Mapping discontinuous epitopes for MRK-16, UIC2 and 4E3 antibodies to extracellular loops 1 and 4 of human P-glycoprotein.

P-glycoprotein (P-gp), an ATP-dependent efflux pump, is associated with the development of multidrug resistance in cancer cells. Antibody-mediated blockade of human P-gp activity has been shown to overcome drug resistance by re-sensitizing resistant cancer cells to anticancer drugs. Despite the potential clinical application of this finding, the epitopes of the three human P-gp-specific monoclonal antibodies MRK-16, UIC2 and 4E3, which bind to the extracellular loops (ECLs) have not yet been mapped.

Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms.

Objective: To provide clinical data on a cohort of 6 patients with massive expansion (>200 CAG repeats) of spinocerebellar ataxia type 2 (SCA2) and investigate possible pathways of pathogenesis using bioinformatics analysis of ATXN2 networks.

Methods: We present data on 6 patients with massive expansion of SCA2 who presented in infancy with variable combinations of hypotonia, global developmental delay, infantile spasms, and retinitis pigmentosa. ATXN2 is known to interact with a network of synaptic proteins.

Beta-barrel models of soluble amyloid beta oligomers and annular protofibrils.

Both soluble and membrane-bound prefibrillar assemblies of Abeta (Aβ) peptides have been associated with Alzheimer's disease (AD). The size and nature of these assemblies vary greatly and are affected by many factors. Here, we present models of soluble hexameric assemblies of Aβ42 and suggest how they can lead to larger assemblies and eventually to fibrils.

Structural model of the Ca V 1.2 pore.

Understanding the structure and functional mechanisms of voltage-gated calcium channels remains a major task in membrane biophysics. In the absence of three dimensional structures, homology modeling techniques are the method of choice, to address questions concerning the structure of these channels. We have developed models of the open Ca(V)1.

Models of the structure and gating mechanisms of the pore domain of the NaChBac ion channel.

The NaChBac prokaryotic sodium channel appears to be a descendent of an evolutionary link between voltage-gated K(V) and Ca(V) channels. Like K(V) channels, four identical six-transmembrane subunits comprise the NaChBac channel, but its selectivity filter possesses a signature sequence of eukaryotic Ca(V) channels. We developed structural models of the NaChBac channel in closed and open conformations, using K(+)-channel crystal structures as initial templates.

Models of voltage-dependent conformational changes in NaChBac channels.

Models of the transmembrane region of the NaChBac channel were developed in two open/inactivated and several closed conformations. Homology models of NaChBac were developed using crystal structures of Kv1.2 and a Kv1.

STAM: simple transmembrane alignment method.

Motivation: The database of transmembrane protein (TMP) structures is still very small. At the same time, more and more TMP sequences are being determined. Molecular modeling is an interim answer that may bridge the gap between the two databases.

Mechanotransduction through the cytoskeleton.

We constructed a model cytoskeleton to investigate the proposal that this interconnected filamentous structure can act as a mechano- and signal transducer. The model cytoskeleton is composed of rigid rods representing actin filaments, which are connected with springs representing cross-linker molecules. The entire mesh is placed in viscous cytoplasm.

Trafficking and signaling through the cytoskeleton: a specific mechanism.

A specific mechanism for the intracellular translocation of nonvesicle-associated proteins is proposed. This movement machinery is based on the assumption that the cytoskeleton represents an interconnected network of filamentous macromolecules, which extends over the entire cytoplasm. Diffusion along the filaments provides an efficient way for movement and with this, for signal transduction, between various intracellular compartments.

Viscoelastic properties of living embryonic tissues: a quantitative study.

A number of properties of certain living embryonic tissues can be explained by considering them as liquids. Tissue fragments left in a shaker bath round up to form spherical aggregates, as do liquid drops. When cells comprising two distinct embryonic tissues are mixed, typically a nucleation-like process takes place, and one tissue sorts out from the other.

Acquired epileptiform opercular syndrome: a second case report, review of the literature, and comparison to the Landau-Kleffner syndrome.

A 5-year-old girl developed recurrent prolonged episodes of severe oral apraxia, dysarthria, and drooling, similar to the opercular syndrome in children. Each episode lasted several weeks to > 6 months and was associated with exacerbation of epileptiform activity in her EEG. Electrographic status epilepticus during slow wave sleep (ESES) was recorded during three of the exacerbations.

Quadriplegia after chiropractic manipulation in an infant with congenital torticollis caused by a spinal cord astrocytoma.

An infant with congenital torticollis underwent chiropractic manipulation, and within a few hours had respiratory insufficiency, seizures, and quadriplegia. A holocord astrocytoma, with extensive acute necrosis believed to be a result of the neck manipulation, was found and resected. We believe that every child with torticollis, regardless of age, should undergo neurologic and radiologic evaluation before any form of physical treatment is instituted.

Acute dystonic reaction to bethanechol--a direct acetylcholine receptor agonist.

Bethanechol is a direct agonist of the acetylcholine receptor that was recently introduced in the therapy of gastro-oesophageal reflux. Acute dystonic reactions to bethanechol were observed in a 10-month-old infant who also demonstrated similar dystonic reactions to dopamine receptor blocking agents of two different classes. This first report of acute dystonic reaction to cholinergic agonists in human is in accord with the current theories of the rôle of acetylcholine and dopamine in the pathogenesis of acute dystonic reactions.

Thyroid-stimulating hormone, prolactin, and growth hormone response to thyrotropin-releasing hormone in treated children with congenital hypothyroidism.

The purpose of the present study was to assess thyroid-stimulating hormone (TSH), prolactin, and growth hormone responses to TRH stimulation in 12 congenitally hypothyroid children adequately treated with L-thyroxine from the first weeks of life. Although clinically euthyroid, six of these children were found to have abnormally high basal serum TSH concentrations despite clinical euthyroidism. Serum triiodothyroxine and L-thyroxine concentrations were normal and did not differ whether the children had elevated or normal basal serum TSH.