tbuckley/cabot-search huggingface dataset:
Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP
Authors: Anaïs Aulas, Stéphanie Stabile, Christine Vande Velde
Journal: Molecular Neurodegeneration (2012)

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, a cell type that is intrinsically more vulnerable than other cell types to exogenous stress. The interplay between genetic susceptibility and environmental exposures to toxins has long been thought to be relevant to ALS. One cellular mechanism to overcome stress is the formation of small dense cytoplasmic domains called stress granules (SG) which contain translationally arrested mRNAs. TDP-43 (encoded by TARDBP ) is an ALS-causative gene that we have previously implicated in the regulation of the core stress granule proteins G3BP and TIA-1. TIA-1 and G3BP localize to SG under nearly all stress conditions and are considered essential to SG formation. Here, we report that TDP-43 is required for proper SG dynamics, especially SG assembly as marked by the secondary aggregation of TIA-1. We also show that SG assembly, but not initiation, requires G3BP. Furthermore, G3BP can rescue defective SG assembly in cells depleted of endogenous TDP-43. We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation and assembly occur normally in the absence of FUS. Lastly, we observe that SG assembly is a contributing factor in the survival of neuronal-like cells responding to acute oxidative stress. These data raise the possibility that disruptions of normal stress granule dynamics by loss of nuclear TDP-43 function may contribute to neuronal vulnerability in ALS.
Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury.
Authors: M H Crawford, F L Grover, W P Kolb, C A McMahan, R A O'Rourke, L M McManus, R N Pinckard
Journal: Circulation (1988)

Complement depletion with cobra venom factor (CVF) before coronary artery ligation has been previously shown to reduce subsequent ischemic myocardial tissue injury in the baboon; however, whether complement depletion after the initiation of acute myocardial ischemia affords similar myocardial preservation is not known. Both complement depletion with CVF or the administration of certain nonsteroidal anti-inflammatory drugs, including ibuprofen, are thought to decrease myocardial infarct size by reducing polymorphonuclear leukocytic (PMN) infiltration; nevertheless, complement activation also could alter tissue injury by PMN-independent actions. Thus, the relative effects of CVF administered after coronary artery ligation on the subsequent development of myocardial tissue injury were assessed in a baboon myocardial infarction model. The animals were randomized into three treatment groups (n = 6): either CVF (125 units/kg) or saline was given 30 minutes after coronary artery ligation, and ibuprofen (12.5 mg/kg) was administered 30 minutes and 4 hours after ligation. The extent of ischemic myocardial injury was assessed 24 hours later. Relative to saline-treated baboons, both CVF and ibuprofen reduced PMN infiltration (36 +/- 4 vs. 24 +/- 4 and 24 +/- 4 PMN/mm2, respectively; mean +/- SEM) and histological evidence of transmural myocardial infarction (100% vs. 47% and 53%, respectively) in electrocardiographically designated, expected infarct sites. In both saline- and ibuprofen-treated animals, there was extensive localization of C4, C3, and C5 in all infarct sites; in contrast, there was only C4 localization in the CVF-treated baboons. When expected infarct sites were assessed for creatine kinase content as an indicator of tissue injury, there was significantly less epicardial and endocardial creatine kinase depletion in the CVF-treated animals (31.7 +/- 5.6% and 39.3 +/- 4.8%) than in the saline-treated animals (54.1 +/- 5.4% and 59.0 +/- 4.7%; p = 0.012 and 0.011, respectively). The percent creatine kinase depletion in the ibuprofen-treated animals was intermediate between the two other groups. These results suggest that depletion of complement after coronary ligation has beneficial effects in reducing tissue injury that cannot be explained solely on the basis of reducing PMN infiltration into the ischemic myocardium.
Expression of the Insulin-Like Growth Factor I Receptor and Urokinase Plasminogen Activator in Breast Cancer Is Associated with Poor Survival
Authors: Torsten O. Nielsen, Heather N. Andrews, Maggie Cheang, Jill E. Kucab, Forrest D. Hsu, Joseph Ragaz, C. Blake Gilks, Nikita Makretsov, Chris D. Bajdik, Christy Brookes, Leonard M. Neckers, Valentina Evdokimova, David G. Huntsman, Sandra E. Dunn
Journal: Cancer Research (2004)

