Checkpoint genes and Exo1 regulate nearby inverted repeat fusions that form dicentric chromosomes in Saccharomyces cerevisiae

Genomic rearrangements are common, occur by largely unknown mechanisms, and can lead to human diseases. We previously demonstrated that some genome rearrangements occur in budding yeast through the fusion of two DNA sequences that contain limited sequence homology, lie in inverted orientation, and are within 5 kb of one another. This inverted repeat fusion reaction forms dicentric chromosomes, which are well-known intermediates to additional rearrangements. We have previously provided evidence indicating that an error of stalled or disrupted DNA replication forks can cause inverted repeat fusion. Here we analyze how checkpoint protein regulatory pathways known to stabilize stalled forks affect this form of instability. We find that two checkpoint pathways suppress inverted repeat fusion, and that their activities are distinguishable by their interactions with exonuclease 1 (Exo1). The checkpoint kinase Rad53 (Chk2) and recombination protein complex MRX(MRN) inhibit Exo1 in one pathway, whereas in a second pathway the ATR-like kinases Mec1 and Tel1, adaptor protein Rad9, and effector kinases Chk1 and Dun1 act independently of Exo1 to prevent inverted repeat fusion. We provide a model that indicates how in Rad53 or MRX mutants, an inappropriately active Exo1 may facilitate faulty template switching between nearby inverted repeats to form dicentric chromosomes. We further investigate the role of Rad53, using hypomorphic alleles of Rad53 and null mutations in Rad9 and Mrc1, and provide evidence that only local, as opposed to global, activity of Rad53 is sufficient to prevent inverted repeat fusion.     

Mortality among chemical workers at Texas City plant: 1940–2001

Objectives  To evaluate the mortality experience of workers at a major chemical manufacturing site and to examine brain and liver cancers excesses reported at this site in previous studies. Methods  This study included 9,730 employees at the Texas City location who worked between 1940 and 2001. Standardized mortality ratios and confidence intervals were calculated. Results  There was less than expected deaths due to all cause mortality and no increase in all cancer mortality. Brain tumor mortality, which did exceed expected rates in past years, was at expected levels in recent years. Liver cancer mortality was greater than expected. Conclusion  Brain tumor mortality was either due to chance in the early years or the cause of the brain tumors has been eliminated. Mortality due to liver cancer is higher than expected but only among men hired before 1950. Eugenio Salazar is deceased.     

Onopordum cynarocephalum induces apoptosis and protects against 1,2 dimethylhydrazine-induced colon cancer

The potential chemopreventive properties of the crude extract of Onopordum cynarocephalum were evaluated. Growth inhibition was investigated in FHs74Int human normal intestinal cells and ModeK mouse normal intestinal cell line and in two human colon cancer cells HCT-116 (p53+/+) and HT-29 (p53+/-). The extract was not cytotoxic to FHs74Int cells at concentrations 2-fold higher than the IC50 of HCT-116 cells. The extract inhibited dose-dependently the growth of HCT-116 cells (IC50=0.18 mg/ml) to a greater extent than HT-29 cells (IC50=1.8 mg/ml). The p53 wild-type HCT-116 cells were more sensitive than p53 mutant HT-29 cells to the pro-apoptotic effects of the plant extract; five times lower concentrations were needed to induce apoptosis in HCT-116 cells. Apoptosis induction by the extract was associated with an increase in the expression of pro-apoptotic proteins such as p53 and Bax, and a significant inhibition of the anti-apoptotic protein Bcl-2. Significant decrease in cyclin D1 protein and increase in p21 protein was observed in extract-treated HCT-116 cells. In vivo, the crude extract injected intra-peritoneally reduced the number of tumors by 64% (p<0.0001) and decreased the mean size of aberrant crypt foci in the DMH model of colon cancer. These data collectively suggest that O. cynarocephalum has potential anti-colon cancer effects.     

