Effect of insulin on the synthesis and release of lipid peroxide by cultured hepatocytes isolated from normal and diabetic rats

Lipid peroxide content in hepatocytes isolated from ketotic diabetic rats was higher than normal, and the release of peroxide into the media was also elevated for the initial 18 h. Insulin suppressed both peroxide release and synthesis by cultured hepatocytes isolated from normal and from diabetic rats.     

The opportunistic pathogen Pseudomonas aeruginosa activates the DNA double-strand break signaling and repair pathway in infected cells

Highly hazardous DNA double-strand breaks can be induced in eukaryotic cells by a number of agents including pathogenic bacterial strains. We have investigated the genotoxic potential of Pseudomonas aeruginosa, an opportunistic pathogen causing devastating nosocomial infections in cystic fibrosis or immunocompromised patients. Our data revealed that infection of immune or epithelial cells by P. aeruginosa triggered DNA strand breaks and phosphorylation of histone H2AX (γH2AX), a marker of DNA double-strand breaks. Moreover, it induced formation of discrete nuclear repair foci similar to gamma-irradiation-induced foci, and containing γH2AX and 53BP1, an adaptor protein mediating the DNA-damage response pathway. Gene deletion, mutagenesis, and complementation in P. aeruginosa identified ExoS bacterial toxin as the major factor involved in γH2AX induction. Chemical inhibition of several kinases known to phosphorylate H2AX demonstrated that Ataxia Telangiectasia Mutated (ATM) was the principal kinase in P. aeruginosa-induced H2AX phosphorylation. Finally, infection led to ATM kinase activation by an auto-phosphorylation mechanism. Together, these data show for the first time that infection by P. aeruginosa activates the DNA double-strand break repair machinery of the host cells. This novel information sheds new light on the consequences of P. aeruginosa infection in mammalian cells. As pathogenic Escherichia coli or carcinogenic Helicobacter pylori can alter genome integrity through DNA double-strand breaks, leading to chromosomal instability and eventually cancer, our findings highlight possible new routes for further investigations of P. aeruginosa in cancer biology and they identify ATM as a potential target molecule for drug design.     

Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.     

Scientific authorship in the age of collaborative research

I examine two challenges that collaborative research raises for science. First, collaborative research threatens the motivation of scientists. As a result, I argue, collaborative research may have adverse effects on what sorts of things scientists can effectively investigate. Second, collaborative research makes it more difficult to hold scientists accountable. I argue that the authors of multi-authored articles are aptly described as plural subjects, corporate bodies that are more than the sum of the individuals involved. Though journal editors do not currently conceive of the authors of multi-authored articles this way, this conception provides us with the conceptual resources to make sense of how collaborating scientists behave.     

Gastric mucus effusion elicited by oral copper compounds: Potential anti-ulcer activity

Summary In rats, both Cu(I) and Cu(II) show an irritancy profile not shared with Cu^o or Zn(II) or Ni(II). The gastric response to Cu(II), i.e. copius fluid and mucus secretion, can protect the stomach from the acute ulcerative effects of aspirin or physical stress administered subsequently.to whom all enquiries should be addressed, Supported by grants from the National Health and Medical Research Council (Austr.) and University of Tasmania Research Commitee.Acknowledgments: ProfessorsW. R. Walker (Newcastle, Austr.) andL. Field (Nashville, Tenn.) for gifts of Cu(I) and Zn complexes;Dr. J. R. J. Sorenson (Cincinnatti, Ohio) for illuminating discussion; Drs.D. D. Perrin (Canberra) andR. P. Agarwal (Washington D. C.) for providing stability constants and much helpful advice.     

Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.     

The evaluation of biologically active supernatants of cultures of lymphoid cells from rabbits with delayed (cellular) hypersensitivity on a macrophage layer

Zusammenfassung Supernatanten aus Kulturen überempfindlicher Lymphozyten und dem spezifischen Antigen mit MIF-Aktivität können die Entstehung der Pseudopodien normaler Makrophagen verhindern und zeigen nach längerem Kultivieren zuweilen toxische Eigenschaften.