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PubMed1975

Atlas of estrogen-concentrating cells in the central nervous system of the squirrel monkey.

Estrogen is concentrated within cellular nuclei in discrete regions of the monkey brain 30 and 60 minutes following intravenous injection of [3H] estradiol. Chromatographic data is provided to suggest that most of the localized estrogen is in the form of estradiol with lesser amounts of estrone and estriol. Three "major" areas of estrogen accumulation include: (1) preopticostrial accumulation: n. preopticus medialis--n. interstitialis striae terminalis, (2) basal hypothalamic accumulation: n. infundibularis--n. ventromedialis--n. premammillaris ventralis, and (3) the amygdaloid accumulation. Several "minor" areas of estrogen accumulation include the tuberculum olfactorium, insulae Calleja, n. triangularis septi, a. hypothalamica anterior, n. anterior hypothalami, n. paraventricularis, n. supraopticus, n. periventricularis and the substantia grisea centralis. The neocortex, rhombencephalon and spinal cord are essentially unlabeled. The major areas of accumulation are similar in several other mammalian and avian species while these, and some minor areas of accumulation, have been shown in neuroanatomical studies to be interconnected by several pathways, especially the stria terminalis. Lesion, implant, stimulation, recording and morphometric studies, in several species, support the concept that this arrangement provides a neuroanatomical substrate which would allow the integration of the various facets of the neuroendocrine reproductive response.

Amygdala↗
PubMed2001

Statistical multilocus methods for disequilibrium analysis in complex traits.

Hundreds of thousands of SNP markers are being generated with the purpose of carrying out case-control association studies for complex traits, which are thought to be due to multiple underlying susceptibility genes. The number of markers is typically much larger than the number of observations so that joint analysis of marker genotypes and their interactions is not feasible. We discuss a two-stage approach to first select a small subset of markers and then model the effects of the selected markers on disease. Examples of two procedures for marker selection are given with subsequent modeling of main and interaction effects. The approaches are applied to a data set with 89 SNPs in lieu of a genome screen with many more markers.

Alleles↗
PubMed1993

Development of PharmTest: a unique personal computer-mediated tool for assessment of pharmacology.

This report concerns the development of an assessment* model (PharmTest) for further evaluation by academic pharmacologists. The content area chosen for this model is the pharmacology of affective disorders. The components of the PharmTest system are: 1) a cognitive map of the content area used to develop the learning objectives (Figure): 2) both lower- and higher-level objectives developed jointly by basic and clinical faculty; 3) a bank of multiple choice questions (MCQ) judged to be congruent to the objectives by an expert panel; 4) a software program (SP) to manage the testing process; and 5) an annotated self-study document to aid students in their review after computer self-testing. PharmTest is designed to assist faculty in producing tests, making possible student self-testing and study. PharmTest was developed during a 6-month cooperative project between a faculty member from the University of North Carolina (HJB) and faculty of the University of Dundee. This report presents the learning objectives and cognitive map developed for the model content topic of "Pharmacology of Affective Disorders." Also it suggests a recipe for development of other content areas of pharmacology based on this project. Also, it presents the development process for PharmTest. Finally a plan for collecting evaluation data from academic pharmacology faculty is presented. Implications of the increased efficiency to faculty in linking learning objectives and testing are discussed, and a suggestion is made for national evaluation of learning in pharmacology.

Computer-Assisted Instruction↗
PubMed1989

31P-NMR spectroscopy: the metabolic profile of malignant hyperpyrexic porcine skeletal muscle.

31Phosphorus-NMR spectroscopy may have the potential to help in the noninvasive diagnosis of malignant hyperpyrexia (MH). Changes in the phosphate-metabolite profile of MH-susceptible (MHS) skeletal muscle occur more readily under conditions of anoxia than in control muscle. Induction of anoxia caused a rapid fall in intracellular phosphocreatine, an elevation of inorganic phosphate, and finally a diminution of ATP in MHS muscle. The onset of metabolic change was slower in control tissue. Increased oxygen consumption may occur in anoxic MHS muscle, which leads to accelerated glycolysis and a rapid fall in the intracellular high-energy phosphates. In MHS muscle an abnormality may exist in carbohydrate metabolism linked with poor resynthesis of the high-energy phosphates, which may be precipitated under anaerobic conditions. Accelerated muscle metabolism is also observed in the presence of 2 mM caffeine and 3% halothane in MHS muscle. Changes in the concentrations of metabolites could be mapped noninvasively under anoxic conditions using topical 31P-NMR.

Animals↗
PubMed1995

NeuroNames Brain Hierarchy.