Abstract Urokinase plasminogen activator (uPA) expression in breast cancer is associated with relapse and a reduction in disease-specific survival. Thus, efforts are under way to identify uPA inhibitors. By screening a chemical library of &amp;gt;1000 compounds, 17-allyaminogeldanamycin (17AAG) was identified as a potent inhibitor of uPA by the National Cancer Institute and is now in Phase I clinical trials. At this time, it remains unclear how 17AAG blocks uPA; one possibility is through disruption of the insulin-like growth factor I receptor (IGF-IR) pathway. This would be consistent with studies from our laboratory showing that activation of IGF-IR results in the induction of uPA protein. In the study described herein, we observed that IGF-IR and uPA were highly expressed in 87 and 55% of breast cancer by screening tumor tissue microarrays representing 930 cases. A significant proportion (52.1% = 354 of 680 cases, P &amp;lt; 0.0001) of the patients had tumors expressing both proteins. uPA alone (P = 0.033) or in combination with IGF-IR (P = 0.0104) was indicative of decreased disease-specific survival. Next, we demonstrated that treating MDA-MB-231 cells with increasing concentrations of 17AAG resulted in IGF-IR degradation (IC50 = 1.0 μm) and blocked signal transduction through the Akt and mitogen-activated protein kinase pathways. Finally, we found that 17AAG had a robust inhibitory effect on the production of uPA mRNAand protein in the presence of IGF-I. Thus, our study raises the possibility that 17AAG could prove to be an effective therapeutic agent for a large number of breast cancer patients by inhibiting the IGF-IR and ultimately uPA.
Lack of mother-to-infant transmission of hepatitis C virus in human immunodeficiency virus–seronegative women: A prospective study with hepatitis C virus RNA testing
Authors: Françoise Roudot-Thoraval, Jean-Michel Pawlotsky, Valérie Thiers, Lionel Deforges, Pierre-Paul Girollet, François Guillot, Christiane Huraux, Pascale Aumont, Christian Brechot, Daniel Dhumeaux
Journal: Hepatology (1993)

The published risk of mother-to-infant transmission of hepatitis C virus varies according to the population studied and the tests used. In a prospective study we used the polymerase chain reaction to assess the risk of vertical transmission of hepatitis C virus in an unselected population of women uninfected by human immunodeficiency virus. Hepatitis C virus antibodies were sought with a second-generation enzyme-linked immunosorbent assay in 2,367 consecutive pregnant women. Forty-one were positive, and 17 consented to serological follow-up of their offspring (n = 18). A second-generation recombinant immunoblot assay, ALT determination and hepatitis C virus RNA testing were performed on maternal sera obtained during pregnancy and sera from the offspring at birth and thereafter. Five older brothers or sisters were also tested. Hepatitis C virus RNA sequences in serum were amplified with a modified nested polymerase chain reaction procedure with primers from the highly conserved 5' noncoding region of the hepatitis C virus genome. All the neonates were positive for hepatitis C virus antibodies, with enzyme-linked immunosorbent assay titers and recombinant immunoblot assay patterns similar to those of their mothers. After birth hepatitis C virus antibodies gradually disappeared within 6 mo. Hepatitis C virus RNA was consistently negative in the 18 children from birth to 24 mo (range = 3 to 24 mo) and in the 5 older children, regardless of the hepatitis C virus polymerase chain reaction status of the mothers (8 of whom were positive).(ABSTRACT TRUNCATED AT 250 WORDS)
Taxonomic distribution of large DNA viruses in the sea
Authors: Adam Monier, Jean-Michel Claverie, Hiroyuki Ogata
Journal: Genome biology (2008)

