tbuckley/cabot-search huggingface dataset:
The Ataxia Telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary <i>Vκ</i>-to-<i>Jκ</i> rearrangements
Authors: Natalie C. Steinel, Baeck-Seung Lee, Anthony T. Tubbs, Jeffrey J. Bednarski, Emily Schulte, Katherine S. Yang-Iott, David G. Schatz, Barry P. Sleckman, Craig H. Bassing
Journal: The Journal of Experimental Medicine (2013)

Allelic exclusion is enforced through the ability of antigen receptor chains expressed from one allele to signal feedback inhibition of V-to-(D)J recombination on the other allele. To achieve allelic exclusion by such means, only one allele can initiate V-to-(D)J recombination within the time required to signal feedback inhibition. DNA double-strand breaks (DSBs) induced by the RAG endonuclease during V(D)J recombination activate the Ataxia Telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) kinases. We demonstrate that ATM enforces Igκ allelic exclusion, and that RAG DSBs induced during Igκ recombination in primary pre–B cells signal through ATM, but not DNA-PK, to suppress initiation of additional Igκ rearrangements. ATM promotes high-density histone H2AX phosphorylation to create binding sites for MDC1, which functions with H2AX to amplify a subset of ATM-dependent signals. However, neither H2AX nor MDC1 is required for ATM to enforce Igκ allelic exclusion and suppress Igκ rearrangements. Upon activation in response to RAG Igκ cleavage, ATM signals down-regulation of Gadd45α with concomitant repression of the Gadd45α targets Rag1 and Rag2. Our data indicate that ATM kinases activated by RAG DSBs during Igκ recombination transduce transient H2AX/MDC1-independent signals that suppress initiation of further Igκ rearrangements to control Igκ allelic exclusion.
Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator
Authors: Masahiro Shuda, Hyun Jin Kwun, Huichen Feng, Yuan Chang, Patrick S. Moore
Journal: Journal of Clinical Investigation (2011)

Merkel cell polyomavirus (MCV) is the recently discovered cause of most Merkel cell carcinomas (MCCs), an aggressive form of nonmelanoma skin cancer. Although MCV is known to integrate into the tumor cell genome and to undergo mutation, the molecular mechanisms used by this virus to cause cancer are unknown. Here, we show that MCV small T (sT) antigen is expressed in most MCC tumors, where it is required for tumor cell growth. Unlike the closely related SV40 sT, MCV sT transformed rodent fibroblasts to anchorage- and contact-independent growth and promoted serum-free proliferation of human cells. These effects did not involve protein phosphatase 2A (PP2A) inhibition. MCV sT was found to act downstream in the mammalian target of rapamycin (mTOR) signaling pathway to preserve eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation, resulting in dysregulated cap-dependent translation. MCV sT-associated 4E-BP1 serine 65 hyperphosphorylation was resistant to mTOR complex (mTORC1) and mTORC2 inhibitors. Steady-state phosphorylation of other downstream Akt-mTOR targets, including S6K and 4E-BP2, was also increased by MCV sT. Expression of a constitutively active 4E-BP1 that could not be phosphorylated antagonized the cell transformation activity of MCV sT. Taken together, these experiments showed that 4E-BP1 inhibition is required for MCV transformation. Thus, MCV sT is an oncoprotein, and its effects on dysregulated cap-dependent translation have clinical implications for the prevention, diagnosis, and treatment of MCV-related cancers.
The Circulating Proteinase Inhibitor α-1 Antitrypsin Regulates Neutrophil Degranulation and Autoimmunity
Authors: David A. Bergin, Emer P. Reeves, Killian Hurley, Rebecca Wolfe, Ramia Jameel, Sean Fitzgerald, Noel G. McElvaney
Journal: Science Translational Medicine (2014)

Pathological inflammation and autoimmune disease frequently involve elevated neutrophil activity in the absence of infectious agents. Tumor necrosis factor-α (TNF-α) contributes to many of the problems associated with autoimmune diseases. We investigated the ability of serum α-1 antitrypsin (AAT) to control TNF-α biosynthesis and signaling in neutrophils and assessed whether AAT deficiency (AATD) is a TNF-α-related disease. In vitro studies demonstrate that serum AAT coordinates TNF-α intracellular signaling and neutrophil degranulation of tertiary and secondary granules via modulation of ligand-receptor interactions. AATD patients homozygous for the Z allele were characterized by increased activation of the TNF-α system, as demonstrated by increased membrane TNF-α levels and increased plasma concentrations of TNF receptor 1 and neutrophil-released secondary and tertiary granule proteins. The incidence of autoantibodies directed against degranulated lactoferrin and surface protein accessible to these antibodies was increased in ZZ-AATD, leading to an enhanced rate of neutrophil reactive oxygen species production. Treatment of ZZ-AATD individuals with AAT augmentation therapy resulted in decreased membrane TNF-α expression and plasma levels of granule antigenic proteins and immunoglobulin G class autoantibodies. These results provide a mechanism by which AAT augmentation therapy affects TNF-α signaling in the circulating neutrophil, indicating promising potential of this therapy for other TNF-α-related diseases.
Characterization of complex chromosomal abnormalities in B-cell lymphoma by a combined spectral karyotyping (SKY) analysis and fluorescence in situ hybridization (FISH) using a 14q telomere probe
Authors: Naoki Kakazu, Katsuyuki Kito, Tatefumi Hitomi, Jiro Oita, Kazuhiro Nishida, Kento Masuda, Tohru Miki, Tatsuo Abe
Journal: American Journal of Hematology (2000)

