On the length of the longest exact position match in a random sequence.

A mixed Poisson approximation and a Poisson approximation for the length of the longest exact match of a random sequence across another sequence are provided, where the match is required to start at position 1 in the first sequence. This problem arises when looking for suitable anchors in whole genome alignments.

Accuracy assessment of diploid consensus sequences.

If the origins of fragments are known in genome sequencing projects, it is straightforward to reconstruct diploid consensus sequences. In reality, however, this is not true. Although there are proposed methods to reconstruct haplotypes from genome sequencing projects, an accuracy assessment is required to evaluate the confidence of the estimated diploid consensus sequences.

Wingless directly represses DPP morphogen expression via an armadillo/TCF/Brinker complex.

Background: Spatially restricted morphogen expression drives many patterning and regeneration processes, but how is the pattern of morphogen expression established and maintained? Patterning of Drosophila leg imaginal discs requires expression of the DPP morphogen dorsally and the wingless (WG) morphogen ventrally. We have shown that these mutually exclusive patterns of expression are controlled by a self-organizing system of feedback loops that involve WG and DPP, but whether the feedback is direct or indirect is not known.

Methods/findings: By analyzing expression patterns of regulatory DNA driving reporter genes in different genetic backgrounds, we identify a key component of this system by showing that WG directly represses transcription of the dpp gene in the ventral leg disc.

[The significance of IL-13 gene +2044G/A mutation in patients with inflammatory bowel disease].

Background: Inflammatory bowel disease (IBD) is caused by a combination of genetic, immunological and environmental factors. Despite recent advances in the study of IBD pathogenesis, including the discovery of the NOD2/CARD15 mutation in 40% of Crohn's Disease (CD) patients, in most IBD patients no known mutations have yet been discovered. The interleukin (IL)-13 gene is located near the IBD5 locus on chromosome 5q31, known to be in linkage disequilibrium with CD.

Diversity of LEF/TCF action in development and disease.

Lymphoid enhancer factor/T cell factor proteins (LEF/TCFs) mediate Wnt signals in the nucleus by recruiting beta-catenin and its co-activators to Wnt response elements (WREs) of target genes. This activity is important during development but its misregulation plays a role in disease such as cancer, where overactive Wnt signaling drives LEF/TCFs to transform cells. The size of the LEF/TCF family is small: approximately four members in vertebrates and one orthologous form in flies, worms and hydra.

Vitality, mental health, and satisfaction with information after breast cancer.

Objective: The purpose of this study was to investigate the relationship between satisfaction with information about treatment-related and survivorship issues and mental health outcomes, including vitality, in long-term breast cancer survivors.

Methods: Participants who had finished treatment for breast cancer at least 3 months before enrollment completed a survey instrument designed to evaluate satisfaction with diagnostic and treatment information and satisfaction with survivorship information. Mental health and vitality were measured using the Medical Outcomes Study SF-36, and distress was measured using the impact of events scale.

The cytochrome P450 gene family CYP157 does not contain EXXR in the K-helix reducing the absolute conserved P450 residues to a single cysteine.

In this work, we have spectroscopically characterised CYP157C1 from Streptomyces coelicolor A3(2) which has the motif E(297)QSLW(301) rather than the invariant EXXR motif in the P450 K-helix. Site-directed mutagenesis of native E(297)QSLW(301) in CYP157C1 to E(297)ESLR(301) or E(297)QSRW(301) both containing standard EXXR motifs produced cytochrome P420 proteins thought to be inactive forms of P450 even though wild type CYP157C1 has the spectral properties of a normal P450. These results indicate that the EXXR motif is not required in all CYP tertiary architectures and only a single cysteine residue, which coordinates as the fifth thiolate ligand to the P450 haem iron, is invariant in all CYPs structures.

Gene Aging Nexus: a web database and data mining platform for microarray data on aging.

The recent development of microarray technology provided unprecedented opportunities to understand the genetic basis of aging. So far, many microarray studies have addressed aging-related expression patterns in multiple organisms and under different conditions. The number of relevant studies continues to increase rapidly.

Understanding electron transport systems of Streptomyces cytochrome P450.

Streptomyces spp. are known to produce various types of biologically active compounds including antibiotics, antiparasitic agents, herbicides and immunosuppressants. P450 (cytochrome P450) enzymes may have key roles in these biosynthetic and biotransformation reactions.

Biodiversity of CYP51 in trypanosomes.

Sterol 14alpha-demethylases (CYP51) are metabolic cytochromes P450, found in each biological kingdom. They catalyse a single three-step reaction included in all sterol biosynthetic pathways. Plant CYP51s have strict preference towards their physiological substrate O (obtusifoliol), which is C-4-monomethylated.

Evaluation of the PillCam Colon capsule in the detection of colonic pathology: results of the first multicenter, prospective, comparative study.

Background And Study Aims: Population-based screening for colorectal cancer is widely recommended, with conventional colonoscopy considered to be the preferred diagnostic modality. However, compliance with screening colonoscopy is low and manpower capacity is limited. Capsule endoscopy might therefore represent a desirable alternative strategy.

An algorithm for assembly of ordered restriction maps from single DNA molecules.

The restriction mapping of a massive number of individual DNA molecules by optical mapping enables assembly of physical maps spanning mammalian and plant genomes; however, not through computational means permitting completely de novo assembly. Existing algorithms are not practical for genomes larger than lower eukaryotes due to their high time and space complexity. In many ways, sequence assembly parallels map assembly, so that the overlap-layout-consensus strategy, recently shown effective in assembling very large genomes in feasible time, sheds new light on solving map construction issues associated with single molecule substrates.