The NeuroNames Brain Hierarchy is a structured system of neuroanatomical terminology that provides a comprehensive representation of virtually all human and nonhuman primate brain structures that are identifiable either grossly or in Niss1-stained histological sections. This system was devised for computer applications to address deficiencies in the brain terminology presented in Nomina Anatomica. English terms are listed for 783 structures in nine levels of hierarchical ranking. Abbreviations are provided for all superficial and primary volumetric structures. The substructures that constitute the total volume of every superstructure are identified. Superficial features of the brain are clearly distinguished from internal, volumetric brain structures. Structures found solely in either humans or macaques are identified. The purpose of the NeuroNames Brain Hierarchy is to bring greater standardization to the neuroanatomical terminology used by scientific investigators, clinicians, and students. This effort is consistent with the goals of the Unified Medical Language System program of the National Library of Medicine. It is hoped that the systematic construction of the NeuroNames Brain Hierarchy will facilitate use of the most widely accepted definitions of classical neuroanatomy in quantitative computerized neuroimaging applications. It should provide an accurate structural framework against which to reference the many other kinds of neuroanatomical information that are acquired by modern imaging, mapping, and histological labeling techniques.

Animals↗
PubMed1999

The evolution of the calpain family as reflected in paralogous chromosome regions.

Calpains, the Ca(2+)-dependent intracellular proteinases, are involved in the regulation of distinct cellular pathways including signal transduction and processing, cytoskeleton dynamics, and muscle homeostasis. To investigate the evolutionary origin of diverse calpain subfamilies, a phylogenetic study was carried out. The topology of the calpain phylogenetic tree has shown that some of the gene duplications occurred before the divergence of the protostome and deuterostome lineages. Other gene doublings, leading to vertebrate-specific calpain forms, took place during early chordate evolution and coincided with genome duplications as disclosed by the localization of calpain genes to paralogous chromosome regions in the human genome. On the basis of the phylogenetic tree, the time of gene duplications, and the localization of calpain genes, we propose a model of tandem and chromosome duplications for the evolution of vertebrate-specific calpain forms. The data presented here are consistent with scenarios proposed for the evolution of other multigene families.

Amino Acid Sequence↗
PubMed2005

Large-scale morphometric analysis of neuroanatomy and neuropathology.

Brain imaging research with MRI spans a wide area, covering both structure and function, and ranging from basic research through clinical research to drug design and clinical trials. In recent years there has been a trend towards the collection of very large MRI databases which can allow for the detection of very small group-dependent effects. However, the logistical challenges of analysing such large datasets presents new challenges. This paper describes the "pipeline" framework developed at the Montreal Neurological Institute for the fully automated morphometric analysis of large brain imaging databases. The potential use of these techniques is illustrated by examples of their applications in multiple sclerosis, Alzheimer's disease, and pediatric development.

Alzheimer Disease↗
PubMed2001

The human olfactory subgenome: from sequence to structure and evolution.

Olfactory receptors (ORs) constitute the largest multigene family in multicellular organisms. Their evolutionary proliferation has been driven by the need to provide recognition capacity for millions of potential odorants with arbitrary chemical configurations. Human genome sequencing has provided a highly informative picture of the "olfactory subgenome", the repertoire of OR genes. We describe here an analysis of 224 human OR genes, a much larger number than hitherto systematically analyzed. These are derived by literature survey, data mining at 14 genomic clusters, and by an OR-targeted experimental sequencing strategy. The presented set contains at least 53% pseudogenes and is minimally divided into 11 gene families. One of these (no. 7) has undergone a particularly extensive expansion in primates. The analysis of this collection leads to insight into the origin of OR genes, suggesting a graded expansion through mammalian evolution. It also allows us to delineate a structural map of the respective proteins. A sequence database and analysis package is provided (http://bioinformatics.weizmann.ac.il/HORDE), which will be useful for analyzing human OR sequences genome-wide.

Amino Acid Sequence↗
PubMed2004

Rapid isolation of viral integration site reveals frequent integration of HTLV-1 into expressed loci.

Although there is tight association of the human T-cell leukemia virus type-1 (HTLV-1) with adult T-cell leukemia/lymphoma (ATLL), it has remained unresolved whether the HTLV-1 integration into the host genome has any role in the development of this disease. We isolated a total of 58 HTLV-1 integration sites using newly developed, adaptor-ligated PCR from 33 ATLL patients and five ATLL cell lines. We compared our data as well as the previously reported ones with the complete human genomic sequence for the location of its placement, structure, and expression of genes nearby the integration site. The chromosomal target for integration was selected at random, but the integration favorably occurred within the transcription units; more than 59.5% of total integration was observed within the transcriptional unit. All inserted genes by HTLV-1 integration were expressed in normal T cells. Upregulation of genes due to viral integration was found in two out of nine ATLL cases; about 4.4- and 102-fold elevated ankyrin-1 ( ANK-1) and gephyrin ( GPHN) gene expressions were observed, respectively. These data suggest that the preferential integration of HTLV-1 into an expressed locus occasionally causes deregulation of corresponding gene, which may lead to leukemogenesis of a fraction of ATLL.