We report a case of non-Hodgkin's lymphoma of unknown origin with invasion into bone marrow and brain. This case showed complex chromosomal abnormalities, including five clonal marker chromosomes (mar) and four additional materials of unknown origin (add) that could not be identified by means of conventional G-banding. Spectral karyotyping (SKY) analysis could not only determine the origin and organization of all thus far unidentified structural chromosomal abnormalities but also detect two cryptic unbalanced translocations, which had been erroneously considered to be normal on the basis of G-banding analysis, and correct one abnormality misidentified by G banding. Among these abnormalities, we identified the new partner site of the 14q32 translocation, 22q13, and the jumping translocations involving 2p23 as a new donor chromosome. Furthermore, by using fluorescence in situ hybridization (FISH) with the probes specific for the 14q telomere, we could identify the unbalanced translocation of t(3;14)(q27;q32), which had been erroneously considered to be normal chromosome 3 on the basis of not only G-banding but also of SKY analysis. This translocation is one of the most frequent chromosomal abnormalities in B-cell lymphoma, especially diffuse large cell lymphoma. After SKY and FISH analysis, the original descriptions in the G-band karyotype were modified for a total of 13 chromosomes. The combination of SKY and FISH using the 14q telomere probe was therefore considered very useful for the characterization of complex cytogenetic cases in B-cell lymphoma. Am. J. Hematol. 65:291–297, 2000. © 2000 Wiley-Liss, Inc.
Breath-actuated inhalers in chronic asthma: comparison of Diskhaler and Turbohaler for delivery of beta-agonists
Authors: PH Brown, J Lenney, S Armstrong, AC Ning, GK Crompton
Journal: European Respiratory Journal (1992)

An open, randomized, cross-over study was performed to compare the efficacy and acceptability of two breath-actuated inhalers, the Turbohaler (T) and Diskhaler (D), for delivery of beta-agonists. Thirty six adults with chronic asthma requiring beta-agonists four times daily were treated with terbutaline 500 micrograms via T and salbutamol 400 micrograms via D four times daily, each period lasting four weeks. Additional bronchodilator via pressurized aerosol was permitted as required. Peak expiratory flow (PEF) was recorded in the morning (before and after beta-agonist) and in the evening. The mean morning PEF was higher during the first two weeks using T (295 l.min-1) than whilst using D (281 l.min-1, p < 0.01), but this difference did not persist during the second two weeks and there were no differences in post-bronchodilator PEF or rescue beta-agonist use. After four weeks, > 90% of patients used both inhaler devices efficiently and they were equally acceptable in terms of ease of use and convenience to carry. The Diskhaler and Turbohaler achieve similar clinical efficacy for delivery of beta-agonists.
Immune history shapes specificity of pandemic H1N1 influenza antibody responses
Authors: Yang Li, Jaclyn L. Myers, David L. Bostick, Colleen B. Sullivan, Jonathan Madara, Susanne L. Linderman, Qin Liu, Donald M. Carter, Jens Wrammert, Susanna Esposito, Nicola Principi, Joshua B. Plotkin, Ted M. Ross, Rafi Ahmed, Patrick C. Wilson, Scott E. Hensley
Journal: The Journal of Experimental Medicine (2013)

