Party finance reform as constitutional engineering? The effectiveness and unintended consequences of party finance reform in France and Britain

In both Britain and France, party funding was traditionally characterized by a laissez faire approach and a conspicuous lack of regulation. In France, this was tantamount to a 'legislative vacuum'. In the last two decades, however, both countries have sought to fundamentally reform their political finance regulation regimes. This prompted, in Britain, the Political Parties, Elections and Referendums Act 2000, and in France a bout of 'legislative incontinence' — profoundly transforming the political finance regime between 1988 and 1995. This article seeks to explore and compare the impacts of the reforms in each country in a bid to explain the unintended consequences of the alternative paths taken and the effectiveness of the new party finance regime in each country. It finds that constitutional engineering through party finance reform is a singularly inexact science, largely due to the imperfect nature of information, the limited predictability of cause and effect, and the constraining influence of non-party actors, such as the Constitutional Council in France, and the Electoral Commission in Britain

MYOD1 involvement in myopathy

[Excerpt] Introduction Myogenic Differentiation 1 (MYOD1) encodes a transcription factor that plays an important role in myogenic determination into mature skeletal muscle [1]. The first loss-of-function mutation of MYOD1 in humans was described in three siblings with perinatal lethal fetal akinesia [2].[...]We thank the individual and family. Funding was provided by The Fonds de recherche du Québec - Santé (FRQS) and Canadian Institutes of Health Research (CIHR) to P.M.C., Fundação para a Ciência e Tecnologia (FCT) with the fellowship SFRH/BD/84650/2010 to F.L. and Groupe Pasteur Mutualité Foundation (GPM Foundation) to M.M.info:eu-repo/semantics/publishedVersio

The VICI-trial: high frequency oscillation versus conventional mechanical ventilation in newborns with congenital diaphragmatic hernia: an international multicentre randomized controlled trial

Background: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly of the diaphragm resulting in pulmonary hypoplasia and pulmonary hypertension. It is associated with a high risk of mortality and pulmonary morbidity. Previous retrospective studies have reported high frequency oscillatory ventilation (HFO) to reduce pulmonary morbidity in infants with CDH, while others indicated HFO to be associated with worse outcome. We therefore aimed to develop a randomized controlled trial to compare initial ventilatory treatment with high-frequency oscillation and conventional ventilation in infants with CDH.Methods/design: This trial is designed as a multicentre trial in which 400 infants (200 in each arm) will be included. Primary outcome measures are BPD, described as oxygen dependency by day 28 according to the definition of Jobe and Bancalari, and/or mortality by day 28. All liveborn infants with CDH born at a gestational age of over 34 weeks and no other severe congenital anomalies are eligible for inclusion. Parental informed consent is asked antenatally and the allocated ventilation mode starts within two hours after birth. Laboratory samples of blood, urine and tracheal aspirate are taken at the first day of life, day 3, day 7, day 14 and day 28 to evaluate laboratory markers for ventilator-induced lung injury and pulmonary hypertension.Discussion: To date, randomized clinical trials are lacking in the field of CDH. The VICI-trial, as the first randomized clinical trial in the field of CDH, may provide further insight in ventilation strategies in CDH patient. This may hopefully prevent mortality and morbidity.Trial registration: Netherlands Trial Register (NTR): NTR1310

New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria

BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for beta-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. METHODOLOGY/PRINCIPAL FINDINGS: Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. CONCLUSIONS: We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria.Eur-Intafa

Insights into the Binding of Phenyltiocarbamide (PTC) Agonist to Its Target Human TAS2R38 Bitter Receptor

Humans' bitter taste perception is mediated by the hTAS2R subfamily of the G protein-coupled membrane receptors (GPCRs). Structural information on these receptors is currently limited. Here we identify residues involved in the binding of phenylthiocarbamide (PTC) and in receptor activation in one of the most widely studied hTAS2Rs (hTAS2R38) by means of structural bioinformatics and molecular docking. The predictions are validated by site-directed mutagenesis experiments that involve specific residues located in the putative binding site and trans-membrane (TM) helices 6 and 7 putatively involved in receptor activation. Based on our measurements, we suggest that (i) residue N103 participates actively in PTC binding, in line with previous computational studies. (ii) W99, M100 and S259 contribute to define the size and shape of the binding cavity. (iii) W99 and M100, along with F255 and V296, play a key role for receptor activation, providing insights on bitter taste receptor activation not emerging from the previously reported computational models

Probenecid Inhibits the Human Bitter Taste Receptor TAS2R16 and Suppresses Bitter Perception of Salicin

Bitter taste stimuli are detected by a diverse family of G protein-coupled receptors (GPCRs) expressed in gustatory cells. Each bitter taste receptor (TAS2R) responds to an array of compounds, many of which are toxic and can be found in nature. For example, human TAS2R16 (hTAS2R16) responds to β-glucosides such as salicin, and hTAS2R38 responds to thiourea-containing molecules such as glucosinolates and phenylthiocarbamide (PTC). While many substances are known to activate TAS2Rs, only one inhibitor that specifically blocks bitter receptor activation has been described. Here, we describe a new inhibitor of bitter taste receptors, p-(dipropylsulfamoyl)benzoic acid (probenecid), that acts on a subset of TAS2Rs and inhibits through a novel, allosteric mechanism of action. Probenecid is an FDA-approved inhibitor of the Multidrug Resistance Protein 1 (MRP1) transporter and is clinically used to treat gout in humans. Probenecid is also commonly used to enhance cellular signals in GPCR calcium mobilization assays. We show that probenecid specifically inhibits the cellular response mediated by the bitter taste receptor hTAS2R16 and provide molecular and pharmacological evidence for direct interaction with this GPCR using a non-competitive (allosteric) mechanism. Through a comprehensive analysis of hTAS2R16 point mutants, we define amino acid residues involved in the probenecid interaction that result in decreased sensitivity to probenecid while maintaining normal responses to salicin. Probenecid inhibits hTAS2R16, hTAS2R38, and hTAS2R43, but does not inhibit the bitter receptor hTAS2R31 or non-TAS2R GPCRs. Additionally, structurally unrelated MRP1 inhibitors, such as indomethacin, fail to inhibit hTAS2R16 function. Finally, we demonstrate that the inhibitory activity of probenecid in cellular experiments translates to inhibition of bitter taste perception of salicin in humans. This work identifies probenecid as a pharmacological tool for understanding the cell biology of bitter taste and as a lead for the development of broad specificity bitter blockers to improve nutrition and medical compliance

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes