Following the signal sequence from ribosomal tunnel exit to signal recognition particle.

Membrane and secretory proteins can be co-translationally inserted into or translocated across the membrane. This process is dependent on signal sequence recognition on the ribosome by the signal recognition particle (SRP), which results in targeting of the ribosome-nascent-chain complex to the protein-conducting channel at the membrane. Here we present an ensemble of structures at subnanometre resolution, revealing the signal sequence both at the ribosomal tunnel exit and in the bacterial and eukaryotic ribosome-SRP complexes.

Medication management and adherence among cognitively impaired older adults.

This study examined the relationship between patients' cognitive status, deficit awareness, medication management skills, and actual medication adherence. Twenty-seven persons with Alzheimer's disease and 20 healthy controls were evaluated for their predicted and objective performance on tasks related to medication management. Caregivers were also evaluated for their prediction of the care recipient's management abilities.

Correlations of Perceived Deficits Questionnaire of Multiple Sclerosis Quality of Life Inventory with Beck Depression Inventory and neuropsychological tests.

The Perceived Deficits Questionnaire (PDQ) is a part of the Multiple Sclerosis (MS) Quality of Life Inventory that assesses self-perceived cognitive difficulties. We used baseline data from 49 MS subjects participating in a clinical trial to evaluate the correlation of the PDQ with two measures of cognitive impairment, the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test, 2nd edition (CVLT-II), total score, and one measure of depression, the Beck Depression Inventory-Amended (BDI-IA). The PDQ correlated significantly (r = 0.

The structure of the mammalian signal recognition particle (SRP) receptor as prototype for the interaction of small GTPases with Longin domains.

The eukaryotic signal recognition particle (SRP) and its receptor (SR) play a central role in co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum. The SR is a heterodimeric complex assembled by the two GTPases SRalpha and SRbeta, which is membrane-anchored. Here we present the 2.

Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1.

Vanilloid receptor 1 (TRPV1) is activated by chemical ligands (e.g., capsaicin and protons) and heat.

AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties.

The vanilloid receptor 1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel expressed by peripheral sensory neurons. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Here, we describe the in vitro and in vivo pharmacology of a novel TRPV1 antagonist, AMG 9810, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide.

SRP meets the ribosome.

Cotranslational targeting directly couples synthesis of proteins to their translocation across or insertion into membranes. The signal recognition particle (SRP) and its membrane-bound receptor facilitate the targeting of the translation machinery, the ribosome, via recognition of a signal sequence in the nascent peptide chain. By combining structures of free and ribosome-bound SRP we derive a structural model describing the dynamic nature of SRP when it meets the ribosome.

A structural step into the SRP cycle.

Co-translational targeting of secretory and membrane proteins to the translocation machinery is mediated by the signal recognition particle (SRP) and its membrane-bound receptor (SR) in all three domains of life. Although the overall composition of the SRP system differs, the central ribonucleoprotein core and the general mechanism of GTP-dependent targeting are highly conserved. Recently, structural studies have contributed significantly to our understanding of the molecular organization of SRP.

The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction.

Artemin (ART) signals through the GFR alpha-3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesions including fusion of adrenal medullae with adjacent paraganglia, adrenal medullary dysplasia, and marked enlargement of sympathetic (superior cervical and sympathetic chain ganglia) and parasympathetic (enteric, pelvic) ganglia.

Molecular determinants of vanilloid sensitivity in TRPV1.

Vanilloid receptor 1 (TRPV1), a membrane-associated cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by physical stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [(3)H]RTX binding in membranes prepared from their dorsal root ganglia.

The fate of intravenously administered tetrahydrobiopterin and its implications for heterologous gene therapy of phenylketonuria.

Tetrahydrobiopterin (BH(4)) is a required cofactor for the enzymatic activity of phenylalanine hydroxylase (PAH) and is synthesized de novo from GTP in several tissues. Heterologous expression of PAH in tissues other than liver is a potential novel therapy for human phenylketonuria that is completely dependent upon BH(4) supply in the PAH-expressing tissue. Previous experiments with liver PAH-deficient transgenic mice that expressed PAH in skeletal muscle demonstrated transient correction of hyperphenylalaninemia only with hourly parenteral BH(4) administration.

Crystallization of the crenarchaeal SRP core.

Protein translocation across or targeting to membranes mediated by the signal recognition particle (SRP) is a universal mechanism conserved in all domains of life. SRP54 from the crenarchaeon Sulfolobus solfataricus has been recombinantly expressed and crystallized with and without SRP RNA helix 8. The RNA has been transcribed in vitro using ribozyme technology.

Crystal structure of the complete core of archaeal signal recognition particle and implications for interdomain communication.

Targeting of secretory and membrane proteins by the signal recognition particle (SRP) is evolutionarily conserved, and the multidomain protein SRP54 acts as the key player in SRP-mediated protein transport. Binding of a signal peptide to SRP54 at the ribosome is coordinated with GTP binding and subsequent complex formation with the SRP receptor. Because these functions are localized to distinct domains of SRP54, communication between them is essential.

Expression of phenylalanine hydroxylase (PAH) in erythrogenic bone marrow does not correct hyperphenylalaninemia in Pah(enu2) mice.

Background: Treatment of many inherited liver enzyme deficiencies requires the removal of toxic intermediate metabolites from the blood of affected individuals. We propose that circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver, such as bone marrow. Our specific hypothesis was that phenylalanine hydroxylase (PAH) expressed in bone marrow would lower blood phenylalanine levels in hyperphenylalaninemic Pah(enu2) mice, a model of human phenylketonuria (PKU).

