58 050 patients entering 1086 hospitals up to 24 h (median 8 h) after the onset of suspected acute myocardial infarction (Ml) with no clear contraindications to the study treatments (in particular, ...no cardiogenic shock or persistent severe hypotension) were randomised in a "2 x 2 x 2 factorial" study. The treatment comparisons were: (i) 1 month of oral captopril (6·25 mg initial dose titrated up to 50 mg twice daily) versus matching placebo; (ii) 1 month of oral controlled-release mononitrate (30 mg initial dose titrated up to 60 mg once daily) versus matching placebo; and (iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus followed by 72 mmol) versus open control. There were no significant "interactions" between the effects of these three treatments, and the results for each are based on the randomised comparison of about 29 000 active versus 29 000 control allocated patients. Captopril There was a significant 7% (SD 3) proportional reduction in 5-week mortality (2088 7·19% captopril-allocated deaths vs 2231 7·69% placebo; 2p=0·02), which corresponds to an absolute difference of 4·9 SD 2·2 fewer deaths per 1000 patients treated for 1 month. The absolute benefits appeared to be larger (perhaps about 10 fewer deaths per 1000) in certain higher-risk groups, such as those presenting with a history of previous Ml or with heart failure. The survival advantage appeared to be maintained in the longer term (5·4 SD 2·8 fewer deaths per 1000 at 12 months). Captopril was associated with an increase of 52 (SD 2) patients per 1000 in hypotension considered severe enough to require termination of study treatment, of 5 (SD 2) per 1000 in reported cardiogenic shock, and of 5 (SD 1) per 1000 in some degree of renal dysfunction. It produced no excess of deaths on days 0-1, even among patients with low blood pressure at entry. Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 7·34% mononitrate-allocated deaths vs 2190 7·54% placebo) or in any subgroup examined (including those not receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did not indicate any later survival advantage. The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension. Those allocated active treatment had somewhat fewer deaths on days 0-1, which is reassuring about the safety of using nitrates early in acute MI. Magnesium There was no significant reduction in 5-week mortality, either overall (2216 7·64% magnesium- allocated deaths vs 2103 7·24% control) or in any subgroup examined (including those treated early or late after symptom onset or in the presence or absence of fibrinolytic or antiplatelet therapies, or those at high risk of death). Further follow-up did not indicate any later survival advantage. In contrast with some previous small trials, there was a significant excess with magnesium of 12 (SD 3) per 1000 in heart failure and of 5 (SD 2) per 1000 in reported cardiogenic shock during or just after the infusion period. Magnesium was also associated with an increase of 11 (SD 2) per 1000 in hypotension considered severe enough to require termination of study treatment, of 3 (SD 0·6) per 1000 in bradycardia, and of 3 (SD 0·4) per 1000 in a cutaneous flushing or burning sensation (but assessment of magnesium involved open control). There was no evidence of a net adverse effect on mortality on days 0-1. Because of its size, ISIS-4 provides reliable evidence about the effects of adding each of these three treatments to established treatments for acute Ml. Intravenous magnesium was ineffective, and although oral nitrate therapy appeared safe it did not produce a clear reduction in 1-month mortality. Other trials have shown that starting long-term converting enzyme inhibitor (CEI) therapy in the weeks or months after Ml in patients with impaired ventricular function avoids about 2 deaths per 1000 patients per month of treatment. ISIS-4, GISSI-3, and smaller studies now collectively demonstrate that, for a wide range of patients without clear contraindications, CEI therapy started early in acute MI prevents about 5 deaths per 1000 in the first month (2p=0·006), with somewhat greater benefits in higher-risk patients. This benefit from 1 month of early CEI treatment seems to persist for at least the first year.
233U is of key importance among the fissile nuclei in the Th-U fuel cycle. A particularity of 233U is its small neutron capture cross-section, which is on average about one order of magnitude lower ...than the fission cross-section. The accuracy in the measurement of the 233U capture cross-section depends crucially on an efficient capture-fission discrimination, thus a combined set-up of fission and γ-detectors is needed. A measurement of the 233U capture cross-section and capture-to-fission ratio was performed at the CERN n_TOF facility. The Total Absorption Calorimeter (TAC) of n_TOF was employed as γ-detector coupled with a novel compact ionization chamber as fission detector. A brief description of the experimental set-up will be given, and essential parts of the analysis procedure as well as the preliminary response of the set-up to capture are presented and discussed.
