.001 versus CyA alone). Jagged1 blocked Egfl7-induced nuclear factor-κB inhibition (105±4% of control; P &lt;0.05 versus CyA plus Egfl7). CyA upregulated cell-surface intercellular adhesion molecule-1 expression (215±13% of control; P &lt;0.001), as determined by flow cytometry. This expression was suppressed by Egfl7 (148±5%; P &lt;0.001 versus CyA alone). Jagged1 attenuated the intercellular adhesion molecule-1–suppressive effect of Egfl7 when administered with CyA (193±3% versus 148±5%; P &lt;0.01). CyA increased neutrophil adhesion to human coronary endothelial cells (control 20±5%, CyA 37±3%; P &lt;0.001 versus control) in a nonstatic neutrophil adhesion assay. This increase was attenuated by Egfl7 (22±6%; P &lt;0.001 versus CyA alone). Jagged 1 attenuated the effect of Egfl7 on neutrophil adhesion (31±3%; P &lt;0.001 versus Egfl7 plus CyA). Conclusions— Our study reveals that Egfl7 is a potent inhibitor of neutrophil adhesion to human coronary endothelial cells subsequent to calcineurin-inhibition–induced injury. Mechanistically, Egfl7 blocked nuclear factor-κB pathway activation and intercellular adhesion molecule-1 expression, which suggests that it may have significant antiinflammatory properties. Because Jagged1 blocked the effect of Egfl7, Notch receptor antagonism may contribute to the mechanism of action of Egfl7.
Ancient DNA Reveals Genetic Stability Despite Demographic Decline: 3,000 Years of Population History in the Endemic Hawaiian Petrel
Authors: Andreanna J. Welch, Anne E. Wiley, Helen F. James, Peggy H. Ostrom, Thomas W. Stafford, Robert C. Fleischer
Journal: Molecular Biology and Evolution (2012)

In the Hawaiian Islands, human colonization, which began approximately 1,200 to 800 years ago, marks the beginning of a period in which nearly 75% of the endemic avifauna became extinct and the population size and range of many additional species declined. It remains unclear why some species persisted whereas others did not. The endemic Hawaiian petrel (Pterodroma sandwichensis) has escaped extinction, but colonies on two islands have been extirpated and populations on remaining islands have contracted. We obtained mitochondrial DNA sequences from 100 subfossil bones, 28 museum specimens, and 289 modern samples to investigate patterns of gene flow and temporal changes in the genetic diversity of this endangered species over the last 3,000 years, as Polynesians and then Europeans colonized the Hawaiian Islands. Genetic differentiation was found to be high between both modern and ancient petrel populations. However, gene flow was substantial between the extirpated colonies on Oahu and Molokai and modern birds from the island of Lanai. No significant reductions in genetic diversity occurred over this period, despite fears in the mid-1900s that this species may have been extinct. Simulations show that even a decline to a stable effective population size of 100 individuals would result in the loss of only 5% of the expected heterozygosity. Simulations also show that high levels of genetic diversity may be retained due to the long generation time of this species. Such decoupling between population size and genetic diversity in long-lived species can have important conservation implications. It appears that a pattern of dispersal from declining colonies, in addition to long generation time, may have allowed the Hawaiian petrel to escape a severe genetic bottleneck, and the associated extinction vortex, and persist despite a large population decline after human colonization.
Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells
Authors: H.B.P.M. Dijkman, J.J. Weening, B. Smeets, K.C.N. Verrijp, T.H. van Kuppevelt, K.K.J.M. Assmann, E.J. Steenbergen, J.F.M. Wetzels
Journal: Kidney International (2006)
Cardiac regulation by phosphoinositide 3-kinases and PTEN
Authors: G. Y. Oudit, J. M. Penninger
Journal: Cardiovascular Research (2008)

