The pobA gene of Burkholderia cenocepacia encodes a group I Sfp-type phosphopantetheinyltransferase required for biosynthesis of the siderophores ornibactin and pyochelin.

The opportunistic pathogen Burkholderia cenocepacia produces the siderophores ornibactin and pyochelin under iron-restricted conditions. Biosynthesis of both siderophores requires the involvement of non-ribosomal peptide synthetases (NRPSs). Using a transposon containing the lacZ reporter gene, two B.

Detecting gene duplications in the human lineage.

Gene duplications represent an important class of evolutionary events that is likely to have contributed to the unique human phenotype in the short evolutionary time since the human-chimpanzee divergence. With the availability of both human and chimpanzee genome drafts in high coverage re-sequencing assemblies and the high annotation quality of most human genes, it should now be possible to identify all human lineage-specific gene duplication events (human inparalogues) and a few pioneering studies have attempted to do that. However, the different levels of coverage in the human and chimpanzee's genomes assemblies, and the differing levels of gene annotation, have led to problematic assumptions and oversimplifications in the algorithms and the datasets used to detect human lineage-specific gene duplications.

CYP1A2 is more variable than previously thought: a genomic biography of the gene behind the human drug-metabolizing enzyme.

Background And Objectives: CYP1A2 metabolizes various drugs, endogenous compounds and procarcinogens. As human genetic diversity has been reported to decrease with distance from Ethiopia, we resequenced CYP1A2 in five Ethiopian ethnic groups representing a rough northeast to southwest transect across Ethiopia to establish: (i) what variation exists in comparison with what is already known globally and (ii) what CYP1A2 pharmacogenetic profiles may be present as several CYP1A2-metabolized drugs are administered to Ethiopians.

Results And Conclusions: We found 49 different variable sites (30 of which are novel), nine nonsynonymous changes (seven of which are novel), one synonymous change and 55 different haplotypes, only three of which are previously reported.

Ancient urbanization predicts genetic resistance to tuberculosis.

A link between urban living and disease is seen in recent and historical records, but the presence of this association in prehistory has been difficult to assess. If the transition to urban living does result in an increase in disease-based mortality, we might expect to see evidence of increased disease resistance in longer-term urbanized populations, as the result of natural selection. To test this, we determined the frequency of an allele (SLC11A1 1729 + 55del4) associated with natural resistance to intracellular pathogens such as tuberculosis and leprosy.

Episodic withdrawal promotes psychomotor sensitization to morphine.

The relative intermittency or continuity of drug delivery is a major determinant of addictive liability, and also influences the impact of drug exposure on brain function and behavior. Events that occur during the offset of drug action (ie, acute withdrawal) may have an important role in the consequences of intermittent drug exposure. We assessed whether recurrent episodes of acute withdrawal contribute to the development of psychomotor sensitization in rodents during daily morphine exposure.

Bicyclic derivatives of the potent dual aromatase-steroid sulfatase inhibitor 2-bromo-4-{[(4-cyanophenyl)(4h-1,2,4-triazol-4-yl)amino]methyl}phenylsulfamate: synthesis, SAR, crystal structure, and in vitro and in vivo activities.

The design and synthesis of a series of bicyclic ring containing dual aromatase-sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4-[(4-bromobenzyl)(4H-1,2,4-triazol-4-yl)amino]benzonitrile are reported. Biological evaluation with JEG-3 cells revealed structure-activity relationships. The X-ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures.

Increased prevalence of M694V in patients with ankylosing spondylitis: additional evidence for a link with familial mediterranean fever.

Objective: To assess whether there is a statistically significant difference in the frequency of common MEFV allele variants in patients with ankylosing spondylitis (AS) as compared with control patients with rheumatoid arthritis (RA) and with healthy control subjects.

Methods: Sixty-two patients with AS, 50 healthy control subjects, and 46 patients with RA were assessed for the presence of MEFV variants. Exon 10 was analyzed by direct sequencing.

Discovery of adamantyl ethanone derivatives as potent 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors.

11Beta-hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones. The modulation of 11beta-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Inhibition of tissue-specific glucocorticoid action by regulating 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases.

Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors.

Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds.

Gbeta5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling.

The type 5 G protein beta subunit (Gbeta5) can form complexes with members of the regulator of G protein signaling 7 (RGS7) family, but its relevance to neuronal G protein signaling is unclear. We found that mouse RGS7-Gbeta5 complexes bound to G protein-gated potassium channels and facilitated their functional coupling to GABA(B) receptors in neurons. Our findings identify a compartmentalization mechanism that is critical for ensuring high temporal resolution of neuronal G protein signaling.

The grape microvine - a model system for rapid forward and reverse genetics of grapevines.

A grapevine model system is described that is suitable for rapid forward and reverse genetic studies in small controlled environments. It is based on the Vvgai1 mutant allele that confers a dwarf stature, short generation cycles and continuous flowering ('microvine'). Black and white berry microvine genotypes were developed that can be transformed by Agrobacterium tumefaciens.