It has been understood since 1897 that accelerating charges should emit electromagnetic radiation. Cyclotron radiation, the particular form of radiation emitted by an electron orbiting in a magnetic ...field, was first derived in 1904. Despite the simplicity of this concept, and the enormous utility of electron spectroscopy in nuclear and particle physics, single-electron cyclotron radiation has never been observed directly. Here we demonstrate single-electron detection in a novel radiofrequency spectrometer. We observe the cyclotron radiation emitted by individual electrons that are produced with mildly-relativistic energies by a gaseous radioactive source and are magnetically trapped. The relativistic shift in the cyclotron frequency permits a precise electron energy measurement. Precise beta electron spectroscopy from gaseous radiation sources is a key technique in modern efforts to measure the neutrino mass via the tritium decay endpoint, and this work is a proof-of-concept for future neutrino mass experiments using this technique.
Fission program at n_TOF Tassan-Got, L.; Colonna, N.; Eleme, Z. ...
EPJ Web of Conferences,
2019, Letnik:
211
Journal Article, Conference Proceeding, Publication
Recenzirano
Odprti dostop
Since its start in 2001 the n_TOF collaboration developed a measurement program on fission, in view of advanced fuels in new generation reactors. A special effort was made on measurement of cross ...sections of actinides, exploiting the peculiarity of the n_TOF neutron beam which spans a huge energy domain, from the thermal region up to GeV. Moreover fission fragment angular distributions have also been measured. An overview of the cross section results achieved with different detectors is presented, including a discussion of the
237
Np case where discrepancies showed up between different detector systems. The results on the anisotropy of the fission fragments and its implication on the mechanism of neutron absorption, and in applications, are also shown.
Oxidative damage of endothelial tight junction permeability is involved in the pathophysiology of a variety of vascular diseases. The authors studied the role of the antioxidant enzyme, human ...glutathione-S-transferase A4-4 (hGSTA4-4), in regulating expression of major molecules of tight junction in vascular endothelial cells under oxidative stress induced by H2O2. A vascular endothelial cell line, mouse pancreatic endothelial cells (MS1), was transduced with recombinant adenoviral vector containing hGSTA4-4 gene. hGSTA4-4 induced expression of tight junction proteins occludin and zonula occludens (ZO)-1 under oxidative stress. Increased hGSTA4-4 expression correlated with increased transepithelial electrical resistance and decreased tyrosine phosphorylation of occludin and ZO-1 following exposure to H2O2. In addition, morphologic dissociation of occludin, ZO-1, and F-actin during oxidative stress was reduced in hGSTA4-4-expressing cells. To explore a genetic approach for vascular diseases associated with disruption of tight junction proteins, we introduced the same viral vector to blood vessels of mice, rats, and rabbits ex vivo and found strong expression of hGSTA4-4 in endothelial cells. These results demonstrate that oxidative stress mediated disruption of tight junctions in endothelial cells may be attenuated by hGSTA4-4 expression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Tumor suppressor genes, whose products are required for the control of cell proliferation, have been identified by their mutant phenotype of tissue overgrowth. Here we describe recent work on the ...molecular identification of tumor suppressor genes that function in two different cell types of the Drosophila larva: the blood cells, and the undifferentiated epithelial cells of developing imaginal discs. Mutations in the aberrant immune response8 (air8) gene lead to overproduction and precocious differentiation of blood cells. This gene encodes the Drosophila homolog of human ribosomal protein S6. The mutant phenotype is consistent with a role for S6 in the control of cell proliferation, and is compatible with findings from mammalian cells where alterations in S6 expression and phosphorylation are associated with changes in cell proliferation. Mutations in the discs large (dlg) gene cause neoplastic overgrowth of imaginal discs in the larva. The mutant discs show loss of septate junctions and of apical-basal cell polarity, and they also lose the ability to differentiate cuticular structures. The dlg protein product (DlgA) is localized at septate junctions between epithelial cells, and cDNA sequencing indicates that the gene product includes a domain with homology to guanylate kinase (GUK). Two mammalian