Human antibody responses against the 2009 pandemic H1N1 (pH1N1) virus are predominantly directed against conserved epitopes in the stalk and receptor-binding domain of the hemagglutinin (HA) protein. This is in stark contrast to pH1N1 antibody responses generated in ferrets, which are focused on the variable Sa antigenic site of HA. Here, we show that most humans born between 1983 and 1996 elicited pH1N1 antibody responses that are directed against an epitope near the HA receptor–binding domain. Importantly, most individuals born before 1983 or after 1996 did not elicit pH1N1 antibodies to this HA epitope. The HAs of most seasonal H1N1 (sH1N1) viruses that circulated between 1983 and 1996 possess a critical K133 amino acid in this HA epitope, whereas this amino acid is either mutated or deleted in most sH1N1 viruses circulating before 1983 or after 1996. We sequentially infected ferrets with a 1991 sH1N1 virus and then a pH1N1 virus. Sera isolated from these animals were directed against the HA epitope involving amino acid K133. These data suggest that the specificity of pH1N1 antibody responses can be shifted to epitopes near the HA receptor–binding domain after sequential infections with sH1N1 and pH1N1 viruses that share homology in this region.
Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators
Authors: Ulrike Flierl, Tracy L. Nero, Bock Lim, Jane F. Arthur, Yu Yao, Stephanie M. Jung, Eelo Gitz, Alice Y. Pollitt, Maria T.K. Zaldivia, Martine Jandrot-Perrus, Andreas Schäfer, Bernhard Nieswandt, Robert K. Andrews, Michael W. Parker, Elizabeth E. Gardiner, Karlheinz Peter
Journal: The Journal of Experimental Medicine (2015)

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function–deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone–dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.
Spirometric reference values in Senegalese black adults
Authors: P Dufétel, B Pigearias, J Lonsdorfer, G Derossi, C Diaine, P J Faltot
Journal: European Respiratory Journal (1989)

Spirometric volumes and expiratory flows were measured among 448 Senegalese males and females of 25-80 yrs of age. The values obtained are similar to those reported for black Africans and black Americans in the literature. Volumes are 15-25% lower in males and 23% lower in females than in Caucasians. Forced expiratory flow between 25-75% of vital capacity (VC), (FEF25-75) is 5-18% lower in males and 19% lower in females. FEF25-75/VC ratio is higher in blacks than in Whites, but the forced expiratory volume in one second FEV1/VC ratio is similar in black and white subjects. However, we cannot use proportional factors to determine spirometric black standards from white reference values, so, equations of regression and nomograms with age and height are proposed for black Africans.
Recurrent gastric carcinoma treated by the Geiger probe technique.
Authors: D J Martin
Journal: Gut (1966)

EDITORIAL COMMENT Conventional radiotherapy or chemotherapy has little success in the treatment of adenocarcinoma of the stomach.It is suggested that if radiotherapy can be given at times of tumour mitotic activity then greater success might be achieved.In this case a pattern of tumour activity was induced by Methotrexate and radiotherapy given during peaks of activity as judged by the Geiger probe technique.A single case is recorded though, naturally, conclusions cannot be drawn from an isolated success.
Household chemicals: good housekeeping or occupational hazard?
Authors: P. Franklin
Journal: European Respiratory Journal (2008)

In the Western world the role of air pollution in the initiation of respiratory disease in children is contentious 1. There is good evidence that air pollution can trigger symptoms in susceptible children but its contribution to the pathogenesis of childhood respiratory disorders, such as asthma, remains unclear. There has been considerable interest in traffic-related pollutants and studies have investigated the prevalence of asthma and wheeze in children living near main roads 2–4. While this remains an important area of research, there is also concern about exposure to air pollutants in the indoor environment. In developed countries, people spend most of their time indoors and in the case of many air pollutants, the indoor environment is the principal source of exposure.

For young children, the most important indoor environment is the home. On average, children spend ∼15 h a day indoors at home 5. Infants average nearly 20 h per day indoors 6. Indoor air pollutants, such as environmental tobacco smoke (ETS), nitrogen dioxide and formaldehyde, have been associated with adverse respiratory health outcomes in children 7. In recent times, there have been concerns about domestic exposure to volatile organic compounds (VOCs) and other air toxics. Indoor air toxics, including VOCs, are emitted from a broad range of sources, including cleaning agents, furnishings, paints, cosmetics, aerosol sprays and pesticides. These products also contain chlorine, ammonia, surfactants, acids, bases and oxidants, and reactions between compounds can create highly irritative secondary pollutants 8. The health effects of this chemical mix, at concentrations normally encountered in homes, is not yet known but there is some evidence that these exposures may be associated with wheeze 9–11 and allergy 12 in young children. The data, however, …
Sodium channels as macromolecular complexes: Implications for inherited arrhythmia syndromes
Authors: L MEADOWS, L ISOM
Journal: Cardiovascular Research (2005)

Mutations in cardiac ion channels and their auxiliary subunits can lead to life-threatening cardiac arrhythmias. In recent years it has become apparent that ion channels are part of large, multi-protein complexes, comprising not only the ion channels and their auxiliary subunits, but also components of the cytoskeleton, regulatory kinases and phosphatases, trafficking proteins, extracellular matrix proteins, and possibly even other ion channels. Disruption of any member of a particular ion channel complex has the potential to disrupt the function of the associated channels, resulting in paroxysmal disease. Understanding the molecular composition of individual ion channel signaling complexes in heart may yield important insights into the molecular basis of cardiac arrhythmias and may suggest novel therapeutic approaches to treatment of these life-threatening conditions.
Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1
Authors: King-Tung Chin, Abel C.S. Chun, Yick-Pang Ching, Kuan-Teh Jeang, Dong-Yan Jin
Journal: Cancer Research (2007)

