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At least 1,099 records · Page 61Linked to original sources
PubMed1991

Individual differences in locomotor activity and sensitization.

Male rats were screened for locomotor activity in a novel environment and divided into high (HR) and low (LR) responders based on whether their locomotor activity score for the first hour was above or below the median locomotor activity for the subject sample. Subsequently, the locomotor response to repeated administration of either amphetamine (AMPH; 0.5 mg/kg), cocaine (10 mg/kg), scopolamine (0.5 mg/kg) or saline was monitored in separate groups of HR and LR rats. HR rats had significantly higher overall activity scores than LR rats for all 3 drugs. Both HR and LR rats developed tolerance at the same rate to repeated scopolamine administration. In contrast, only HR rats showed pronounced sensitization to the locomotor stimulating properties of AMPH and a direct correlation was evident between the locomotor response to novelty and the magnitude of sensitization. These results suggest that an individual's response to a novel environment can, to a certain extent, predict drug-induced locomotor activity and that individual differences in the response to novelty and sensitization to AMPH may result from individual variations in a common neural mechanism.

Amphetamine↗
PubMed1993

Structure and function of voltage-gated ion channels.

The principal subunits of the voltage-gated Na+, Ca2+ and K+ channels are members of a related gene family and are functionally autonomous in voltage-dependent activation, ion conductance and inactivation. In this article, recent work locating the structural elements that are responsible for these three basic functions of the voltage-gated ion channels is reviewed. These studies reveal strong functional analogies among the different ion channels and suggest that the striking differences in their properties arise as variations on a common structural and functional theme.

Animals↗
PubMedDate not supplied

Internal carotid artery hypoplasia.

Hypoplasia of the carotid arteries is a rare congenital anomaly which when clinically symptomatic presents as cerebral ischemia or hemorrhage. Patients with this anomaly commonly have associated variations of the circle of Willis, an increased incidence of intracranial aneurysms and extensive networks of collateral vessels to accommodate the diminished carotid flow. Carotid artery hypoplasia should not be confused with other conditions which may have a similar appearance such as arterial dissection, vasculitis, and tubular fibromuscular hyperplasia.

Adult↗
PubMedDate not supplied

Cerebral arterial fenestration.

Fenestration or duplication of a cerebral vessel is a rare congenital variation which most commonly involves the vertebral artery and is usually of no clinical significance. Fenestrations may have associated aneurysms remote to the anomaly or involving the proximal bifurcation of the fenestration. They may also be associated with other vascular malformations e.g. arteriovenous malformations and venous angiomas. Four fenestrated cerebral vessels and their angiographic appearances are reported in this study.

Adolescent↗
PubMed1992

Recent developments in the molecular cloning and characterization of hepatitis C and E viruses.

The molecular properties of the genomes of both hepatitis C virus (HCV) and hepatitis E virus (HEV), the major etiologic agents of non-A, non-B hepatitis, are briefly described. The organization of the genome of each of these viruses is discussed and compared to those of other related or distantly related viruses that contain single-stranded, positive-sense RNA genomes. In the case of HEV, the reactivity of expressed proteins and genetic divergence of geographically distinct isolates are also described within the context of sequence variation, type-common epitopes and type-specific epitopes.

Cloning, Molecular↗
PubMed1994

Molecular properties of a superfamily of plasma-membrane cation channels.

The principal subunits of a large superfamily of plasma-membrane cation channels are functionally autonomous in ion conductance and in gating by membrane potential and intracellular ligands. Recent work has located the structural elements responsible for the ion conductance and gating of these channels. These studies reveal strong functional analogies among the different ion channels and suggest that the striking differences in their properties arise as variations on a common structural and functional theme.

Animals↗
PubMed1993

Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes.

Some P-450 systems, notably aromatase and 14 alpha-demethylase catalyse not only the hydroxylate reaction but also the oxidation of an alcohol into a carbonyl compound as well as a C-C bond cleavage process. All these reactions occur at the same active site. A somewhat analogous situation is noted with 17 alpha-hydroxylase-17,20-lyase that participates in hydroxylation as well as C-C bond cleavage process. The C-C bond cleavage reactions catalysed by the above enzymes conform to the general equation: [formula: see text] It is argued that all three types of reaction catalyzed by these enzymes may be viewed as variations on a common theme. In P-450 dependent hydroxylation the initially formed FeIII-O-O. species is converted into FeIII-O-OH and the heterolysis of the oxygen-oxygen bond of the latter then gives the oxo-derivative for which a number of canonical structures are possible; for example FeV = O<==>(+.)FeIV = O<==>FeIV-O.. One of these, FeIV-O. behaves like an alkoxyl radical and participates in hydrogen abstraction from C-H bond to produce FeIV-OH and carbon radical. The latter is then quenched by the delivery of hydroxyl radical from FeIV-OH. The latter species may thus be regarded as a carrier of hydroxyl radical. We have proposed that the C-C bond cleavage reaction occurs through the participation of the FeIII-O-OH species that is trapped by the electrophilic property of the carbonyl compound giving a peroxide adduct that fragments to produce an acyl-carbon cleavage. Scientific developments leading up to this conclusion are considered. In the first author's views, "The study of mechanisms is not a scientific but a cultural activity. Mechanisms do not aim at an absolute truth but are intended to be a "running" commentary on the status of knowledge in a field. As the structural knowledge in a field advances Mechanisms evolve to take note of the new findings. Just as a constructive "running" commentary provides the stimulus for higher standards of performance, so Mechanisms call for better and firmer structural information from their practitioners".

Animals↗
PubMed2004

Ubiquitin and endocytic internalization in yeast and animal cells.

Endocytosis is involved in a wide variety of cellular processes, and the internalization step of endocytosis has been extensively studied in both lower and higher eukaryotic cells. Studies in mammalian cells have described several endocytic pathways, with the main emphasis on clathrin-dependent endocytosis. Genetic studies in yeast have underlined the critical role of actin and actin-binding proteins, lipid modification, and the ubiquitin conjugation system. The combined results of studies of endocytosis in higher and lower eukaryotic cells reveal an interesting interplay in the two systems, including a crucial role for ubiquitin-associated events. The ubiquitylation of yeast cell-surface proteins clearly acts as a signal triggering their internalization. Mammalian cells display variations on the common theme of ubiquitin-linked endocytosis, according to the cell-surface protein considered. Many plasma membrane channels, transporters and receptors undergo cell-surface ubiquitylation, required for the internalization or later endocytic steps of some cell-surface proteins, whereas for others, internalization involves interaction with the ubiquitin conjugation system or with ancillary proteins, which are themselves ubiquitylated. Epsins and Eps15 (or Eps15 homologs), are commonly involved in the process of endocytosis in all eukaryotes, their critical role in this process stemming from their capacity to bind ubiquitin, and to undergo ubiquitylation.

Animals↗
PubMed2006

The effect of histidine oxidation on the dissociation patterns of peptide ions.

Oxidative modifications to amino acid side chains can change the dissociation pathways of peptide ions, although these variations are most commonly observed when cysteine and methionine residues are oxidized. In this work we describe the very noticeable effect that oxidation of histidine residues can have on the dissociation patterns of peptide ions containing this residue. A common product ion spectral feature of doubly charged tryptic peptides is enhanced cleavage at the C-terminal side of histidine residues. This preferential cleavage arises as a result of the unique acid/base character of the imidazole side chain that initiates cleavage of a proximal peptide bond for ions in which the number of protons does not exceed the number of basic residues. We demonstrate here that this enhanced cleavage is eliminated when histidine is oxidized to 2-oxo-histidine because the proton affinity and nucleophilicity of the imidazole side chain are lowered. Furthermore, we find that oxidation of histidine to 2-oxo-histidine can cause the misassignment of oxidized residues when more than one oxidized isomer is simultaneously subjected to tandem mass spectrometry (MS/MS). These spectral misinterpretations can usually be avoided by using multiple stages of MS/MS (MS(n)) or by specially optimized liquid chromatographic separation conditions. When these approaches are not accessible or do not work, N-terminal derivatization with sulfobenzoic acid avoids the problem of mistakenly assigning oxidized residues.

Chromatography, High Pressure Liquid↗
PubMed2005

Scaling properties of childhood infectious diseases epidemics before and after mass vaccination in Canada.

The goal of this paper is to analyse the scaling properties of childhood infectious disease time-series data. We present a scaling analysis of the distribution of epidemic sizes of measles, rubella, pertussis, and mumps outbreaks in Canada. This application provides a new approach in assessing infectious disease dynamics in a large vaccinated population. An inverse power-law (IPL) distribution function has been fit to the time series of epidemic sizes, and the results assessed against an exponential benchmark model. We have found that the rubella epidemic size distribution and that of measles in highly vaccinated periods follow an IPL. The IPL suggests the presence of a scale-invariant network for these diseases as a result of the heterogeneity of the individual contact rates. By contrast, it was found that pertussis and mumps were characterized by a uniform network of transmission of the exponential type, which suggests homogeneity in the contact rate or, more likely, boiled down heterogeneity by large intermixing in the population. We conclude that the topology of the network of infectious contacts depends on the disease type and its infection rate. It also appears that the socio-demographic structure of the population may play a part (e.g. pattern of contacts according to age) in the structuring of the topology of the network. The findings suggest that there is relevant information hidden in the variation of the common contagious disease time-series data, and that this information can have a bearing on the strategy of vaccination programs.