homologs of this gene have been identified, and one of them (PSD-95/SAP90) encodes a component of synaptic densities in the brain; this protein therefore resembles the DlgA protein in being located in a specialized cell junction that functions in information transfer between cells. Mutations in the fat gene cause hyperplastic imaginal disc overgrowth, in which the overgrowing disc tissue retains its epithelial structure and its ability to differentiate. Some of the excess disc tissue is shed as vesicles suggesting a loss of cell adhesion. In support of this hypothesis, the predicted gene product shows homology to cadherins in its extracellular domain. However, the fat protein is much larger than known cadherins. As in human cancer, somatic loss of the normal alleles of tumor suppressor genes can lead to tumor formation in Drosophila; an example of this is provided by the warts (wts) locus. The wts gene was identified by the dramatic overgrowth of mitotic recombination clones that are homozygous for a wts deletion. In these clones the cuticle intrudes between epithelial cells, suggesting an alteration in cell adhesion. The study of these and other tumor suppressor genes in Drosophila is providing new evidence supporting the critical role of cell interactions and specialized apical junctions in controlling epithelial cell proliferation.
ABSTRACT Genetic analysis in Drosophila has led to the identification of several proteins that mediate cell-cell interactions controlling the fate and proliferation of epithelial cells. These ...proteins are localized or enriched in the adherens and septate junctions at the apical end of the lateral membranes between cells. The proteins localized or enriched at adherens junctions include Notch, which is important for the cell interactions controlling neuroblast and bristle patterning; Boss and sevenless, which are required for the cell interaction that establishes the R7 photoreceptor cell; and Armadillo, required for the wingless-dependent cell interactions that control segment polarity and imaginai disc patterning. Proteins localized at septate junctions include the product of the tumor suppressor gene dig, which is required for septate junction formation, apical basal cell polarity, and the cell interactions that control proliferation. The results suggest that the cell signalling events important for cell fate determination and for cell proliferation control in epithelia occur at the apical junctions. The migration of the nucleus to the apical surface of the epithelium for mitosis may enable it to interact directly with the junction-associated signalling mechanisms.
We report the molecular characterization of rotavirus genotype P8G5 strains found in fecal specimens collected in four different regions of Brazil, using digoxigenin(dig)-labeled oligonucleotide ...probes, sequence analysis, and RNA-RNA hybridization. The closest sequence relationships of the neutralization antigens of these strains were to the VP4 protein of P1A8G1 strain KU (93.3% identity in amino acids 11 to 282) and to the VP7 protein of G serotype 5 strain OSU (87.6% identity in amino acids 8 to 232). Based on VP7 sequence differences, we designed dig-probes that allowed us to discriminate porcine OSU-like strains from G5 strains isolated from Brazilian infants. The genetic relationships of two P8G5 isolates to other rotavirus genogroups were analyzed by RNA-RNA hybridization with 32P-GTP probes representative of serotypes P1A8G1 (Wa), P8G3 (AU17), and P97G5 (OSU). The Brazilian P8G5 strains showed sequence homology with genes of Wa-like and OSU-like strains, suggesting that these two strains were naturally occurring reassortants between members of the Wa and porcine rotavirus genogroups. The identification of these strains in diverse geographic areas of Brazil underscores their stability and demonstrates the emergence of clinically important rotavirus diarrhea strains by reassortment.
Background
Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose ...homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.
Methods
To improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.
Results
Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5).
Conclusions
Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.
Novel findings of this study include: the genetically predicted expressions of FOXA1, PSMC5 and CD33 modified the association of BMI on CRC risk for men; KIAA0753 and SCN1B modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes. These findings provide support for potential new biological insights that could help in understanding the underlying mechanisms of BMI and diabetes on CRC.
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