Abstract Human T-cell leukemia virus type 1 oncoprotein Tax is a transcriptional regulator that interacts with a large number of host cell factors. Here, we report the novel characterization of the interaction of Tax with a human cell protein named Tax1-binding protein 1 (TAX1BP1). We show that TAX1BP1 is a nuclear receptor coactivator that forms a complex with the glucocorticoid receptor. TAX1BP1 and Tax colocalize into intranuclear speckles that partially overlap with but are not identical to the PML oncogenic domains. Tax binds TAX1BP1 directly, induces the dissociation of TAX1BP1 from the glucocorticoid receptor–containing protein complex, and represses the coactivator function of TAX1BP1. Genetic knockout of Tax1bp1 in mice abrogates the influence of Tax on the activation of nuclear receptors. We propose that Tax-TAX1BP1 interaction mechanistically explains the previously reported repression of nuclear receptor activity by Tax. [Cancer Res 2007;67(3):1072–81]
Expression of the Transcriptional Repressor Gfi-1 Is Regulated by C/EBPα and Is Involved in Its Proliferation and Colony Formation–Inhibitory Effects in p210BCR/ABL-Expressing Cells
Authors: Maria Rosa Lidonnici, Alessandra Audia, Angela Rachele Soliera, Marco Prisco, Giovanna Ferrari-Amorotti, Todd Waldron, Nick Donato, Ying Zhang, Robert V. Martinez, Tessa L. Holyoake, Bruno Calabretta
Journal: Cancer Research (2010)

Ectopic expression of CAAT/enhancer binding protein α (C/EBPα) in p210BCR/ABL-expressing cells induces granulocytic differentiation, inhibits proliferation, and suppresses leukemogenesis. To dissect the molecular mechanisms underlying these biological effects, C/EBPα-regulated genes were identified by microarray analysis in 32D-p210BCR/ABL cells. One of the genes whose expression was activated by C/EBPα in a DNA binding-dependent manner in BCR/ABL-expressing cells is the transcriptional repressor Gfi-1. We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1. Moreover, in K562 cells, RNA interference-mediated downregulation of Gfi-1 expression partially rescued the proliferation-inhibitory but not the differentiation-inducing effect of C/EBPα. Ectopic expression of wild-type Gfi-1, but not of a transcriptional repressor mutant (Gfi-1P2A), inhibited proliferation and markedly suppressed colony formation but did not induce granulocytic differentiation of BCR/ABL-expressing cells. By contrast, Gfi-1 short hairpin RNA-tranduced CD34(+) chronic myeloid leukemia cells were markedly more clonogenic than the scramble-transduced counterpart. Together, these studies indicate that Gfi-1 is a direct target of C/EBPα required for its proliferation and survival-inhibitory effects in BCR/ABL-expressing cells.
Injury surveillance in the World Football Tournaments 1998–2012
Authors: Astrid Junge, Jiri Dvorak
Journal: British Journal of Sports Medicine (2013)

International sports bodies should protect the health of their athletes, and injury surveillance is an important pre-requisite for injury prevention. The Fédération International de Football Association (FIFA) has systematically surveyed all football injuries in their tournaments since 1998.Analysis of the incidence, characteristics and changes of football injury during international top-level tournaments 1998-2012.All newly incurred football injuries during the FIFA tournaments and the Olympic Games were reported by the team physicians on a standardised injury report form after each match. The average response rate was 92%.A total of 3944 injuries were reported from 1546 matches, equivalent to 2.6 injuries per match. The majority of injuries (80%) was caused by contact with another player, compared with 47% of contact injuries by foul play. The most frequently injured body parts were the ankle (19%), lower leg (16%) and head/neck (15%). Contusions (55%) were the most common type of injury, followed by sprains (17%) and strains (10%). On average, 1.1 injuries per match were expected to result in absence from a match or training. The incidence of time-loss injuries was highest in the FIFA World Cups and lowest in the FIFA U17 Women's World Cups. The injury rates in the various types of FIFA World Cups had different trends over the past 14 years.Changes in the incidence of injuries in top-level tournaments might be influenced by the playing style, refereeing, extent and intensity of match play. Strict application of the Laws of the Games is an important means of injury prevention.
Effect of 1-week losartan administration on bile duct-ligated cirrhotic rats with portal hypertension
Authors: Ying-Ying Yang, Han-Chieh Lin, Yi-Tsau Huang, Tzung-Yen Lee, Ming-Chih Hou, Fa-Yauh Lee, Ren-Shyan Liu, Full-Young Chang, Shou-Dong Lee
Journal: Journal of Hepatology (2002)