The diverse effects mediated by PI3K/PTEN (phosphoinositide 3-kinase/phosphatase and tensin homologue deleted on chromosome 10) signalling in the heart clearly support an important biological and pathophysiological role for this signalling cascade. PI3Ks are a family of evolutionarily conserved lipid kinases that mediate many cellular responses to physiological and pathophysiological stimuli. Class I PI3K can be activated by either receptor tyrosine kinase/cytokine receptor activation (class IA) or G-protein-coupled receptors (class IB), leading to the generation of phosphatidyl inositol (3,4,5)P3 and recruitment and activation of Akt/protein kinase B, 3′-phosphoinositide-dependent kinase-1 (PDK1), or monomeric G-proteins, and phosphorylation of a wide range of downstream targets including glycogen synthase kinase 3β (GSK3β), mTOR (mammalian target of rapamycin), p70S6 kinase, endothelial nitric oxide synthase, and several anti-apoptotic effectors. Class IA (PI3Kα, β, and δ) and class IB (PI3Kγ) PI3Ks mediate distinct phenotypes in the heart under negative control by the 3′-lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3 to generate PtdIns(4,5)P2. PI3Kα, PI3Kγ, and PTEN are expressed in cardiomyocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells, where they modulate cell survival, hypertrophy, contractility, metabolism, and mechanotransduction. The PI3K/PTEN signalling pathways are involved in a wide variety of diseases including myocardial hypertrophy and contractility, heart failure, and preconditioning. In this review, we discuss the signalling pathways mediated by PI3K class I isoforms and PTEN and their roles in cardiac structure and function.
Palivizumab epitope–displaying virus-like particles protect rodents from RSV challenge
Authors: Jeanne H. Schickli, David C. Whitacre, Roderick S. Tang, Jasmine Kaur, Heather Lawlor, Cory J. Peters, Joyce E. Jones, Darrell L. Peterson, Michael P. McCarthy, Gary Van Nest, David R. Milich
Journal: Journal of Clinical Investigation (2015)

Respiratory syncytial virus (RSV) is the most common cause of serious viral bronchiolitis in infants, young children, and the elderly. Currently, there is not an FDA-approved vaccine available for RSV, though the mAb palivizumab is licensed to reduce the incidence of RSV disease in premature or at-risk infants. The palivizumab epitope is a well-characterized, approximately 24-aa helix-loop-helix structure on the RSV fusion (F) protein (F254–277). Here, we genetically inserted this epitope and multiple site variants of this epitope within a versatile woodchuck hepadnavirus core–based virus-like particle (WHcAg-VLP) to generate hybrid VLPs that each bears 240 copies of the RSV epitope in a highly immunogenic arrayed format. A challenge of such an epitope-focused approach is that to be effective, the conformational F254–277 epitope must elicit antibodies that recognize the intact virus. A number of hybrid VLPs containing RSV F254–277 were recognized by palivizumab in vitro and elicited high-titer and protective neutralizing antibody in rodents. Together, the results from this proof-of-principle study suggest that the WHcAg-VLP technology may be an applicable approach to eliciting a response to other structural epitopes.
From non-A, non-B hepatitis to hepatitis C virus cure
Authors: Jean-Michel Pawlotsky, Jordan J. Feld, Stefan Zeuzem, Jay H. Hoofnagle
Journal: Journal of Hepatology (2015)

The hepatitis C virus (HCV) was discovered in the late 1980s. Interferon (IFN)-α was proposed as an antiviral treatment for chronic hepatitis C at about the same time. Successive improvements in IFN-α-based therapy (dose finding, pegylation, addition of ribavirin) increased the rates of sustained virologic response, i.e. the rates of curing HCV infection. These rates were further improved by adding the first available direct-acting antiviral (DAA) drugs to the combination of pegylated IFN-α and ribavirin. An IFN-free era finally started in 2014, yielding rates of sustained virologic response over 90% in patients treated for 8 to 24 weeks with all-oral regimens. Major challenges however remain in implementation of these new treatment strategies, not only in low- to middle-income countries, but also in high-income countries where the price of these therapies is still prohibitive. Elimination of HCV infection through treatment in certain areas is possible but raises major public health issues.
Cloning of Porcine 25-Hydroxyvitamin D3 1α-Hydroxylase and Its Regulation by cAMP in LLC-PK1 Cells
Authors: TADASHI YOSHIDA, NORIKO YOSHIDA, AKIRA NAKAMURA, TOSHIAKI MONKAWA, MATSUHIKO HAYASHI, TAKAO SARUTA
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The 25-hydroxyvitamin D 3 1α-hydroxylase, also referred to as CYP27B1, is a mitochondrial cytochrome P450 enzyme that catalyzes the biosynthesis of 1α, 25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) from 25-hydroxyvitamin D 3 in renal proximal tubular cells. Recently, human, mouse, and rat CYP27B1 cDNA have been cloned, however the gene regulation has not been fully elucidated. In the present study, porcine CYP27B1 cDNA was cloned, and the effects of cAMP and vitamin D 3 on the regulation of CYP27B1 mRNA expression in LLC-PK 1 cells were examined. PCR cloning revealed that porcine CYP27B1 cDNA consisted of 2316 bp, encoding a protein of 504 amino acids. The deduced amino acid sequence showed over 80% identity to the human, mouse, and rat enzyme. LLC-PK 1 cells were incubated with humoral factors, and expression of CYP27B1 mRNA was measured by a quantitative reverse transcription-PCR. At the completion of 3-, 6-, 12-, and 24-h incubations, 500 μmol/L 8-bromo-cAMP had significantly increased CYP27B1 mRNA expression (260 to 340%). The adenylate cyclase activator forskolin at 50 μmol/L also had a stimulatory effect at 6 h (190%). Moreover, the protein kinase A inhibitor H-89 reduced the cAMP effect. On the other hand, 1α,25(OH) 2 D 3 had no effect on CYP27B1 mRNA expression at 10 and 100 nmol/L, whereas expression of 25-hydroxyvitamin D 3 24-hydroxylase (CYP24) mRNA was markedly increased by 1α,25(OH) 2 D 3 . These findings suggest that LLC-PK 1 cells express CYP27B1 mRNA, and that cAMP is an upregulating factor of the CYP27B1 gene in vitro.
Disease-Causing Dysfunctions of Barttin in Bartter Syndrome Type IV
Authors: Audrey G.H. Janssen, Ute Scholl, Constanze Domeyer, Doreen Nothmann, Ariane Leinenweber, Christoph Fahlke
Journal: Journal of the American Society of Nephrology (2008)

