Modeling Nonlinear Synaptic Dynamics: A Laguerre-Volterra Network Framework for Improved Computational Efficiency in Large Scale Simulations.

Synapses are key components in signal transmission in the brain, often exhibiting complex non-linear dynamics. Yet, they are often crudely modelled as linear exponential equations in large-scale neuron network simulations. Mechanistic models that use detailed channel receptor kinetics more closely replicate the nonlinear dynamics observed at synapses, but use of such models are generally restricted to small scale simulations due to their computational complexity. Previously, we have developed an ``input-output'' (IO) synapse model using the Volterra functional series to estimate nonlinear synaptic dynamics. Here, we present an improvement on the IO synapse model using the extbf{Laguerre-Volterra network (LVN) framework. We demonstrate that utilization of the LVN framework helps reduce memory requirements and improves the simulation speed in comparison to the previous iteration of the IO synapse model. We present results that demonstrate the accuracy, memory efficiency, and speed of the LVN model that can be extended to simulations with large numbers of synapses. Our efforts enable complex nonlinear synaptic dynamics to be modelled in large-scale network models, allowing us to explore how synaptic activity may influence network behavior and affects memory, learning, and neurodegenerative diseases.

Evolution of the management of acquired neurogenic bladder in children using intradetrusor botulinum toxin type A injections: 5-year experience and perspectives.

OBJECTIVE: To report the clinical and urodynamic results of repeated intradetrusor botulinum toxin type A injections in children with an acquired neurogenic bladder. PATIENTS AND METHOD: We reviewed the data of 8 patients presenting an acquired neurogenic bladder treated between 2005 and 2010. Their mean age was 12.4 years old (range: 5-18). They were all on clean intermittent catheterization. All patients presented detrusor overactivity resistant to oral anticholinergic treatment. They received between 2 and 6 injections at a dose of 12 botulinum toxin units (BU)/kg (maximum 300 BU). Cystometry was performed 4-8 weeks after treatment. RESULTS: Five patients became completely dry, 2 were only rarely wet, and data are lacking for 1 patient. Febrile urinary tract infections ceased after 1 or 2 injections. The mean maximal detrusor pressure decreased below 40 cmH(2)O after 1, 2 and 3 injections. The normalized safe capacity rose significantly after 1, 2 and 3 injections. The normalized maximal bladder capacity rose similarly after 1, 2 and 3 injections although not always significantly. CONCLUSION: Intradetrusor botulinum toxin-A injections significantly reduce detrusor pressure and can be repeated with efficacy. They have their place in between anticholinergic treatment and surgery. The procedure could be simplified and the dosage reduced.

Inbreeding in the greater white-toothed shrew, Crocidura russula.

We combined mark-and-recapture studies with genetic techniques of parentage assignment to evaluate the interactions between mating, dispersal, and inbreeding, in a free-ranging population of Crocidura russula. We found a pattern of limited and female-biased dispersal, followed by random mating within individual neighborhoods. This results in significant inbreeding at the population level: mating among relatives occurs more often than random, and F(IT) analyses reveal significant deficits in heterozygotes. However, related mating partners were not less fecund, and inbred offspring had no lower lifetime reproductive output. Power analyses show these negative results to be quite robust. Absence of phenotypic evidence of inbreeding depression might result from a history of purging: local populations are small and undergo disequilibrium gene dynamics. Dispersal is likely caused by local saturation and (re)colonization of empty breeding sites, rather than inbreeding avoidance.

Individual reproductive success and effective population size in the greater white-toothed shrew Crocidura russula.

In order to investigate the determinants of effective population size in the socially monogamous Crocidura russula, the reproductive output of 44 individuals was estimated through genetic assignment methods. The individual variance in breeding success turned out to be surprisingly high, mostly because the males were markedly less monogamous than expected from previous behavioural data. Males paired simultaneously with up to four females and polygynous males had significantly more offspring than monogamous ones. The variance in female reproductive success also exceeded that of a Poisson distribution (though to a lesser extent), partly because females paired with multiply mated males weaned significantly more offspring. Polyandry also occurred occasionally, but only sequentially (i.e. without multiple paternity of litters). Estimates of the effective to census size ratio were ca. 0.60, which excluded the mating system as a potential explanation for the high genetic variance found in this shrew's populations. Our data suggest that gene flow from the neighbourhood (up to one-third of the total recruitment) is the most likely cause of the high levels of genetic diversity observed in this shrew's subpopulations.

Antiproliferative effects of SR31747A in animal cell lines are mediated by inhibition of cholesterol biosynthesis at the sterol isomerase step.