Abstract Background Viruses are ubiquitous and the most abundant biological entities in marine environments. Metagenomics studies are increasingly revealing the huge genetic diversity of marine viruses. In this study, we used a new approach - 'phylogenetic mapping' - to obtain a comprehensive picture of the taxonomic distribution of large DNA viruses represented in the Sorcerer II Global Ocean Sampling Expedition metagenomic data set. Results Using DNA polymerase genes as a taxonomic marker, we identified 811 homologous sequences of likely viral origin. As expected, most of these sequences corresponded to phages. Interestingly, the second largest viral group corresponded to that containing mimivirus and three related algal viruses. We also identified several DNA polymerase homologs closely related to Asfarviridae, a viral family poorly represented among isolated viruses and, until now, limited to terrestrial animal hosts. Finally, our approach allowed the identification of a new combination of genes in 'viral-like' sequences. Conclusion Albeit only recently discovered, giant viruses of the Mimiviridae family appear to constitute a diverse, quantitatively important and ubiquitous component of the population of large eukaryotic DNA viruses in the sea.
Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media
Authors: P. Little
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To compare immediate with delayed prescribing of antibiotics for acute otitis media. <b>Design:</b> Open randomised controlled trial. <b>Setting:</b> General practices in south west England. <b>Participants:</b> 315 children aged between 6 months and 10 years presenting with acute otitis media. <b>Interventions:</b> Two treatment strategies, supported by standardised advice sheets—immediate antibiotics or delayed antibiotics (antibiotic prescription to be collected at parents9 discretion after 72 hours if child still not improving). <b>Main outcome measures:</b> Symptom resolution, absence from school or nursery, paracetamol consumption. <b>Results:</b> On average, symptoms resolved after 3 days. Children prescribed antibiotics immediately had shorter illness (−1.1 days (95% confidence interval −0.54 to −1.48)), fewer nights disturbed (−0.72 (−0.30 to −1.13)), and slightly less paracetamol consumption (−0.52 spoons/day (−0.26 to −0.79)). There was no difference in school absence or pain or distress scores since benefits of antibiotics occurred mainly after the first 24 hours—when distress was less severe. Parents of 36/150 of the children given delayed prescriptions used antibiotics, and 77% were very satisfied. Fewer children in the delayed group had diarrhoea (14/150 (9%) <i>v</i> 25/135 (19%), χ<sup>2</sup>=5.2, P=0.02). Fewer parents in the delayed group believed in the effectiveness of antibiotics and in the need to see the doctor with future episodes. <b>Conclusion:</b> Immediate antibiotic prescription provided symptomatic benefit mainly after first 24 hours, when symptoms were already resolving. For children who are not very unwell systemically, a wait and see approach seems feasible and acceptable to parents and should substantially reduce the use of antibiotics for acute otitis media.
AN ENZYMATIC FUNCTION ASSOCIATED WITH TRANSFORMATION OF FIBROBLASTS BY ONCOGENIC VIRUSES
Authors: J. C. Unkeless, A. Tobia, L. Ossowski, J. P. Quigley, D. B. Rifkin, E. Reich
Journal: The Journal of Experimental Medicine (1973)

Chick embryo fibroblast cultures develop fibrinolytic activity after transformation by Rous sarcoma virus (RSV). This fibrinolytic activity is not present in normal cultures, and it does not appear after infection with either nontransforming strains of avian leukosis viruses or cytocidal RNA and DNA viruses. In cultures infected with a temperature sensitive mutant of RSV the onset of fibrinolysis appears after exposure to permissive temperatures and precedes by a short interval the appearance of morphological evidence of transformation. See PDF for Structure The rate of fibrinolysis in transformed cultures depends on the nature of the serum that is present in the growth medium: some sera (e.g., monkey or chicken serum) promote high enzymatic activity, while others (calf, fetal bovine) do not. Some sera contain inhibitors of the fibrinolysin. Based on the effect of a small number of known inhibitors, at least one step of the fibrinolytic process shows specificity resembling that of trypsin. The sera of sarcoma-bearing chickens contain an inhibitor of the fibrinolysin, whereas normal chicken sera do not. For general discussion, conclusions, and summary see the accompanying paper, part II, (J. Exp. Med. 137:112).
A Refocus on the Bladder as the Originator of Storage Lower Urinary Tract Symptoms: A Systematic Review of the Latest Literature
Authors: Alexander Roosen, Christopher R. Chapple, Roger R. Dmochowski, Clare J. Fowler, Christian Gratzke, Claus G. Roehrborn, Christian G. Stief, Karl-Erik Andersson
Journal: European Urology (2009)
Testicular function following chemotherapy
Authors: S.J. Howell, S.M. Shalet
Journal: Human Reproduction Update (2001)

