Chopper, a new death domain of the p75 neurotrophin receptor that mediates rapid neuronal cell death

The cytoplasmic juxtamembrane region of the p75 neurotrophin receptor (p75(NTR)) has been found to be necessary and sufficient to initiate neural cell death. The region was named Chopper to distinguish it from CD95-like death domains. A 29-amino acid peptide corresponding to the Chopper region induced caspase- and calpain-mediated death in a variety of neural and nonneural cell types and was not inhibited by signaling through Trk (unlike killing by full-length p75(NTR)). Chopper triggered cell death only when bound to the plasma membrane by a lipid anchor, whereas non-anchored Chopper acted in a dominant-negative manner, blocking p75(NTR)-mediated death both in vitro and in vivo. Removal of the ectodomain of p75(NTR) increased the potency of Chopper activity, suggesting that it regulates the association of Chopper with downstream signaling proteins.

Structured modeling of recombinant protein production in batch and fed-batch culture of baculovirus-infected insect cells

The infection of insect cells with baculovirus was described in a mathematical model as a part of the structured dynamic model describing whole animal cell metabolism. The model presented here is capable of simulating cell population dynamics, the concentrations of extracellular and intracellular viral components, and the heterologous product titers. The model describes the whole processes of viral infection and the effect of the infection on the host cell metabolism. Dynamic simulation of the model in batch and fed-batch mode gave good agreement between model predictions and experimental data. Optimum conditions for insect cell culture and viral infection in batch and fed-batch culture were studied using the model.

Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes

omega -Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega -conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other omega -conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, omega -conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha (1B-d)) and peripheral (alpha (1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta (3) in Xenopus oocytes, However, the potency of CVID and MVIIA increased when alpha (1B-d) and alpha (1B-b) were expressed in the absence of rat beta (3), an effect most pronounced for CVID at alpha (1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha (1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. H-1 NMR studies reveal that CMD possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined.

Finite element modeling of fluid-rock interaction problems in pore-fluid saturated hydrothermal/sedimentary basins

In order to use the finite element method for solving fluid-rock interaction problems in pore-fluid saturated hydrothermal/sedimentary basins effectively and efficiently, we have presented, in this paper, the new concept and numerical algorithms to deal with the fundamental issues associated with the fluid-rock interaction problems. These fundamental issues are often overlooked by some purely numerical modelers. (1) Since the fluid-rock interaction problem involves heterogeneous chemical reactions between reactive aqueous chemical species in the pore-fluid and solid minerals in the rock masses, it is necessary to develop the new concept of the generalized concentration of a solid mineral, so that two types of reactive mass transport equations, namely, the conventional mass transport equation for the aqueous chemical species in the pore-fluid and the degenerated mass transport equation for the solid minerals in the rock mass, can be solved simultaneously in computation. (2) Since the reaction area between the pore-fluid and mineral surfaces is basically a function of the generalized concentration of the solid mineral, there is a definite need to appropriately consider the dependence of the dissolution rate of a dissolving mineral on its generalized concentration in the numerical analysis. (3) Considering the direct consequence of the porosity evolution with time in the transient analysis of fluid-rock interaction problems; we have proposed the term splitting algorithm and the concept of the equivalent source/sink terms in mass transport equations so that the problem of variable mesh Peclet number and Courant number has been successfully converted into the problem of constant mesh Peclet and Courant numbers. The numerical results from an application example have demonstrated the usefulness of the proposed concepts and the robustness of the proposed numerical algorithms in dealing with fluid-rock interaction problems in pore-fluid saturated hydrothermal/sedimentary basins. (C) 2001 Elsevier Science B.V. All rights reserved.

Neuronal sodium-channel alpha 1-subunit mutations in generalized epilepsy with febrile seizures plus

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel beta1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations-D188V, V1353L, and I1656M-were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%.

An L-system-based plant modeling language

Cpfg is a program for simulating and visualizing plant development, based on the theory of L-systems. A special-purpose programming language, used to specify plant models, is an essential feature of cpfg. We review postulates of L-system theory that have influenced the design of this language. We then present the main constructs of this language, and evaluate it from a user's perspective.

L-studio/cpfg: A software system for modeling plants

L-studio/cpfg is a plant modeling software system designed for Windows 95/98/NT platforms. Its key components are the L-system-based plant simulator cpfg and the modeling environment called L-studio. We overview version 1.0 of this system from the user's perspective.