Canada↗
PubMed2005

Pharmacogenomics of cholesterol-lowering therapy.

The prevention of cardiovascular disease is critically dependent on lipid-lowering therapy, including 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), cholesterol absorption inhibitors, bile acid resins, fibrates, and nicotinic acid. Although these drugs are generally well tolerated, severe adverse effects can occur in a minority of patients. Furthermore, a subset of patients does not respond to cholesterol-lowering therapy with a reduction in coronary heart disease progression. Significant progress has been made in the identification of common DNA sequence variations in genes influencing the pharmacokinetics and pharmacodynamics of statins and in disease-modifying genes relevant for coronary heart disease (CHD). Among the most promising candidate genes for pharmacogenomic analysis of statin therapy are HMG-CoA reductase as a direct target gene and other genes modulating lipid and lipoprotein homeostasis. Based on data from pharmacogenetic trials, a combined analysis of multiple genetic variants in several genes is more likely to give significant results than single gene studies in small cohorts. In the future, pharmacogenomic testing may allow risk stratification of patients to avoid serious side effects and enable clinicians to select lipid-lowering drugs with the highest efficacy resulting in the best response to therapy.

Apolipoproteins E↗
PubMed1986

Linking phenomenon during atrial stimulation with accessory pathways.

Linking is an electrophysiologic phenomenon in which each successive impulse entering a macroreentry circuit propagates preferentially along 1 limb because of the functional impedance to conduction in the contralateral limb produced by the previous impulse. Electrophysiologic studies were performed in 12 patients with a bidirectionally conducting accessory pathway. Linking was analyzed while 1:1 atrioventricular conduction took place through the normal pathway. When atrial pacing (at the same cycle length) could be initiated during sinus rhythm in patients with rapidly conducting accessory pathways, linking was dynamically maintained by repetitive local refractoriness (interference). When it could be initiated during the usual type of orthodromic circus movement tachycardia, linking was sustained by actual impulse collision, the underlying mechanism having also been called entrainment. When it could be initiated during sinus rhythm in a patient with a slowly conducting accessory pathway, linking was maintained by impulse collision, but the underlying mechanism could not be called entrainment because stimulation had not been started during tachycardia. This study showed that 2 terms--linking and entrainment--may be applied to the same mechanism and, conversely, that the same name could not be used in reference to the same mechanism when pacing was initiated under different circumstances. However, using the proposed conceptual formulation for linking, it is apparent that seemingly diverse mechanisms associated with macroreentry circuits involving accessory pathways are, in fact, variations on a common electrophysiologic theme.

Adolescent↗
PubMed1984

Nonsteroidal anti-inflammatory drugs and immunologic function. Overview of the European experience.

A large number of nonsteroidal anti-inflammatory drugs are available in Europe. There appears to be little difference in overall clinical effectiveness of these drugs, despite individual patient variation, suggesting a common mode of action. Occasionally, a nonsteroidal anti-inflammatory drug will show some evidence of a more impressive anti-rheumatic effect, perhaps related to a more prolonged or different mode of action. The evidence for an immunologic effect of nonsteroidal anti-inflammatory drugs is largely derived from in vitro studies. In patients with rheumatoid arthritis treated with piroxicam, there are no overall changes in lymphocyte numbers or T4/T8 ratios, but numbers of activated cells expressing la decrease and rheumatoid factor titers may also fall. It is suggested that this is not a direct immunosuppressive effect, but one that is related to local inhibition of polymorphonuclear leukocyte-derived free radical production within the joint, which may lower the antigenic load of IgG altered by free radicals, with subsequent diminished immune stimulation.

Anti-Inflammatory Agents↗
PubMed2000

Re-emerging structures: continuing crystallography of the bacterial reaction centre.

The reaction centre is nature's solar battery, and is found in a number of variations on a common theme in plants, algae and photosynthetic bacteria. During the last 20 years, a combination of X-ray crystallography, spectroscopy and mutagenesis has provided increasingly detailed insights into the mechanism of light energy transduction in the bacterial reaction centre. This mini-review looks at the application of X-ray crystallography to the bacterial reaction centre, focussing in particular on recent information on the structural consequences of site-directed mutagenesis, the roles played by water molecules in the reaction centre, the mechanism of ubiquinone reduction, and studies of the phospholipid environment of the protein.

