Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

Data Mining Practical Machine Learning Tools and Techniques

Demand has never been greater for revolutionary technologies that deliver fast, inexpensive and accurate genome information. This challenge has catalysed the development of next-generation sequencing (NGS) technologies. The inexpensive production of large volumes of sequence data is the primary advantage over conventional methods. Here, I present a technical review of template preparation, sequencing and imaging, genome alignment and assembly approaches, and recent advances in current and near-term commercially available NGS instruments. I also outline the broad range of applications for NGS technologies, in addition to providing guidelines for platform selection to address biological questions of interest.

/pdf/sequencing-technologies-the-next-generation-599pyrfdla.pdf

Sequencing technologies-the next generation

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Modern Applied Statistics With S

Sulfation is an important pathway in the metabolism of many hormones and drugs. Human liver contains at least three well characterized sulfotransferase (ST) enzymes, i.e., dehydroepiandrosterone (DHEA) ST and two forms of phenol sulfotransferase (PST). Our goal was to purify, to obtain partial amino acid sequence for, and to clone and express cDNA for human liver DHEA ST. Polymerase chain reaction primers were designed on the basis of homology among rat liver hydroxysteroid ST, rat liver PST, and bovine estrogen ST. These primers amplified a unique sequence from human liver cDNA, and this polymerase chain reaction product was used to screen a human liver cDNA library. Two clones were isolated that contained identical open reading frames, of 855 nucleotides, that encoded a protein of 285 amino acids. The deduced amino acid sequence of the encoded protein included two separate 27- and 23-amino acid sequences that were identical to those obtained by microsequencing of proteolytic fragments from purified human liver DHEA ST. Translation, in a rabbit reticulocyte lysate system, of mRNA transcribed in vitro from the two cDNA clones resulted in a 35-kDa translation product that comigrated with purified human liver DHEA ST during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This translation product also catalyzed the sulfation of DHEA but not the sulfation of model substrates for the two forms of PST found in human liver. The two cDNA clones were also used to create expression constructs with the eukaryotic expression vector P91023(B), and these constructs were used to transfect COS-1 cells. The transfected cells expressed a high level of DHEA ST activity, and this enzyme activity displayed a pattern of inhibition by the ST inhibitor 2,6-dichloro-4-nitrophenol identical to that of human liver DHEA ST. Cloning of cDNA for this important human sulfate-conjugating enzyme will enhance understanding of the relationship between DHEA ST and other human liver STs, as well as ST enzymes in other species.

Human liver dehydroepiandrosterone sulfotransferase: molecular cloning and expression of cDNA.

Dopamine-β-hydroxylase activity is released into the blood with catecholamines from the adrenal medulla and sympathetic nerves. This enzyme activity has been measured in the blood of 317 normal children and 227 normal adults. A significant sibling-sibling correlation of serum dopamine-β-hydroxylase values was found in the 94 sibling pairs tested. Frequency distributions of serum enzyme values in both children and adults suggest the existence of two populations with regard to serum activity of this enzyme.

http://science.sciencemag.org/content/sci/181/4103/943.full.pdf

Serum Dopamine-β-Hydroxylase Activity: Sibling-Sibling Correlation

Metabolomics, the study of metabolism at an "omic" level, has the potential to transform our understanding of mechanisms of drug action and the molecular basis for variation in drug response. It is now possible to define metabolic signatures of drug exposure that can identify pathways involved in both drug efficacy and adverse drug reactions. In addition, the "metabotype," the metabolic "signature" of a patient, is a unique identity that contains information about drug response and disease heterogeneity. The application of metabolomics for the study of drug effects and variation in drug response is creating "pharmacometabolomics," a discipline that will contribute to personalized drug therapy and will complement pharmacogenomics by capturing environmental and microbiome-level influences on response to drug therapy. This field has the potential to transform pharmacology and clinical pharmacology in significant ways and will contribute to efforts for personalized therapy. This overview highlights developments in the new discipline of pharmacometabolomics.

Pharmacometabolomics: Implications for Clinical Pharmacology and Systems Pharmacology

The development of a sensitive and specific enzymatic assay for dopamine-β-hydroxylase has enabled us to measure the activity of this enzyme in several tissues where it has previously been measured. The administration of reserpine leads to an increase in dopamine-β-hydroxylase activity in the rat adrenal, heart, salivary gland, and in sympathetic ganglia. The increase in the heart is preceded by a small but significant fall. We have confirmed the increase in tyrosine hydroxylase which follows the administration of reserpine and have found that the activity of phenylethanolamine-N-methyltransferase also increases after administration of this drug. The activities of two enzymes not involved in the synthesis of catecholamines, monoamine oxidase and lactate dehydrogenase, are not affected by reserpine treatment. The rise of dopamine-β-hydroxylase activity in the sympathetic ganglia is blocked by surgical decentralization.

Neurally Mediated Increase in Dopamine-β-Hydroxylase Activity

Low catechol-O-methyltransferase (COMT) activity (less than 8 units per milliliter) in the human erythrocyte is inherited as an autosomal recessive trait (COMTL). The average half-life of COMT in erythrocyte lysates incubated at 48 degrees C was significantly shorter in lysates from three subjects with low enzyme activity than in lysates from three subjects with high enzyme activity (12.5 +/- 0.9 minutes compared with 21.2 +/- 1.4 minutes, P less than .01). When the ratios of COMT activities in lysates heated at 48 degrees C for 15 minutes to enzyme activities in unheated samples were used as a measure of enzyme thermostability in blood samples from 316 randomly selected subjects, the ratios were significantly less for subjects with low enzyme activity than for subjects with higher enzyme activity. The presense of thermolabile COMT in blood of individuals homozygous for COMTL raises the possibility that the locus COMT may represent the structural gene for the human enzyme.

http://science.sciencemag.org/content/sci/203/4375/63.full.pdf

Richard M. Weinshilboum

Papers

Human liver dehydroepiandrosterone sulfotransferase: molecular cloning and expression of cDNA.

Serum Dopamine-β-Hydroxylase Activity: Sibling-Sibling Correlation

Pharmacometabolomics: Implications for Clinical Pharmacology and Systems Pharmacology

Neurally Mediated Increase in Dopamine-β-Hydroxylase Activity

Catechol-O-methyltransferase: thermolabile enzyme in erythrocytes of subjects homozygous for allele for low activity