Modeling of heat transfer in fluidized-bed coating of cylinders

A numerical model of heat transfer in fluidized-bed coating of solid cylinders is presented. By defining suitable dimensionless parameters, the governing equations and its associated initial and boundary conditions are discretized using the method of orthogonal collocation and the resulting ordinary differential equations simultaneously solved for the dimensionless coating thickness and wall temperatures. Parametric Studies showed that the dimensionless coating thickness and wall temperature depend on the relative heat capacities of the polymer powder and object, the latent heat of fusion and the size of the cylinder. Model predictions for the coating thickness and wall temperature compare reasonably well with numerical predictions and experimental coating data in the literature and with our own coating experiments using copper cylinders immersed in nylon-11 and polyethylene powders. (C) 2001 Elsevier Science Ltd. All rights reserved.

Channels underlying neuronal calcium-activated potassium currents

In many cell types rises in cytosolic calcium, either due to influx from the extracellular space, or by release from an intracellular store activates calcium dependent potassium currents on the plasmalemma. In neurons, these currents are largely activated following calcium influx via voltage gated calcium channels active during the action potentials. Three types of these currents are known: I-c. I-AHP and I-sAHP. These currents can be distinguished by clear differences in their pharmacology and kinetics. Activation of these potassium currents modulates action potential time course and the repetitive firing properties of neurons. Single channel studies have identified two types of calcium-activated potassium channel which can also be separated on biophysical and pharmacological grounds and have been named BK and SK channels. It is now clear that BK channels underlie Ic whereas SK channels underlie I-AHP. The identity of the channels underlying I-sAHP are not known. In this review, we discuss the properties of the different types of calcium-activated potassium channels and the relationship between these channels and the macroscopic currents present in neurons. (C) 2002 Elsevier Science Ltd. All rights reserved.

Mantle convection modeling with viscoelastic/brittle lithosphere: Numerical methodology and plate tectonic modeling

The earth's tectonic plates are strong, viscoelastic shells which make up the outermost part of a thermally convecting, predominantly viscous layer. Brittle failure of the lithosphere occurs when stresses are high. In order to build a realistic simulation of the planet's evolution, the complete viscoelastic/brittle convection system needs to be considered. A particle-in-cell finite element method is demonstrated which can simulate very large deformation viscoelasticity with a strain-dependent yield stress. This is applied to a plate-deformation problem. Numerical accuracy is demonstrated relative to analytic benchmarks, and the characteristics of the method are discussed.

Low-affinity neurotrophin receptor with targeted mutation of exon 3 is capable of mediating the death of axotomized neurons

1. In vivo studies have shown that the low-affinity 75 kDa neurotrophin receptor (p75NTR) is involved in axotomy-induced cell death of sensory and motor neurons. To further examine the importance of p75NTR in mediating neuronal death in vivo , we examined the effect of axotomy in the p75NTR-knockout mouse, which has a disrupted ligand-binding domain. 2. The extent of sensory and motor neuron loss in the p75NTR-knockout mouse following axotomy was not significantly different to that in wild-type mice. This suggests that disruption of the ligand-binding domain is insufficient to block the cell death process in axotomized neurons. 3. Immunohistochemical studies showed that axotomized neurons continue to express this mutant receptor with its intracellular death-signalling moiety intact. 4. Treatment with antisense oligonucleotides targeted against p75NTR resulted in significant reduction in the loss of axotomized neurons in the knockout mouse. 5. These data suggest that the intracellular domain of p75NTR is essential for death-signalling and that p75NTR can signal apoptosis, despite a disrupted ligand-binding domain.

Calcium-activated potassium channels: Multiple contributions to neuronal function

Calcium-activated potassium channels are a large family of potassium channels that are found throughout the central nervous system and in many other cell types. These channels are activated by rises in cytosolic calcium largely in response to calcium influx via voltage-gated calcium channels that open during action potentials. Activation of these potassium channels is involved in the control of a number of physiological processes from the firing properties of neurons to the control of transmitter release. These channels form the target for modulation for a range of neurotransmitters and have been implicated in the pathogenesis of neurological and psychiatric disorders. Here the authors summarize the varieties of calcium-activated potassium channels present in central neurons and their defining molecular and biophysical properties.