Ankyrins↗
PubMed2001

Catalog of 46 single-nucleotide polymorphisms (SNPs) in the microsomal glutathione S-transferase 1 (MGST1) gene.

A major goal in our laboratory is to understand the role of common genetic variations among individual patients as regards susceptibility to common diseases and differences in therapeutic efficacy and/or side effects of drugs. As an addition to the high-density SNP (single-nucleotide polymorphism) maps of 12 glutathione S-transferase and related genes reported earlier, we provide here an SNP map of the microsomal glutathione S-transferase 1 (MGST1) gene. Among 48 healthy Japanese volunteers examined. we identified a total of 46 SNPs at this locus, 36 of which had not been reported before: 4 in the promoter region, 34 in introns, 3 in the 3' untranslated region, and 5 in the 3' flanking region. No SNP was found in 5'untranslated or coding regions. The ratio of transition to transversion was approximately 1.2:1. Among the 13 insertion-deletion polymorphisms was a 2-bp deletion in the coding region of MGST1 in DNA from one of the volunteers, which resulted in a frame-shift mutation. Since the gene product encoded by this mutant allele would lack the C-terminal half including the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) domain, MGST1 activity is likely to be reduced in the carrier's cells. The SNP map presented here adds to the archive of tools for studying complex genetic diseases, population migration patterns, and a variety of pharmacogenetic possibilities.

3' Untranslated Regions↗
PubMed1995

Comparison of lipases from different strains of the fungus Geotrichum candidum.

The type A lipase and the cis-9 18:1 specific type B lipase of different strains of Geotrichum candidum were compared. Comparing the enzyme activity of crude lipase preparation and purified type A and type B lipases and the protein pattern of these preparations in denaturing polyacrylamide gel electrophoresis (SDS-PAGE) revealed that the specific activity for cis-9 18:1 fatty acids was related to the content of the type B lipase. Tandem-crossed immunoelectrophoresis was used to demonstrate immunological identity between type A and type B lipase of G. candidum ATCC 66592. Partial immunological identity was observed between type B lipase of this strain and type A lipase of G. candidum ATCC 34614 and two commercial crude G. candidum lipase preparations (Amano and Biocatalyst), i.e., the type B lipase of G. candidum ATCC 66592 had immunogenic epitopes which are not present on the other lipases. Enzymatic deglycosylation of the lipases did not alter this pattern. After partial proteolysis of purified type A and type B lipases of G. candidum ATCC 66592, Amano and Biocatalyst, no difference between the type A lipase of the three strains was observed in SDS-PAGE. For all strains the type B lipase exhibited a distinctly different peptide pattern to that of the type A lipase. In addition, the type B lipase of G. candidum ATCC 66592 differed from the type B lipase of Amano and Biocatalyst by having an additional peptide band. The results indicate that the G. candidum ATCC 66592 should be considered a distinct strain regarding the protein chemical characteristics of its type B lipase, whereas the two commercial lipase preparations appear to be very similar.

Geotrichum↗
PubMed1996

Coronary denervation attenuates coronary constriction induced by muscarinic receptor stimulation in pigs.