Bartter syndrome type IV is an inherited human condition characterized by severe renal salt wasting and sensorineural deafness. The causal gene, BSND, encodes barttin, an accessory subunit of chloride channels located in the kidney and inner ear. Barttin modulates the stability, cell surface localization, and function of ClC-K channels; distinct mutations cause phenotypes of varying severity. For definition of the molecular basis of this diversity, the functional consequences of six disease-causing mutations (R8L, R8W, G10S, Q32X, G47R, and E88X) on ClC-K channel properties were studied by heterologous expression in renal cell lines, electrophysiology, confocal imaging, and biochemical analysis. Three missense mutations (R8L, R8W, and G10S) eliminated the function of ClC-K/barttin channels but did not prevent the insertion of the channels into the surface membrane. Another mutant that produces a mild renal phenotype (G47R) was capable of performing all functions of wild-type barttin but bound to ClC-K channels less effectively. The nonsense mutation E88X affected epithelial sorting, leading to equal amounts of barttin inserting into the basolateral and apical membranes, contrasting with the preferential apical insertion of wild-type barttin. Last, the nonsense mutation Q32X allowed barttin to associate with ClC-K channels but prevented surface membrane insertion and channel activation. These results demonstrate that Bartter syndrome type IV can be caused by various derangements in the function of barttin, likely contributing to the diversity of observed phenotypes.
Methotrexate-induced Changes in the Levels of 1-β-d-Arabinofuranosylcytosine Triphosphate in L1210 Cells
Authors: DeWayne Roberts, Charles Peck, Susan Hilliard, William Wingo
Journal: Cancer Research (1979)

Treatment with methotrexate (MIX) plus 1-/?-D-arabinofuranosylcytosine (ara-C) on Days 1, 4, and 7 after Âi.p.inoculation of L1210 ascites cells was more effective than treatment with one drug on Days 1, 4, and 7 followed by the second drug on Days 2, 5, and 8. Simultaneous treatment with both drugs was associated with a retention of 1-/3-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) but no increase in the activity of deoxycytidine kinase in L1210 cells, whereas pretreatment with MIX 24 hr before the administration of ara-C was asso ciated with approximately 2-fold increases in the level of araCTP and of deoxycytidine kinase in L1210 cells. However, from 5 hr after treatment with ara-C, higher levels of ara-CTP were observed in L1210 cells treated simultaneously with both drugs than in cells from animals pretreated with MTX 24 hr before treatment with ara-C. The superiority of simultaneous treatment over sequential treatment and the synergism between MTX and ara-C, previ ously reported for this schedule of simultaneous treatment, are attributed in part to the MTX-induced retention of ara-CTP and the increased exposure of L1210 cells to ara-CTP that results from the slower clearance of ara-CTP.
Evidence against elevated sympathetic vasoconstrictor activity in borderline hypertension.
Authors: H P Schobel, K Heusser, R E Schmieder, R Veelken, T Fischer, F C Luft
Journal: Journal of the American Society of Nephrology (1998)