Heparanase upregulation by colonic epithelium in inflammatory bowel disease.

Heparanase is an endo-beta-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, yielding HS fragments of still appreciable size ( approximately 5-7 kDa). Heparanase activity has long been detected in a number of cell types and tissues. Importantly, heparanase activity correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the extracellular matrix barrier.

Integrative missing value estimation for microarray data.

Background: Missing value estimation is an important preprocessing step in microarray analysis. Although several methods have been developed to solve this problem, their performance is unsatisfactory for datasets with high rates of missing data, high measurement noise, or limited numbers of samples. In fact, more than 80% of the time-series datasets in Stanford Microarray Database contain less than eight samples.

Expression of lymphoid enhancer factor/T-cell factor proteins in colon cancer.

Molecular genetic analysis of colon cancers has established that the Wnt signaling pathway is involved in early tumor development. Mutation of midstream components can activate the pathway, making it independent of Wnt ligands and maintaining constant pressure to change target gene expression. The transcription factors that connect the pathway to target genes are members of the lymphoid enhancer factor/T-cell factor (LEF/TCF) family.

Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms.

The CYP51 family is an intriguing subject for fundamental P450 structure/function studies and is also an important clinical drug target. This review updates information on the variety of the CYP51 family members, including their physiological roles, natural substrates and substrate preferences, and catalytic properties in vitro. We present experimental support for the notion that specific conserved regions in the P450 sequences represent a CYP51 signature.

Exploiting Streptomyces coelicolor A3(2) P450s as a model for application in drug discovery.

One of the surprising discoveries about the genomics of the cytochrome P450 (CYP) superfamily is the large number of CYPs in the bacterial class of actinomycetes. It had previously been imagined that bacteria have small numbers of CYPs or none at all. Particularly intriguing is that the bacterial genus Streptomyces, which produce a large number of secondary metabolites with important medical application, has a large CYP complement reflecting the ecological niche that the organism finds itself in.

Driving aggression in forensic and non-forensic populations: relationships to self-reported levels of aggression, anger and impulsivity.

A series of four questionnaires - the Buss-Perry Aggression Questionnaire (AQ), the Barratt Impulsivity Scale (BIS-11), the Driving Anger Scale (DAS) and a Driving Violence Inventory (DVI) - were administered to a sample of 473 British drivers consisting of undergraduates (N=185), members of the public (N=106) and offenders (N=182) serving sentences in closed prisons in England (violent=82, non-violent=100). Offenders consistently rated acts of driving aggression as less severe compared with other drivers. Offender attributions of driving violence differed to other drivers in that they were equally likely to perceive obscene gesturing as high or low intensity responses; they also viewed assault as a high intensity response whereas members of the public rated it more severely.

The structural basis for substrate anchoring, active site selectivity, and product formation by P450 PikC from Streptomyces venezuelae.

The pikromycin (Pik)/methymycin biosynthetic pathway of Streptomyces venezuelae represents a valuable system for dissecting the fundamental mechanisms of modular polyketide biosynthesis, aminodeoxysugar assembly, glycosyltransfer, and hydroxylation leading to the production of a series of macrolide antibiotics, including the natural ketolides narbomycin and pikromycin. In this study, we describe four x-ray crystal structures and allied functional studies for PikC, the remarkable P450 monooxygenase responsible for production of a number of related macrolide products from the Pik pathway. The results provide important new insights into the structural basis for the C10/C12 and C12/C14 hydroxylation patterns for the 12-(YC-17) and 14-membered ring (narbomycin) macrolides, respectively.

Biophysical characterization of the sterol demethylase P450 from Mycobacterium tuberculosis, its cognate ferredoxin, and their interactions.

Mycobacterium tuberculosis encodes a P450 of the sterol demethylase family (CYP51) chromosomally located adjacent to a ferredoxin (Fdx). CYP51 and Fdx were purified to homogeneity and characterized. Spectroscopic analyses were consistent with cysteinate- and aqua-ligated heme iron in CYP51.

Wnt activation and alternative promoter repression of LEF1 in colon cancer.

Alternative promoters within the LEF1 locus produce polypeptides of opposing biological activities. Promoter 1 produces full-length LEF-1 protein, which recruits beta-catenin to Wnt target genes. Promoter 2 produces a truncated form that cannot interact with beta-catenin and instead suppresses Wnt regulation of target genes.

Ligand-assisted inhibition in cytochrome P450 158A2 from Streptomyces coelicolor A3(2).

Cytochrome P450 158A2 (CYP158A2) can polymerize flaviolin to red-brown pigments, which may afford physical protection to the organism, possibly against the deleterious effects of UV radiation. We have found that the small molecule malonic acid enables cocrystallization of this mixed function oxidase with the azole inhibitor 4-phenylimidazole. The presence of malonate molecules affects the behavior of the binding of 4-phenylimidazole to CYP158A2 and increases inhibition potency up to 2-fold compared to 4-phenylimidazole alone.

Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel.

Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10-/- mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets.

Raman evidence for specific substrate-induced structural changes in the heme pocket of human cytochrome P450 aromatase during the three consecutive oxygen activation steps.

Specific substrate-induced structural changes in the heme pocket are proposed for human cytochrome P450 aromatase (P450arom) which undergoes three consecutive oxygen activation steps. We have experimentally investigated this heme environment by resonance Raman spectra of both substrate-free and substrate-bound forms of the purified enzyme. The Fe-CO stretching mode (nu(Fe)(-)(CO)) of the CO complex and Fe(3+)-S stretching mode (nu(Fe)(-)(S)) of the oxidized form were monitored as a structural marker of the distal and proximal sides of the heme, respectively.