Testicular dysfunction is a common long-term sequela of cytotoxic chemotherapy used in the treatment of many malignancies. The degree to which testicular function is affected is dose- and agent-dependent. The impact on germinal epithelial function of standard multi-agent regimens used in the treatment of lymphomas has been widely studied. Procarbazine-containing regimens result in azoospermia in the vast majority of patients, but much lesser degrees of long-term gonadotoxicity are apparent with the newer forms of chemotherapy. High-dose chemotherapy used as preparation before bone marrow transplant is also associated with irreversible germinal epithelial failure in the majority of men. Treatment of testicular cancer with cisplatin and carboplatin regimens leads to temporary azoo- and oligozoospermia in most men, with a recovery to normospermia in 80% by 5 years. There is also evidence of mild Leydig cell impairment in a proportion of men treated with cytotoxic agents, although the clinical significance of this is not clear. Several methods of preserving testicular function during potentially sterilizing treatment have been considered. At present, sperm banking remains the only proven method, although hormonal manipulation to enhance recovery of spermatogenesis and cryopreservation of testicular germ cells are possibilities for the future.
Ontogenetic Complexity of Sexual Dimorphism and Sex-Specific Selection
Authors: J. E. Mank, K. Nam, B. Brunstrom, H. Ellegren
Journal: Molecular Biology and Evolution (2010)

Sex-biased gene expression is becoming an increasingly important way to study sexual selection at the molecular genetic level. However, little is known about the timing, persistence, and continuity of gene expression required in the creation of distinct male and female phenotypes, and even less about how sex-specific selection pressures shift over the life cycle. Here, we present a time-series global transcription profile for autosomal genes in male and female chicken, beginning with embryonic development and spanning to reproductive maturity, for the gonad. Overall, the amount and magnitude of sex-biased expression increased as a function of age, though sex-biased gene expression was surprisingly ephemeral, with very few genes exhibiting continuous sex bias in both embryonic and adult tissues. Despite a large predicted role of the sex chromosomes in sexual dimorphism, our study indicates that the autosomes house the majority of genes with sex-biased expression. Most interestingly, sex-specific evolutionary pressures shifted over the course of the life cycle, acting equally strongly on female-biased genes and male-biased genes but at different ages. Female-biased genes exhibited high rates of divergence late in embryonic development, shortly before arrested meiosis halts oogenesis. The level of divergence on female-biased late embryonic genes is similar to that seen in male-biased genes expressed in adult gonads, which correlates with the onset of spermatogenesis. These analyses reveal that sex-specific selection pressure varies over the life cycle as a function of male and female biology.
Effects of Ammonia on Acid-Base Transport by the B-Type Intercalated Cell
Authors: AMY E. FRANK, I. DAVID WEINER
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Ammonia, in addition to its role as a constituent of urinary net acid excretion, stimulates cortical collecting duct (CCD) net bicarbonate reabsorption. The current study sought to begin determining the cellular transport processes through which ammonia regulates bicarbonate reabsorption by testing whether ammonia stimulates B-type intercalated cell bicarbonate secretion, bicarbonate reabsorption, or both. The effects of ammonia on single CCD intercalated cells was studied by use of measurements of intracellular pH taken from in vitro microperfused CCD segments after luminal loading of the pH-sensitive fluorescent dye BCECF. These results showed, first, that ammonia inhibited B-cell unidirectional bicarbonate secretion and that this occurred despite no effect of ammonia on apical Cl - /HCO 3 - exchange activity. Second, ammonia increased the contribution of a SCH28080-sensitive apical H + -K + -ATPase to basal intracellular pH regulation and it stimulated basolateral Cl - /HCO 3 - exchange activity. Thus, ammonia activated both apical proton secretion and basolateral base exit, consistent with stimulation of unidirectional bicarbonate reabsorption. It was concluded that ammonia regulates CCD net bicarbonate reabsorption, at least in part, through the coordinated regulation of the separate processes of B-cell bicarbonate reabsorption and bicarbonate secretion. These effects do not reflect a general activation of ion transport but, instead, reflect coordinated and specific regulation of ion transport.
New perspectives on basic mechanisms in lung disease. 6. Proteinase imbalance: its role in lung disease.
Authors: T D Tetley
Journal: Thorax (1993)