The relationship between sympathetic nerve activity and BP in the early stages of essential hypertension remains unclear. To investigate this relationship further, this study measured resting muscle sympathetic nerve activity (MSNA: representing peripheral vasoconstrictor activity), plasma catecholamines, BP, central venous pressure, and heart rate in 20 young (24 +/- 2 SD yr), lean (body mass index, 24.2 +/- 3.0 kg/m2), male subjects with borderline hypertension (BHT) and in 21 male normotensive (NT) control subjects matched for age and body mass index. A cold pressor test was also performed to evaluate sympathetic reflex responsiveness. Resting mean BP and heart rate were significantly higher in the BHT subjects compared with NT subjects (113 +/- 9 versus 89 +/- 9 mmHg; 74 +/- 8 versus 62 +/- 8 bpm; P < 0.0001 each) with no difference in central venous pressure. Resting MSNA levels tended to be lower in the BHT versus the NT group (12 +/- 6 versus 14 +/- 9 bursts/min, P = NS; 16 +/- 8 versus 22 +/- 13 bursts/100 heartbeats, P = 0.05) and did not correlate with either BP or body mass index. Significant positive correlations were found between resting MSNA and plasma norepinephrine levels in both groups (P < 0.05). Hemodynamic and sympathetic nerve responses to the cold pressor test were similar between the BHT and NT subjects. It is concluded that resting MSNA and plasma norepinephrine levels are correlated in young lean NT and BHT men; however, neither of these variables is correlated with BP. Because MSNA was similar in the two groups, the concept that augmented resting MSNA is important in the early developmental phase of essential hypertension must be reevaluated.
IgA-dependent, monocyte-mediated, antibacterial activity.
Authors: G H Lowell, L F Smith, J M Griffiss, B L Brandt
Journal: The Journal of Experimental Medicine (1980)

IgA purified from the sera of patients convalescing from disseminated group C meningococcal disease induced human monocyte-mediated anti-meningococcal activity in vitro in the absence of complement. Both IgA- and IgG-dependent activity were directed against the group C meningococcal polysaccharide (Csss) capsule. The amount of IgA that was effective bound less than 1 ng of Csss. Antibacterial activity was dependent upon the length and the temperature of the test incubation and on the concentration of monocytes. The implications of this mechanism for local cell-mediated antibacterial immunity are discussed.
Legal aspects of physiotherapy.: B C Dimond. (Pp 496; paperback; pound29.50.) Oxford: Blackwell Science, 1999. ISBN 0-632-05108-6.
Authors: Margaret Rees
Journal: British Journal of Sports Medicine (2000)

My first thought on receiving this book for review was “Oh good a new doorstop!” My second was “Imagine the medico-legal nightmare one would have to be in to wade through 496 pages!”

First impressions, however, are not always accurate. Closer examination reveals a book not just to turn to in times of …
Promotion of access to essential medicines for non-communicable diseases: practical implications of the UN political declaration
Authors: Hans V Hogerzeil, Jonathan Liberman, Veronika J Wirtz, Sandeep P Kishore, Sakthi Selvaraj, Rachel Kiddell-Monroe, Faith N Mwangi-Powell, Tido von Schoen-Angerer
Journal: The Lancet (2013)
Lessons Learned From Lung Cancer Genomics: The Emerging Concept of Individualized Diagnostics and Treatment
Authors: Reinhard Buettner, Jürgen Wolf, Roman K. Thomas
Journal: Journal of Clinical Oncology (2013)

The advent of novel therapeutics that specifically target signaling pathways activated by genetic alterations has revolutionized the way patients with lung cancer are treated. Although only few and largely ineffective chemotherapeutic regimens were available 10 years ago, a lung tumor diagnosed today requires extensive pathologic subtyping and diagnosis of genome alterations to afford more effective treatment (eg, in EGFR-mutant adenocarcinoma). This change of paradigm has several profound implications, ranging from preclinical work on the mechanism of action to a novel, more biologically oriented taxonomy and from genome diagnostics to trial design. Here, we have summarized these developments into six conceptual paradigms that illustrate the transition from empirical cancer medicine to mechanistically based individualized oncology.
GRSF1 Regulates RNA Processing in Mitochondrial RNA Granules
Authors: Alexis A. Jourdain, Mirko Koppen, Mateusz Wydro, Chris D. Rodley, Robert N. Lightowlers, Zofia M. Chrzanowska-Lightowlers, Jean-Claude Martinou
Journal: Cell Metabolism (2013)

