β-hairpin-mediated formation of structurally distinct multimers of neurotoxic prion peptides

Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

S

CARDIOVASCULAR MEDICINE C reactive protein concentration and recurrence of atrial fibrillation after electrical cardioversion

Background: To test the hypothesis that a high C reactive protein (CRP) concentration would predict recurrence of atrial fibrillation (AF) after cardioversion in patients taking antiarrhythmic drugs. Methods: 111 patients who underwent direct current cardioversion for symptomatic AF were enrolled. Blood was drawn for CRP determination before cardioversion on the same day. All patients were taking antiarrhythmic drugs before and after electrical cardioversion. Results: After a mean follow up of 76 days, 75 patients had recurrence of AF. In univariate analysis, the median CRP concentration was significantly higher in patients with AF recurrence (3.95 mg/l v 1.81 mg/l, p = 0.002). Among the 55 patients with CRP in the upper 50th centile, 44 (80%) experienced recurrence of AF over a total follow up of 8.98 patient years, whereas among the 56 patients with CRP in the lower 50th centile, 31 (55%) experienced recurrence of AF over a total follow up of 14.3 patient years (p , 0.001). The adjusted hazard ratio comparing the upper 50th centile of CRP with the lower 50th centile of CRP was 2.0 (95% confidence interval 1.2 to 3.2, p = 0.007). Conclusions: CRP is independently associated with recurrence of AF after electrical cardioversion among patients taking antiarrhythmic drugs. These results suggest that inflammation may have a role in the pathogenesis of AF resistant to antiarrhythmic drugs

Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC

Predictive factors for overactive bladder symptoms after pelvic organ prolapse surgery

Contains fulltext : 89696.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: This study focussed on the factors which predict the presence of symptoms of overactive bladder (OAB) after surgery for pelvic organ prolapse (POP). METHODS: Consecutive women who underwent POP surgery with or without the use of vaginal mesh materials in the years 2004-2007 were included. Assessments were made preoperatively and at follow-up, including physical examination (POP-Q) and standardised questionnaires (IIQ, UDI and DDI). RESULTS: Five hundred and five patients were included with a median follow-up of 12.7 (6-35) months. Bothersome OAB symptoms decreased after POP surgery. De novo bothersome OAB symptoms appeared in 5-6% of the women. Frequency and urgency were more likely to improve as compared with urge incontinence and nocturia. The best predictor for the absence of postoperative symptoms was the absence of preoperative bothersome OAB symptoms. CONCLUSION: The absence of bothersome OAB symptoms preoperatively was the best predictor for the absence of postoperative symptoms.1 september 201

Novel features of ARS selection in budding yeast Lachancea kluyveri

<p>Abstract</p> <p>Background</p> <p>The characterization of DNA replication origins in yeast has shed much light on the mechanisms of initiation of DNA replication. However, very little is known about the evolution of origins or the evolution of mechanisms through which origins are recognized by the initiation machinery. This lack of understanding is largely due to the vast evolutionary distances between model organisms in which origins have been examined.</p> <p>Results</p> <p>In this study we have isolated and characterized autonomously replicating sequences (ARSs) in <it>Lachancea kluyveri </it>- a pre-whole genome duplication (WGD) budding yeast. Through a combination of experimental work and rigorous computational analysis, we show that <it>L. kluyveri </it>ARSs require a sequence that is similar but much longer than the ARS Consensus Sequence well defined in <it>Saccharomyces cerevisiae</it>. Moreover, compared with <it>S. cerevisiae </it>and <it>K. lactis</it>, the replication licensing machinery in <it>L. kluyveri </it>seems more tolerant to variations in the ARS sequence composition. It is able to initiate replication from almost all <it>S. cerevisiae </it>ARSs tested and most <it>Kluyveromyces lactis </it>ARSs. In contrast, only about half of the <it>L. kluyveri </it>ARSs function in <it>S. cerevisiae </it>and less than 10% function in <it>K. lactis</it>.</p> <p>Conclusions</p> <p>Our findings demonstrate a replication initiation system with novel features and underscore the functional diversity within the budding yeasts. Furthermore, we have developed new approaches for analyzing biologically functional DNA sequences with ill-defined motifs.</p