New competitive inhibitors of cytosolic (NADH-dependent) rabbit muscle glycerophosphate dehydrogenase

We report the synthesis and biochemical evaluation of new competitive inhibitors of the cytosolic (NADH-dependent) glycerophosphate dehydrogenase. The best tested compound, phosphono-propionohydroxamic acid, with a Ki of 6 microM, might be of interest as an anti-obesity drug.     

Seasonal encoding by the circadian pacemaker of the SCN

The circadian pacemaker of the suprachiasmatic nucleus (SCN) functions as a seasonal clock through its ability to encode day length [1-6]. To investigate the mechanism by which SCN neurons code for day length, we housed mice under long (LD 16:8) and short (LD 8:16) photoperiods. Electrophysiological recordings of multiunit activity (MUA) in the SCN of freely moving mice revealed broad activity profiles in long days and compressed activity profiles in short days. The patterns remained consistent after release of the mice in constant darkness. Recordings of MUA in acutely prepared hypothalamic slices showed similar differences between the SCN electrical activity patterns in vitro in long and short days. In vitro recordings of neuronal subpopulations revealed that the width of the MUA activity profiles was determined by the distribution of phases of contributing units within the SCN. The subpopulation patterns displayed a significantly broader distribution in long days than in short days. Long-term recordings of single-unit activity revealed short durations of elevated activity in both short and long days (3.48 and 3.85 hr, respectively). The data indicate that coding for day length involves plasticity within SCN neuronal networks in which the phase distribution of oscillating neurons carries information on the photoperiod's duration.     

Pyrazolone methylamino piperidine derivatives as novel CCR3 antagonists

The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.     

Spatial models of political competition with endogenous political parties

Two important human action selection processes are the choice by citizens of parties to support in elections and the choice by party leaders of policy 'packages' offered to citizens in order to attract this support. Having reviewed approaches analysing these choices and the reasons for doing this using the methodology of agent-based modelling, we extend a recent agent-based model of party competition to treat the number and identity of political parties as an output of, rather than an input to, the process of party competition. Party birth is modelled as an endogenous change of agent type from citizen to party leader, which requires describing citizen dissatisfaction with the history of the system. Endogenous birth and death of parties transforms into a dynamic system even in an environment where all agents have otherwise non-responsive adaptive rules. A key parameter is the survival threshold, with lower thresholds leaving citizens on average less dissatisfied. Paradoxically, the adaptive rule most successful for party leaders in winning votes makes citizens on average less happy than under other policy-selection rules.     

Cationic lipids involved in gene transfer mobilize intracellular calcium

Cationic lipids are efficient tools to introduce nucleic acids and proteins into cells. Elucidation of the mechanism and cellular pathways associated with such transport has been relatively tedious, even though significant progress has been made in the characterization of the intracellular trafficking of lipid/DNA complexes. Surprisingly little is known about the effects of these delivery vectors on cell functioning. In this report, we show that both cationic lipids and cationic lipid/DNA complexes mobilize the intracellular calcium. Removal of extracellular calcium did not significantly abolish this effect and preincubating cells with thapsigargin led to a decrease in [Ca2+]i, indicating that calcium was released mainly from internal calcium stores sensitive to thapsigargin. Pretreatment of the cells with the phospholipase C inhibitor U73122, blocked the [Ca2+]i rise, suggesting an inositol dependent mechanism.     

High affinity Grb2-SH3 domain ligand incorporating Cbeta-substituted prolines in a Sos-derived decapeptide

Peptide ligands that disrupt MAPK pathways are of great interest for a better understanding of these signalling cascades and represent therefore an attractive target to control cell degenerative processes. In that context, selective disruption of the upstream Grb2/Sos complex in the Ras/MAPK cascade has focused extensive work. The Sos PPII decapeptide, which interacts with the Grb2-SH3 domains, has been modified in various positions and the best inhibitors designed so far are either dimeric ligands or peptoid analogues of the VPPPVPPRRR sequence. We report the synthesis of new Grb2 ligands in which the key Val5 residue has been replaced by a cis C(beta)-substituted proline. Both fluorescence and ITC assays have been employed to measure the affinity of these substituted peptides for a recombinant Grb2 protein. Whereas proline in position 5 completely abolished the binding potency, a cis C(beta)-methyl-L-proline restored the affinity. Other cis C(beta)-proline substituents led to a complete loss of binding potency. Combining the best modifications: a cis C(beta)-methylproline 5, N-acetylation, C-carboxamide and dimerization yielded a 560-fold affinity enhancement compared to the wild-type VPPPVPPRRR sequence. This study shows that C(beta)-substituted prolines may constitute a new alternative for PPII ligands, combining entropy and enthalpy beneficial effects.     

Phrenic nerve injury after catheter ablation of atrial fibrillation

Phrenic Nerve Injury (PNI) has been well studied by cardiac surgeons. More recently it has been recognized as a potential complication of catheter ablation with a prevalence of 0.11 to 0.48 % after atrial fibrillation (AF) ablation. This review will focus on PNI after AF ablation. Anatomical studies have shown a close relationship between the right phrenic nerve and it's proximity to the superior vena cava (SVC), and the antero-inferior part of the right superior pulmonary vein (RSPV). In addition, the proximity of the left phrenic nerve to the left atrial appendage has been well established. Independent of the type of ablation catheter (4 mm, 8 mm, irrigated tip, balloon) or energy source used (radiofrequency (RF), ultrasound, cryothermia, and laser); the risk of PNI exists during ablation at the critical areas listed above. Although up to thirty-one percent of patients with PNI after AF ablation remain asymptomatic, dyspnea remain the cardinal symptom and is present in all symptomatic patients. Despite the theoretical risk for significant adverse effect on functional status and quality of life, short-term outcomes from published studies appear favorable with 81% of patients with PNI having a complete recovery after 7 +/- 7 months. CONCLUSION: Existing studies have described PNI as an uncommon but avoidable complication in patients undergoing pulmonary vein isolation for AF. Prior to ablation at the SVC, antero-inferior RSPV ostium or the left atrial appendage, pacing should be performed before energy delivery. If phrenic nerve capture is documented, energy delivery should be avoided at this site. Electrophysiologist's vigilance as well as pacing prior to ablation at high risk sites in close proximity to the phrenic nerve are the currently available tools to avoid the complication of PNI.     

Tracking the effects of one century of habitat loss and fragmentation on calcareous grassland butterfly communities

Habitat loss and fragmentation are known to reduce patch sizes and increase their isolation, consequently leading to modifications in species richness and community structure. Calcareous grasslands are among the richest ecosystems in Europe for insect species. About 10% (1,150 ha) of the total area of a calcareous ridge region (Calestienne, Belgium) and its butterfly community was analysed over a timeframe of about 100 years. Since 1905 to present day (2005), the Calestienne region has undergone both calcareous grassland loss and fragmentation: not only did calcareous grassland size decrease and isolation increase, but also, the number of calcareous grassland patches within the landscape increased until 1965, and subsequently decreased, clearly reflecting the effects of fragmentation. These processes have had a profound effect on the butterfly community: extinction and rarefaction affected significantly more often specialist species, which means that generalist species are more and more overrepresented. This ecological drift, i.e. the replacement of specialists by generalists in species assemblages is likely to be a general effect of habitat loss and fragmentation on natural communities.