Various specialized domains have been described in the cytosol and the nucleus; however, little is known about compartmentalization within the mitochondrial matrix. GRSF1 (G-rich sequence factor 1) is an RNA binding protein that was previously reported to localize in the cytosol. We found that an isoform of GRSF1 accumulates in discrete foci in the mitochondrial matrix. These foci are composed of nascent mitochondrial RNA and also contain RNase P, an enzyme that participates in mitochondrial RNA processing. GRSF1 was found to interact with RNase P and to be required for processing of both classical and tRNA-less RNA precursors. In its absence, cleavage of primary RNA transcripts is abnormal, leading to decreased expression of mitochondrially encoded proteins and mitochondrial dysfunction. Our findings suggest that the foci containing GRSF1 and RNase P correspond to sites where primary RNA transcripts converge to be processed. We have termed these large ribonucleoprotein structures "mitochondrial RNA granules."
MethMarker: user-friendly design and optimization of gene-specific DNA methylation assays
Authors: Peter Schüffler, Thomas Mikeska, Andreas Waha, Thomas Lengauer, Christoph Bock
Journal: Genome biology (2009)

DNA methylation is a key mechanism of epigenetic regulation that is frequently altered in diseases such as cancer. To confirm the biological or clinical relevance of such changes, gene-specific DNA methylation changes need to be validated in multiple samples. We have developed the MethMarker http://methmarker.mpi-inf.mpg.de/ software to help design robust and cost-efficient DNA methylation assays for six widely used methods. Furthermore, MethMarker implements a bioinformatic workflow for transforming disease-specific differentially methylated genomic regions into robust clinical biomarkers.
Antibiotics without prescription: more cons than pros
Authors: Carl Llor
Journal: BMJ (2015)

Knox suggests that women should be able to get antibiotics for urinary tract infections (UTI) without prescription in the UK.1 This strategy could avoid unnecessary visits to the GP but might be hazardous for several reasons.

Firstly, the diagnosis of UTIs is not straightforward—34-60% of patients treated with an antibiotic do not have microbiologically confirmed UTI.2

Secondly, the link between this …
Acute PKCδ inhibition limits ischaemia–reperfusion injury in the aged rat heart: Role of GSK-3β
Authors: J KOSTYAK, J HUNTER, D KORZICK
Journal: Cardiovascular Research (2006)

Age is a leading risk factor for the development of ischaemic heart disease and failure. However, the efficacy of cardioprotective strategies designed to rescue the aged myocardium remains controversial. We have previously demonstrated increased levels of basal cardiac protein kinase Cdelta (PKCdelta) with ageing, a well-known mediator of apoptotic cell death following ischaemia and reperfusion (I/R) in adult hearts. Our objective was to determine the contribution of PKCdelta signaling mechanisms to reperfusion injury in the aged heart using local delivery of a novel PKCdelta inhibitory peptide (KID1-1).Contractile responses were assessed in hearts isolated from adult (4 months, n=38) and aged (24 months, n=45) male Fisher 344 rats treated with either KID1-1 (500 nM) or Tat vehicle peptide (500 nM) upon reperfusion for 10 min following 31-min global ischaemia.Recovery of left ventricular (LV) developed pressure was significantly improved by KID1-1 and associated with smaller infarct size in 24 months vs. age-matched controls (p<0.005). We also observed significant reductions in DNA laddering and cytochrome c and caspase 3 levels in aged hearts treated with KID1-1. Interestingly, KID1-1 attenuated mitochondrial and nuclear PKCdelta levels during reperfusion in aged vs. age-matched controls (p<0.01). Further, increases in mitochondrial phosphorylated glycogen synthase kinase-3beta (pGSK-3beta) levels were hastened in aged and adult hearts following KID1-1 (p<0.05), increasing the pGSK-3beta/GSK-3beta ratio.These results provide novel evidence for cardioprotection through acute PKCdelta inhibition in aged rat heart following I/R. Our results also suggest, for the first time, a key role for mitochondrial GSK-3beta as a cellular basis for the protection associated with PKCdelta inhibition with ageing.