Crystallography, X-Ray↗
PubMed1998

Phospholipid-binding protein domains.

Research into cellular mechanisms for signal transduction is currently one of the most exciting and rapidly advancing fields of biological study. It has been known for some time that numerous intracellular signals are transmitted by specific protein-protein interactions, as exemplified by those involving the Src homology domains. However, after some controversy, it has recently been widely accepted that specific protein-phospholipid interactions also play key roles in many signal transduction pathways. In this review, landmark discoveries and recent advances describing protein domains known to associate with phospholipids are discussed. Particular emphasis is placed on the interactions of proteins with phospholipids acting as second messengers in signalling pathways. For this purpose, the pleckstrin homology (PH) domain is highlighted, since studies of this domain provided some of the earliest, detailed data about protein-phospholipid interactions occurring downstream of growth factor-mediated receptor stimulation. Moreover, studies of PH domains have given insight into the mechanisms of certain diseases, revealed a number of intriguing functional variations on a common structural theme and recently culminated in providing the missing links in erstwhile mysteries of phosphoinositide-dependent signal transduction pathways. Finally, a short discussion is devoted to the developing field of protein-phospholipid interactions that influence cytoskeletal organisation.

Carrier Proteins↗
PubMed1988

Pharmacogenetics of methylation: relationship to drug metabolism.

Pharmacogenetics is the study of inherited variation in drug response. Genetic differences in drug metabolism are the most common causes for inherited variations in drug response or adverse reactions to medications. Methyl conjugation is an important pathway in the biotransformation of many drugs. Experiments performed during the past decade showed that individual variations in the activities of enzymes that catalyze S-methylation, O-methylation and N-methylation are under genetic control in human tissue. These inherited variations are responsible for individual differences in metabolism, effect, and toxicity of drugs that undergo methyl conjugation. The approach used to study the pharmacogenetics of methylation may also be applicable to the study of inherited variations in other pathways of drug metabolism.

Adult↗
PubMed1997

Conformational properties of the prion octa-repeat and hydrophobic sequences.

We have used circular dichroism to study synthetic peptides from two important regions of the prion protein: the N-terminal octa-repeat domain and a highly conserved hydrophobic section. Our results show that the octa-repeat sequence in free solution can adopt a non-random, extended conformation with properties similar to the poly-L-proline type II left-handed helix. We also show that the conformation can be changed by temperature, organic solvents (e.g. acetonitrile) and on binding to phospholipid vesicles. We compared CD data from two peptides corresponding to the hydrophobic region between residues 106 and 136 which contained either methionine or valine at position 129. This variation represents a common polymorphism in humans which has been shown to influence predisposition towards iatrogenic and sporadic CJD. There was no detectable difference between the CD spectra of these peptides irrespective of the solvent conditions we used.

Amino Acid Sequence↗
PubMed2001

Hepatic lipase promoter activity is reduced by the C-480T and G-216A substitutions present in the common LIPC gene variant, and is increased by Upstream Stimulatory Factor.

The common -216G-->A and -480C-->T substitutions in the promoter region of the human hepatic lipase (LIPC) gene show high allelic association, and are correlated with decreased hepatic lipase activity and increased high-density lipoprotein cholesterol levels. To test the functionality of these substitutions, CAT-reporter assays were performed in HepG2 cells. LIPC (-650/+48) but not (-650/+61) promoter constructs showed transcriptional activity. LIPC (-650/+48) constructs with both -216A and -480T exhibited significantly lower promoter activity (-45%) than the wild-type form. Activities of -289/+48 constructs were not significantly affected by the -216G-->A substitution. The -480C/T site lies within a binding region for Upstream Stimulatory Factor (USF). Gel-shift assays showed that the binding affinity of USF protein for HL specific oligonucleotides was decreased four-fold by the -480C-->T substitution. However, promoter activity of the -650/+48 constructs was not significantly affected by the -480C-->T substitution alone. Co-transfection of HepG2 cells with USF(43) cDNA yielded a similar dose-dependent increase in activity of all -650/+48 constructs; the absolute difference in promoter activity increased but the relative difference between the variant promoter forms was maintained. Our studies demonstrate that the common LIPC promoter variation is functional, which explains the association of the -480T allele with a lower hepatic lipase activity in man.

Bacterial Proteins↗