OBJECTIVES: We tested the hypothesis that coronary denervation attenuates the reactivity of the coronary vessel to cholinergic stimulation. METHODS: Heart rate, left ventricular (LV) pressure, LV dP/dt, coronary blood flow at the left anterior descending (LAD) coronary artery, and epicardial ECG mapping were measured before and after topical application of 1% methacholine to the LAD in 10 pigs anesthetized with alpha-chloralose (100 mg/kg, i.v.); these were compared with 10 other pigs submitted 2 weeks previously to a denervation of the LAD with phenol. Coronary denervation was confirmed in all cases by adrenergic histofluorescence and by acetyl-cholinesterase staining. Isolated LAD rings from 10 additional pigs (5 controls and 5 treated with phenol) were stimulated with endothelin-1 to verify whether phenol affected coronary reactivity to noncholinergic stimulation. RESULTS: Methacholine induced a fall in coronary blood flow (10.3 +/- 5.3 ml/min vs 4.8 +/- 6.2 ml/min, ANOVA: P < 0.001), a drop in systolic LV pressure (113 +/- 19 mmHg vs 93 +/- 19 mmHg, P < 0.001) and LV dP/dt (1608 +/- 363 mmHg/s vs 1203 +/- 302 mmHg/s, P = 0.02) and elevation of the ST segment (1.4 +/- 0.9 vs 11.1 +/- 4.7 mV, P < 0.001) in controls. These changes were not preceded by heart rate variations and were inhibited by atropine. As compared to controls, phenol-treated pigs showed a smaller decline in coronary blood flow (13.1 +/- 4.5 ml/min to 10.4 +/- 5.4 ml/min, P < 0.001), a lower drop in LV pressure (107 +/- 20 mmHg to 100 +/- 19.7 mmHg, P < 0.001) and lesser ST segment elevation (2.2 +/- 1.7 mV to 5.6 +/- 4.2 mV, P < 0.001). Isolated LAD rings contracted after exposure to endothelin-1 in both controls and phenol-treated pigs (3.5 +/- 0.7 g vs 2.4 +/- 1.0 g, P = 0.06). CONCLUSIONS: Coronary denervation attenuates coronary constriction induced selectively by direct muscarinic receptor stimulation in the in situ pig heart.

Animals↗
PubMed1989

Structure of the bovine eye lens gamma s-crystallin gene (formerly beta s).

The organization of a number of crystallin genes has already been resolved. One of the remaining genes of which the structure was hitherto unknown is the gamma s gene (formerly beta s). We determined the complete sequence of the bovine gamma s-crystallin-coding gene, apart from the middle region of the first intron. Since it contains three exons and two introns, we conclude that the former beta s, also at the gene level is gamma-crystallin-like. However, it is located on chromosome 3, in contrast to other gamma genes which occur in tandem on the human chromosome 2.

Amino Acid Sequence↗
PubMed2006

Application of data mining approaches to drug delivery.

Computational approaches play a key role in all areas of the pharmaceutical industry from data mining, experimental and clinical data capture to pharmacoeconomics and adverse events monitoring. They will likely continue to be indispensable assets along with a growing library of software applications. This is primarily due to the increasingly massive amount of biology, chemistry and clinical data, which is now entering the public domain mainly as a result of NIH and commercially funded projects. We are therefore in need of new methods for mining this mountain of data in order to enable new hypothesis generation. The computational approaches include, but are not limited to, database compilation, quantitative structure activity relationships (QSAR), pharmacophores, network visualization models, decision trees, machine learning algorithms and multidimensional data visualization software that could be used to improve drug delivery after mining public and/or proprietary data. We will discuss some areas of unmet needs in the area of data mining for drug delivery that can be addressed with new software tools or databases of relevance to future pharmaceutical projects.

Computer Simulation↗
PubMed2006

Electrophysiological and behavioral measures of the influence of literal and figurative contextual constraints on proverb comprehension.

Proverbs tend to have meanings that are true both literally and figuratively (i.e., Lightning really doesn't strike the same place twice). Consequently, discourse contexts that invite a literal reading of a proverb should provide more conceptual overlap with the proverb, resulting in more rapid processing, than will contexts biased towards a non-literal reading. Despite this, previous research has failed to find the predicted processing advantage in reading times for familiar proverbs when presented in a literally biasing context. We investigate this issue further by employing both ERP methodology and a self-paced reading task and, second, by creating an item set that controls for problems with items employed in earlier studies. Our results indicate that although people do not take longer to read proverbs in the literally and proverbially biasing contexts, people have less difficulty integrating the statements in literal than figurative contexts, as shown by the ERP data. These differences emerge at the third word of the proverbs.

Aphorisms and Proverbs as Topic↗
PubMed2006

Implicit emotion during recollection of past events: a nonverbal fMRI study.

Faces of other significant people are highly self-relevant and close to our everyday way of recollecting past events. We chose such stimuli to probe the emotional component of autobiographical memory retrieval. Photographs were collected from family members without the participant's involvement, thereby avoiding refreshment of the memory trace prior to the scanning session. We asked the subjects to spontaneously evoke a unique autobiographical episode following the presentation of relatives' and friends' faces. Famous faces recognition was used as a semantic memory control task. We carried out a post-fMRI debriefing session to collect participants' memories and their emotional intensity. The post-scanning behavioural data together with the neuroimaging data provided evidence that emotional aspects were implicitly involved during recollections. Our findings suggest that the use of highly self-relevant stimuli and the collection of data with no previous refreshment of the memory trace influence the right lateralisation of activations in the medial temporal lobe (MTL).

Adult↗