Prothrombin G20210A is a bifunctional gene polymorphism

The G20210A polymorphism has been shown to alter the efficiency of prothrombin mRNA processing. Here we show that the G20210A mutation also alters prothrombin mRNA stability. Three-fold more prothrombin protein and mRNA were produced in NIH-3T3 cells transfected with the prothrombin cDNAs containing the 20210A variant compared to cells expressing the 20210G variant. mRNA stability assays using chimeric globin transcripts harboring the G or A variant of the 97 nt prothrombin 3′ UTR indicated that the 20210G variant conferred greater instability to the globin reporter transcript than the A variant in transfected HepG2 cells. Both variants of the prothrombin 3′-UTR were shown to provide binding sites for a number of cellular proteins including HuR, an RNA binding protein associated with mRNA stability. Our results indicate that the G20210A is a bifunctional polymorphism, as it not only alters the efficiency of mRNA processing, but also the decay rate of prothrombin mRNA

Du hang gliding au vol libre : l'émergence d'un 'sport californien' en France dans les années 1970

En préalable : caractérisation des sports californiens et de leur rôle de contre-culture dans l'histoire des sports. Comparaison des valeurs et de la définition éthique du vol libre des pilotes-précurseurs en France avec l'approche et les conditions de pratique des adeptes du hang gliding californien. Illustration de la complexité des processus à l'oeuvre dans l'importation, la diffusion et la légitimation de nouvelles modalités de pratiques sportives

Tranexamic acid alters the immunophenotype of phagocytes after lower limb surgery

Background: Tranexamic acid (TXA) is an antifibrinolytic agent frequently used in elective surgery to reduce blood loss. We recently found it also acts as a potent immune-modulator in patients undergoing cardiac surgery. Methods: Patients undergoing lower limb surgery were enrolled into the “Tranexamic Acid in Lower Limb Arthroplasty” (TALLAS) pilot study. The cellular immune response was characterised longitudinally pre- and postoperatively using full blood examination (FBE) and comprehensive immune cell phenotyping by flowcytometry. Red blood cells and platelets were determined in the FBE and levels of T cell cytokines and the plasmin-antiplasmin complex determined using ELISA. Results: TXA administration increased the proportion of circulating CD141+ conventional dendritic cells (cDC) on post-operative day (POD) 3. It also reduced the expression of CD83 and TNFR2 on classical monocytes and levels of circulating IL-10 at the end of surgery (EOS) time point, whilst increasing the expression of CCR4 on natural killer (NK) cells at EOS, and reducing TNFR2 on POD-3 on NK cells. Red blood cells and platelets were decreased to a lower extent at POD-1 in the TXA group, representing reduced blood loss. Conclusion: In this investigation we have extended our examination on the immunomodulatory effects of TXA in surgery by also characterising the end of surgery time point and including B cells and neutrophils in our immune analysis, elucidating new immunophenotypic changes in phagocytes as well as NK cells. This study enhances our understanding of TXA-mediated effects on the haemostatic and immune response in surgery, validating changes in important functional immune cell subsets in orthopaedic patients.Dominik F. Draxler, Gryselda Hanafi, Saffanah Zahra, Fiona McCutcheon, Heidi Ho, Charithani B. Keragala, Zikou Liu, David Daly, Thomas Painter, Sophia Wallace, Magdalena Plebanski, Paul S. Myles, and Robert L. Medcal

Plasminogen activator inhibitor type-2 (PAI-2) gene transcription requires a novel NF-kappaB-like transcriptional regulatory motif

Induction of human plasminogen activator inhibitor type-2 (PAI-2) gene transcription is the response of macrophages to inflammatory stimuli, such as the pleiotropic cytokine, tumour necrosis factor-α (TNFα). Here we have examined whether PAI-2 gene transcription in response to TNFα may be mediated through a regulatory pathway involving the transcription factor, NF-κB. We have tested the function of two potential NF-κB-like sites present in the PAI-2 proximal promoter for responsiveness to TNFα using chloramphenicol acetyl transferase reporter gene deletion and mutation analyses. While no evidence was found for TNFα regulation of the PAI-2 gene through either of these two sites, one of the NF-κB-like motifs, transcriptional regulatory motif (TRM), present at position −400 was found to be essential for constitutive PAI-2 transcription, as mutation of this motif abolished basal PAI-2 promoter activity in both monocyte-like U937 cells and HT1080 fibrosarcoma cells. Competition electrophoretic mobility shift assays identified four TRM-binding proteins present in U937, HT1080 and HeLa cell extracts, which bound to this motif but were not components of the NF-κB regulatory complex. Expression screening of a HeLa cell cDNA library using the −400 TRM as a probe identified two cDNAs encoding partial peptides which specifically bound the TRM motif. DNA sequence analysis revealed that one cDNA was novel, and the second cDNA encoded exon 5 of the nephroblastoma overexpressed (novH) proto-oncogene, suggesting a new role for this peptide in gene regulation. Taken together, these findings identify a new regulatory element required for constitutive PAI-2 transcription, and identify potential DNA-binding proteins associated with this element that may play a role in PAI-2 gene regulation

Electroweak measurements in electron–positron collisions at w-boson-pair energies at lep

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