LED controlled flow photolysis for concentration gradients in microfluidic systems.

Many of the channels and reservoirs in microfluidic systems are used simply to allow liquids with different compositions to be delivered to where they are needed. An alternative approach is to use dissolved photochemicals and variable intensity LEDs to generate composition changes in situ. We applied this approach to generate concentration gradients of HCl for gradient ion chromatography.

Little genetic differentiation as assessed by uniparental markers in the presence of substantial language variation in peoples of the Cross River region of Nigeria.

Background: The Cross River region in Nigeria is an extremely diverse area linguistically with over 60 distinct languages still spoken today. It is also a region of great historical importance, being a) adjacent to the likely homeland from which Bantu-speaking people migrated across most of sub-Saharan Africa 3000-5000 years ago and b) the location of Calabar, one of the largest centres during the Atlantic slave trade. Over 1000 DNA samples from 24 clans representing speakers of the six most prominent languages in the region were collected and typed for Y-chromosome (SNPs and microsatellites) and mtDNA markers (Hypervariable Segment 1) in order to examine whether there has been substantial gene flow between groups speaking different languages in the region.

Study Protocol--accurate assessment of kidney function in Indigenous Australians: aims and methods of the eGFR study.

Background: There is an overwhelming burden of cardiovascular disease, type 2 diabetes and chronic kidney disease among Indigenous Australians. In this high risk population, it is vital that we are able to measure accurately kidney function. Glomerular filtration rate is the best overall marker of kidney function.

Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors.

Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K(i) values.

A worldwide correlation of lactase persistence phenotype and genotypes.

Background: The ability of adult humans to digest the milk sugar lactose - lactase persistence - is a dominant Mendelian trait that has been a subject of extensive genetic, medical and evolutionary research. Lactase persistence is common in people of European ancestry as well as some African, Middle Eastern and Southern Asian groups, but is rare or absent elsewhere in the world. The recent identification of independent nucleotide changes that are strongly associated with lactase persistence in different populations worldwide has led to the possibility of genetic tests for the trait.

Nurse-controlled analgesia (NCA) following major surgery in 10,000 patients in a children's hospital.

Background And Objectives: Patients who received NCA with morphine following major surgery between 1996 and 2008 at Great Ormond Street Hospital, London, UK, were prospectively studied in the postoperative period to determine effectiveness, morphine requirements, incidence of common side effects, and serious adverse events.

Methods: The morphine NCA regimen and monitoring was according to standard hospital protocols. Data were collected prospectively and subsequently entered by trained personnel into a secure database.

Epidural corticosteroid injections as a possible cause of menorrhagia: a case report.

A 47-year-old female was referred for evaluation of chronic lower back pain. A magnetic resonance imaging of her lumbar spine revealed a broad-based disc herniation at L4-L5 with bilateral neural foraminal narrowing. A decision was made to treat her with bilateral L4-5 transforaminal epidural steroid injections.

Programmatic effectiveness of a university-based implant training program: long-term, patient-centered outcomes.

The University of Kentucky College of Dentistry established a formal implant program in 1999. The program utilizes a single system (Straumann) and a team concept in which implants are placed by residents in period ontology or oral and maxillofacial surgery and restored by predoctoral dental students. The program features stringent patient inclusion and exclusion criteria, incremental structured learning experiences, formal standardized protocols, and hands-on preclinical learning experiences.

Novel calcium sulfate space-making devices for bone regeneration: a pilot study.

The feasibility of using preformed calcium sulfate (CS) space-making devices (SMDs) for bone regeneration was explored using a rabbit calvarial model. Twenty-four CS devices were fabricated. Twelve of these were SMDs, which consisted of a domed head that served as the actual space-maker, and a stalk or "tail" portion used to affix the device to the bone.

R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine.

In the striatum, signaling through G protein-coupled dopamine receptors mediates motor and reward behavior, and underlies the effects of addictive drugs. The extent of receptor responses is determined by RGS9-2/Gbeta5 complexes, a striatally enriched regulator that limits the lifetime of activated G proteins. Recent studies suggest that the function of RGS9-2/Gbeta5 is controlled by the association with an additional subunit, R7BP, making elucidation of its contribution to striatal signaling essential for understanding molecular mechanisms of behaviors mediated by the striatum.

Multiple rare variants as a cause of a common phenotype: several different lactase persistence associated alleles in a single ethnic group.

Persistence of intestinal lactase into adulthood allows humans to use milk from other mammals as a source of food and water. This genetic trait has arisen by convergent evolution and the derived alleles of at least three different single nucleotide polymorphisms (-13910C>T, -13915T>G, -14010G>C) are associated with lactase persistence in different populations. Each allele occurs on an extended haplotype, consistent with positive directional selection.

Daily brief restraint stress alters signaling pathways and induces atrophy and apoptosis in rat skeletal muscle.

Skeletal muscle protein loss, known as atrophy, occurs during inactivity, disease, and aging. Atrophy may be the result of increased catabolic factors, e.g.