The hypothesis, some 30 years ago, that NE was the sole proteolytic agent responsible for the development of emphysema seems naive in retrospect. The availability of technology to measure NE facilitated the early research into the relationship between NE and lung disease. Despite an abundance of information on the activity of NE in the lung, it will probably require prospective studies in man with specific NE inhibitors or control at the gene level to establish a causal relationship between NE and lung disease. Parallel research has resulted in the isolation and characterisation of NE inhibitors other than PI and, indeed, alternative proteolytic enzymes that might contribute to lung disease. It is perhaps impossible now to think that a single proteinase, however omnipotent it may be, causes lung diseases as diverse as emphysema and fibrosis. An important aspect that is emerging is the interrelationship between proteolytic enzymes produced by different, or sometimes the same, cells that could potentiate tissue proteolysis. The evidence suggests that there is likely to be coordinated action between neutrophils, macrophages, and possibly mesenchymal proteinases which can activate or inactivate each other. In addition, one class of proteinases often appears able to proteolytically inactivate inhibitors of the opposite class, which presumably could amplify proteolysis if it occurred in vivo. Although the work on this aspect of proteinase activity is in its infancy, one suspects that part of the normal regulation of proteinase activity might include compartmentalisation. For example, the neutrophil stores proteinases before appropriate release and can inactivate PI to enable proteolytic action pericellularly, whereas degradation of extracellular matrix by macrophages requires interaction between the cell and matrix which is facilitated by cell receptor bound uPA. Disintegration of these "compartments" due to oedema, proteolysis, or for mechanical reasons could, firstly, expose further extracellular matrix substrates to inflammatory and damaged cell proteinases but, secondly, might enhance proteinase potential by the cooperative action of these enzymes. It seems increasingly likely that, where proteinases play a part, there is a cocktail of proteinases that is characteristic of the injury that develops (fig). What remains unclear is why only a proportion of those susceptible, such as smokers or those with acute lung injury, develop irreversible lung disease. This suggests that there are other factors acquired or inherited that need to be considered.
Centrally infused atrial natriuretic polypeptide attenuates exaggerated salt appetite in spontaneously hypertensive rats.
Authors: H Itoh, K Nakao, G Katsuura, N Morii, S Shiono, M Sakamoto, A Sugawara, T Yamada, Y Saito, A Matsushita
Journal: Circulation Research (1986)

We have previously shown that atrial natriuretic polypeptide is present in the brain with the highest concentration in the hypothalamus and septum and that intracerebroventricular injection of atrial natriuretic polypeptide inhibits water drinking induced by centrally injected angiotensin II or 24-hour water deprivation in rats. To study further the role of brain atrial natriuretic polypeptide in the control of water and electrolyte balance, the effect of chronic intracerebroventricular infusion of atrial natriuretic polypeptide on salt appetite in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats was examined with a free-choice, two-bottle preference test. The intracerebroventricular infusion of 100 ng/hour and 500 ng/hour of alpha-human atrial natriuretic polypeptide preferentially suppressed the intake of 0.30 M NaCl solution and attenuated the elevated preference for the hypertonic saline in spontaneously hypertensive rats while centrally infused alpha-human atrial natriuretic polypeptide had no significant effects on drinking behavior in Wistar-Kyoto rats. Blood pressure did not change significantly throughout the experiment in either rat strain. It is concluded that the exaggerated salt appetite in spontaneously hypertensive rats is blunted by centrally administered atrial natriuretic polypeptide. Such an effect of atrial natriuretic polypeptide along with its antidipsogenic effect suggests that brain atrial natriuretic polypeptide plays a role in water and electrolyte homeostasis and in blood pressure control.