[Tissue toxicity of local anesthetics. An in vivo trial].

Aim: Local anesthetics are often administered intra-articularly after knee surgery. The aim of this study was to determine differences in irritancy of local anesthetics in an in vivo test performed on the chorioallantoic membrane of hen's eggs (HET-CAM test) to evaluate the specific irritation score.

Method: After incubation for 9 days, the chorioallantoic membrane was prepared and then exposed to different local anesthetics (Naropin, Scandicain,Carbostesin,Xyloneural).

Identifying driving impairment in Alzheimer disease: a comparison of self and observer reports versus driving evaluation.

This study examined the relationship between driving behaviors and awareness of deficit in patients with Alzheimer's disease (AD). Fifteen mildly impaired AD patients and 15 healthy elderly controls with valid drivers' licenses were administered a series of questionnaires concerning daily functioning and driving performance, and all 30 subjects were evaluated on a standardized road test. Self-report and caregiver/informant responses were compared with determine levels of discrepancy in ratings, while comparisons of AD and healthy elderly controls revealed group differences.

Characterization of a new brain-derived proteoglycan inhibiting retinal ganglion cell axon outgrowth.

A proteoglycan was identified and isolated from physiological saline extracts of chick embryo brains by using a new monoclonal antibody (hybridoma clone mab Te38). The purified proteoglycan displayed an apparent molecular mass of 2500-3500 kDa, which became reduced to 370 and 600 kDa after digestion with chondroitinase ABC or chondroitinase AC. After additional treatment with keratanase the 600-kDa band was no longer detectable in Western blots.

Towards the structure of the mammalian signal recognition particle.

The signal recognition particle (SRP) is a ubiquitous ribonucleoprotein particle involved in the co-translational targeting of proteins to membranes. Crystal structures are now available for three protein-RNA subcomplexes from the SRP, which give insights into fundamental aspects of protein-RNA recognition, the assembly of stable ribonucleoprotein particles and the mechanism of action of the SRP.

Single amino acid residue influences the distribution pattern of an inwardly rectifying potassium channel in polarized cells.

We used immunohistochemistry to identify the localization of the inwardly rectifying potassium channels K(ir) 2.1 and its mutant K(ir) 2.1 M84K, and P2X(2) receptors heterologously expressed in Xenopus oocytes, opossum kidney (OK) cells and NG108-15 cells.

[Autonomic dysfunction with nocturnal dyspnea (Gerhardt-syndrome) in a patient with multiple system atrophy].

Findings: This case involves a 56-year-old man with a 3-year case history, starting with vertigo, cerebellar symptoms, followed by inspiratory stridor, especially during the night, and autonomic failure with recurrent syncopes. Magnetic resonance imaging confirmed the diagnosis of olivopontocerebellar atrophy and tilting table tests with plasma catecholamine measurement revealed an extensive drop of blood pressure with no adequate change in the heart rate or plasma catecholamine, leading to the diagnosis of multiple system atrophy (MSA). In addition, bronchoscopy revealed that the inspiratory stridor was caused by paradoxical movement of the vocal cords (sometimes known as Gerhardt's syndrome).

Crystal structure of an early protein-RNA assembly complex of the signal recognition particle.

The signal recognition particle (SRP) is a universally conserved ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to cellular membranes. A crucial early step in SRP assembly in archaea and eukarya is the binding of protein SRP19 to specific sites on SRP RNA. Here we report the 1.

[Improved ultrasound imaging of the pancreas with the transsplenic view and Tissue harmonic imaging].

Unlabelled: The conventional ultrasound examination of the pancreas from ventral is - especially concerning the leftsided parts of the organ - limited by interposition of stomach, flexura duodenojejunalis or colon. The transsplenic view to the cauda pancreatis is less known, but allows quite often a good possibility to examine this part of the retroperitoneal organ, even when examination from ventral is impossible.

Aim: Comparison of ventral and transsplenic ultrasound examination - with and without tissue harmonic imaging (THI) - in regard to the diagnostic accessability to the cauda pancreatis.

Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) channel (ENaC) and CFTR: implications for cystic fibrosis.

Cystic fibrosis (CF) is characterized by impaired Cl(-) secretion and increased Na(+) reabsorption in several tissues including respiratory epithelium. Many CFTR mutations have been identified over the past years. However, only a poor correlation between the genotype and lung phenotype was found suggesting additional factors influencing the phenotype and course of the disease.

MRI-based stereolithographic models of the temporomandibular joint: technical innovation.

A new technique of manufacturing dual-colour stereolithographic models of hard and soft tissues of the temporomandibular joint (TMJ) is presented. Sagittal T1/PD weighted magnetic resonance (MR) images of joints with and without disc displacement were obtained in the closed and open mouth positions. Individual interactive contour identification of bony structures and the articular disc followed by binary interpolation provided the data for the generation of acrylic TMJ models.

Linking sight and sound: fMRI evidence of primary auditory cortex activation during visual word recognition.

We describe two studies that used repetition priming paradigms to investigate brain activity during the reading of single words. Functional magnetic resonance images were collected during a visual lexical decision task in which nonword stimuli were manipulated with regard to phonological properties and compared to genuine English words. We observed a region in left-hemisphere primary auditory cortex linked to a repetition priming effect.