SR31747A is a new sigma ligand exhibiting immunosuppressive properties and antiproliferative activity on lymphocyte cells. Only two subtypes of sigma receptor, namely the sigma1 receptor and emopamil-binding protein, have been characterised molecularly. Only the sigma1 receptor has been shown to bind (Z)N-cyclohexyl-N-ethyl-3-(3-chloro4-cyclohexylphenyl)pro pen-2-ylamine hydrochloride (SR31747A) with high affinity. It was demonstrated that the SR31747A effect on the inhibition of T-cell proliferation was consistent with a sigma1 receptor-mediated event. In this report, binding experiments and sterol isomerase assays, using recombinant yeast strains, indicate that the recently cloned emopamil-binding protein is a new SR31747A-binding protein whose activity is inhibited by SR31747A. Sterol analyses reveal the accumulation of a delta8-cholesterol isomer at the expense of cholesterol in SR31747A-treated cells, suggesting that cholesterol biosynthesis is inhibited by SR31747A at the delta8-delta7 sterol isomerase step in animal cells. This observation is consistent with a sterol isomerase role of the emopamil-binding protein in the cholesterol biosynthetic pathway in animal cells. In contrast, there is no evidence for such a role of the sigma1 receptor, in spite of the structural similarity shared by this protein and yeast sterol isomerase. We have found that SR31747A also exerts anti-proliferative effects at nanomolar concentrations on various established cell lines. The antiproliferative activity of SR31747A is reversed by cholesterol. Sterol-isomerase overproduction enhances resistance of CHO cells. This last observation strongly suggests that sterol isomerase is implicated in the antiproliferative effect of the drug in established cell lines.

Both the immunosuppressant SR31747 and the antiestrogen tamoxifen bind to an emopamil-insensitive site of mammalian Delta8-Delta7 sterol isomerase.

SR31747 is a novel agent that elicits immunosuppressive and anti-inflammatory effects. This drug was shown to inhibit Delta8-Delta7 sterol isomerase in yeast. To test whether this enzyme could also be an SR31747 target in mammals, the binding, antiproliferative and sterol biosynthesis inhibitory properties of various drugs were studied in recombinant sterol isomerase-producing yeast cells. Our results clearly show that SR31747 is a high affinity ligand of recombinant mammalian sterol isomerase (Kd = 1 nM). Tridemorph, a sterol biosynthesis inhibitor that is widely used in agriculture as an antifungal agent, is also a powerful inhibitor of murine and human sterol isomerases (IC50 value in the nanomolar range). Some drugs, like cis-flupentixol, trifluoperazine, 7-ketocholestanol and tamoxifen, inhibit SR31747 binding only with the mammalian enzymes, whereas other drugs, like haloperidol and fenpropimorph, are much more effective with the yeast enzyme than with the mammalian ones. Emopamil, a high affinity ligand of human sterol isomerase, is inefficient in inhibiting SR31747 binding to its mammalian target, suggesting that the SR31747 and emopamil binding sites on mammalian sterol isomerase do not overlap. In contrast, SR31747 binding inhibition by tamoxifen is very efficient and competitive (IC50 value in the nanomolar range), indicating that mammalian sterol isomerase contains a so-called antiestrogen binding site. Tamoxifen is found to selectively inhibit sterol biosynthesis at the sterol isomerase step in the cells that are producing the mammalian enzyme in place of their own sterol isomerase. Finally, we also show that tridemorph, a sterol biosynthesis inhibitor widely used in agriculture as an antifungal agent, is not selective of yeast Delta8-Delta7 sterol isomerase but is also highly efficient against murine Delta8-Delta7 sterol isomerase or human Delta8-Delta7 sterol isomerase. This observation contrasts with our already published results showing that fenpropimorph, another sterol isomerase inhibitor used in agriculture, is only poorly efficient against the mammalian enzymes.

Isolation of an IL-13-dependent subclone of the B9 cell line useful for the estimation of human IL-13 bioactivity.

A novel sub-clone of the B9 hybridoma cell line (B9-1-3) has been selected by cloning following continuous culture in rhIL-13. This cell line shows an increased sensitivity to both hIL-13 and mIL-4 compared to the parental B9 cell line. The proliferative response to IL-13 can be blocked with an anti-IL-4 receptor monoclonal antibody but not with the soluble IL-4 receptor, suggesting that IL-13- and IL-4-binding receptor subunits are distinct but form part of a common receptor complex. Although the B9-1-3 cell line is still sensitive to picogrammes of IL-6, it can be used to measure IL-13 in the presence of IL-6 by inclusion of excess neutralizing IL-6 antibody. This cell line should thus prove useful both in measuring the IL-13 bioactivity and for the dissection of the molecular nature of the IL-13:IL-4 receptor complex.