The University Worksite Organ Donation Project: a comparison of two types of worksite campaigns on the willingness to donate

Morgan SE, Stephenson MT, Afifi W, Harrison TR, Long SD, Chewning LV. The University Worksite Organ Donation Project: a comparison of two types of worksite campaigns on the willingness to donate.
Clin Transplant 2011: 25: 600–605. © 2010 John Wiley & Sons A/S. Abstract: To test the impact of different campaign strategies, a year‐long campaign was conducted to promote organ donation among university faculty, staff, and students. Two universities were assigned to each of three conditions: a media‐only campaign, a mass media‐plus‐interpersonal outreach condition, and a control condition. Universities were counter‐balanced by geographic region and diversity of population. Changes from pretest to post‐test on the key‐dependent measures, including signing a donor card and discussing donation with family members, were significantly greater in the media‐plus‐interpersonal condition than either the mass media only or control conditions. Implications for the creation of campaigns to promote other health behaviors are examined.     

Influence of dipyridamole and its combination with NO donor or NO synthase inhibitor on adjuvant arthritis

The anti-arthritic and anti-inflammatory effects of dipyridamole and the possible involvement of NO in the dipyridamole action are not yet clear. The aim of this study was to evaluate the effects of dipyridamole alone and in combination with either the nitric oxide donor, sodium nitroprusside (SNP) or the non-selective nitric oxide synthase inhibitor, L-NG- monomethyl arginine (L-NMMA), on pathogenesis of adjuvant-induced arthritis model in rats. The results of the present work showed that prophylactic administration of dipyridamole alone and dipyridamole administration in combination with either low dose of SNP or L-NMMA significantly ameliorated pathogenesis of adjuvant arthritis in rats as evidenced by significant decrease in arthritis index, hind paws volume, loss of body weight, hyperalgesia compared with control vehicle (1% DMSO) treated adjuvant arthritic rats. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10(IL-10) levels were significantly increased in these groups of animals. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of dipyridamole. The inhibitory effect of therapeutic administration of dipyridamole alone on adjuvant arthritis syndrome was not significantly different from that of vehicle administration. In conclusion, dipyridamole has prophylactic but not therapeutic anti-arthritic and anti-inflammatory effects that appear to be dependent on inhibition of NO synthase. A synergistic combination between dipyridamole and NO synthase inhibitor or low dose of NO donor may have prophylactic and therapeutic values in autoimmune diseases like RA.     

Weaning Recommendations: The Scientific Basis

Current weaning recommendations are based on nutritional need, physiologic maturation, and the behavioral and developmental aspects of infant feeding. Inadequate energy and protein intake and deficiencies of iron, zinc, vitamin A, and vitamin D are the most commonly observed nutrient deficiencies during infancy and weaning recommendations have focused on their prevention. This article reviews the data and summarizes implications for infant weaning in both developed and developing countries. Current published recommendations for infant feeding are outlined and major concerns are highlighted.     

Effects of a Ferula sinaica root extract on the uterine smooth muscle of rat and guinea pig

The effects of an ethanolic extract of Ferula sinaica roots on the uterine smooth muscles of rats and guinea pigs were tested in vitro using isolated uterine horns. The extract inhibited the spontaneous movements of rat and guinea pig uterine smooth muscle and also the contractions induced by oxytocin stimulation. These effects were concentration-dependent and reversible by tissue washing. These data suggest that this plant extract may have some antioxytocic potential.     

Mapping of a novel type III variant of Knobloch syndrome (KNO3) to chromosome 17q11.2

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by ocular abnormalities (myopia and retinal detachment) and occipital encephalocele. The syndrome is clinically and genetically heterogeneous (KNO1, KNO2). Previously germline mutations in COL18A1 (21q22.3) were detected in some families, but in other kindreds linkage to COL18A1 was excluded. We ascertained a large consanguineous family with high myopia, vitreoretinal degeneration and occipital scalp defect with autosomal recessive mode of inheritance. Due to the overlapping clinical presentation of this family with Knobloch syndrome we propose this phenotype as a type III variant of KS (KNO3). A genome wide linkage study using microsatellite markers at 10-20 cM interval revealed linkage to 17q11.2 with a maximum LOD scores 3.40 (theta = 0.00) for markers D17S1307 and D17S1166. Fine mapping defined a 2.67 cM disease region between D17S1307 and D17S798. Mutation analysis of three candidate genes (UNC119, MYO1D, and RAB11FIP4) within the disease region did not identify any disease-associated mutation in affected individuals.