Human CCS gene: genomic organization and exclusion as a candidate for amyotrophic lateral sclerosis (ALS)

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive lethal disorder of large motor neurons of the spinal cord and brain. In approximately 20% of the familial and 2% of sporadic cases the disease is due to a defect in the gene encoding the cytosolic antioxidant enzyme Cu, Zn-superoxide dismutase (SOD1). The underlying molecular defect is known only in a very small portion of the remaining cases and therefore involvement of other genes is likely. As SOD1 receives copper, essential for its normal function, by the copper chaperone, CCS (Copper Chaperone for SOD), we considered CCS as a potential candidate gene for ALS. RESULTS: We have characterized the genomic organization of CCS and determined exon-intron boundaries. The 823 bp coding region of the CCS is organized in 8 exons. We have evaluated involvement of the CCS in ALS by sequencing the entire coding region for mutations in 20 sporadic ALS patients. CONCLUSIONS: No causative mutations for the ALS have been detected in the CCS gene in 20 sporadic ALS patients analyzed, but an intragenic single nucleotide polymorphism has been identified

Draft whole-genome sequence of <em>Bacillus sonorensis </em>strain L12, a source of nonribosomal lipopeptides

The Bacillus sonorensis L12 draft genome sequence is approximately 4,647,754 bp in size with a G+C content of 45.2%. Over 86% of the genome contains protein-encoding genes, including several gene clusters for de novo biosynthesis of the nonribosomal lipopeptides iturin, bacitracin, and fengycin, which could mean that the strain exhibits antifungal effects

Phenotypic and genetic characterization of a novel phenotype in pigs characterized by juvenile hairlessness and age dependent emphysema

<p>Abstract</p> <p>Background</p> <p>A pig phenotype characterized by juvenile hairlessness, thin skin and age dependent lung emphysema has been discovered in a Danish pig herd. The trait shows autosomal co-dominant inheritance with all three genotypes distinguishable. Since the phenotype shows resemblance to the integrin β₆-/- knockout phenotype seen in mice, the two genes encoding the two subunits of integrin α_vβ₆, i.e. <it>ITGB6 </it>and <it>ITGAV</it>, were considered candidate genes for this trait.</p> <p>Results</p> <p>The mutated pig phenotype is characterized by hairlessness until puberty, thin skin with few hair follicles and absence of <it>musculi arrectores pili</it>, and at puberty or later localized areas of emphysema are seen in the lungs. Comparative mapping predicted that the porcine <it>ITGB6 </it>and<it>ITGAV </it>orthologs map to SSC15. In an experimental family (n = 113), showing segregation of the trait, the candidate region was confirmed by linkage analysis with four microsatellite markers. Mapping of the porcine <it>ITGB6 </it>and <it>ITGAV </it>in the IMpRH radiation hybrid panel confirmed the comparative mapping information. Sequencing of the <it>ITGB6 </it>and <it>ITGAV </it>coding sequences from affected and normal pigs revealed no evidence of a causative mutation, but alternative splicing of the <it>ITGB6 </it>pre-mRNA was detected. For both <it>ITGB6 </it>and <it>ITGAV </it>quantitative PCR revealed no significant difference in the expression levels in normal and affected animals. In a western blot, ITGB6 was detected in lung protein samples of all three genotypes. This result was supported by flow cytometric analyses which showed comparable reactions of kidney cells from affected and normal pigs with an integrin α_vβ₆monoclonal antibody. Also, immunohistochemical staining of lung tissue with an integrin β₆antibody showed immunoreaction in both normal and affected pigs.</p> <p>Conclusion</p> <p>A phenotype resembling the integrin β₆-/- knockout phenotype seen in mice has been characterized in the pig. The candidate region on SSC15 has been confirmed by linkage analysis but molecular and functional analyses have excluded that the mutated phenotype is caused by structural mutations in or ablation of any of the two candidate genes.</p

Intervention effects on dietary intake among children by maternal education level: results of the Copenhagen School Child Intervention Study (CoSCIS)

Dietary intake among Danish children, in general, does not comply with the official recommendations. The objectives of the present study were to evaluate the 3-year effect of a multi-component school-based intervention on nutrient intake in children, and to examine whether an intervention effect depended on maternal education level. A total of 307 children (intervention group: n 184; comparison group: n 123) were included in the present study. All had information on dietary intake pre- and post-intervention (mean age 6·8 and 9·5 years for intervention and comparison groups, respectively) assessed by a 7-d food record. Analyses were conducted based on the daily intake of macronutrients (energy percentage (E%)), fatty acids (E%), added sugar (E%) and dietary fibre (g/d and g/MJ). Analyses were stratified by maternal education level into three categories. Changes in nutrient intake were observed in the intervention group, mainly among children of mothers with a short education ( < 10 years). Here, intake of dietary fibre increased (β = 2·1 g/d, 95 % CI 0·5, 3·6, P= 0·01). Intake of protein tended to increase (β = 0·6 E%, 95 % CI − 0·01, 1·2, P= 0·05), while intake of fat (β = − 1·7 E%, 95 % CI − 3·8, 0·3, P= 0·09) and SFA (β = − 0·9, 95 % CI − 2·0, 0·2, P= 0·10) tended to decrease. Also, a significant intervention effect was observed on the intake of SFA among children of mothers with a long education (β = − 0·8, 95 % CI − 1·5, − 0·03, P= 0·04). This multi-component school-based intervention resulted in changes in the dietary intake, particularly among children of mothers with a short education. As the dietary intake of this subgroup generally differs most from the recommendations, the results of the present study are particularly encouraging

COX-2-PGE2 Signaling Impairs Intestinal Epithelial Regeneration and Associates with TNF Inhibitor Responsiveness in Ulcerative Colitis

Background: Inhibition of tumor necrosis factor-α (TNF) signaling is beneficial in the management of ulcerative colitis (UC), but up to one-third of patients do not have a clinical response of relevance to TNF inhibitors during induction therapy (i.e. primary non-responders [PNRs]). Through production of prostaglandins (PGs) and thromboxanes, cyclooxygenase-2 (COX-2) affects inflammation and epithelial regeneration and may in this way be implicated in treatment resistance to TNF inhibitors. Methods: In this study, COX-2 expression was analyzed in human intestinal biopsies and patient-derived monocytes, and the downstream consequences of COX-2 activity was evaluated by assessing the influence of the down-stream effector, PGE2, on intestinal epithelial stem cell self-renewal and differentiation using primary human intestinal organoids (“mini-guts”). Findings: We found that TNF stimulation induced COX-2 expression in monocytes isolated from responders (Rs), whereas COX-2 expression was constitutively high and non-inducible in monocytes from PNRs. Additionally, PGE2 in combination with proliferative signals transformed human intestinal epithelial cells to a proinflammatory state akin to flaring UC, whereas PGE2 in combination with differentiation signals supported robust mucin induction. Interpretation: Our work indicates that COX-2-PGE2 signaling could be a novel target for the management of PNRs to TNF inhibitors. We additionally demonstrate that COX-2–PGE2 signaling has dual functions during tissue repair and normal lineage differentiation, explaining in part the lack of response to TNF inhibitors among PNRs. Fund: This work was funded by grants from the Novo Nordisk Foundation, the Lundbeck Foundation, the Vanderbilt Digestive Disease Research Center, NIH Grants, Aase and Ejnar Danielsen's Foundation and the A.P. Møller Foundation. Keywords: COX-2, Intestinal epithelial cells, Monocytes, Prostaglandin E2, Ulcerative coliti

Molecular and Chemical Characterization of the Biosynthesis of the 6-MSA-Derived Meroterpenoid Yanuthone D in Aspergillus niger.

SummarySecondary metabolites in filamentous fungi constitute a rich source of bioactive molecules. We have deduced the genetic and biosynthetic pathway of the antibiotic yanuthone D from Aspergillus niger. Our analyses show that yanuthone D is a meroterpenoid derived from the polyketide 6-methylsalicylic acid (6-MSA). Yanuthone D formation depends on a cluster composed of ten genes including yanA and yanI, which encode a 6-MSA polyketide synthase and a previously undescribed O-mevalon transferase, respectively. In addition, several branching points in the pathway were discovered, revealing five yanuthones (F, G, H, I, and J). Furthermore, we have identified another compound (yanuthone X1) that defines a class of yanuthones that depend on several enzymatic activities encoded by genes in the yan cluster but that are not derived from 6-MSA