饲喂黄曲霉毒素B_1大鼠肝中AFB_1-DNA加合物的免疫组织化学研究

应用免疫组织化学ＳＰ法对４例饲喂黄曲霉毒素Ｂ１的Ｗｉｓｔａｒ大鼠肝组织中ＡＦＢ１－ＤＮＡ加合物的染色及常规ＨＥ染色发现,４例肝细胞核均出现异型性,但未见肝细胞坏死、增生灶及肝细胞癌;免疫组化揭示部分肝细胞核出现棕黄色、不均质状的ＡＦＢ１－ＤＮＡ加合物,阳性细胞数占１０～８５％。结果提示免疫组织化学方法可作为一种ＡＦＢ１的定位方法,ＡＦＢ１在动物致癌过程中ＡＦＢ１－ＤＮＡ加合物可能具有启动作用     

Encounter with New Resources Causes Polarized Growth of the Cord-Forming Basidiomycete Phanerochaete velutina on Soil

Abstract The development and physiology of cord-forming saprotrophic basidiomycetes, which form extensive and persistent mycelial networks in woodland ecosystems, can be conveniently studied on non-sterile soil in laboratory microcosms mimicking field conditions. Morphological responses of Phanerochaete velutina mycelial systems to resource encounters, and decay partitioning following encounters, varied according to whether simulated woody litter was unsterile or autoclaved and on whether encounter took place at the mycelial foraging front or behind the margin (simulating litter fall onto established systems in the field). Results show that encounter of discrete resources by P. velutina is rapidly communicated to the entire mycelial system; that resource capture takes high priority at the expense of continued system extension and decay-derived carbon reallocation; and that polarized growth toward newly encountered resources, previously considered to occur infrequently with this species, may be readily detected using image analysis techniques. Potential advantages of polarized development of P. velutina are discussed.     

Unusual genotypes in the COL6A1 gene in parents of children with trisomy 21 and major congenital heart defects

Collagen type VI is a candidate for a role in the pathogenesis of congenital heart defects (CHD) in Down's syndrome. Three restriction fragment length polymorphisms of the COL6A1 gene were used to determine COL6A1 genotypes in 50 families of affected children with trisomy 21 (29 with congenital heart defects and 21 without) and 37 unrelated volunteers. We found seven unusual genotypes in the parents of affected children with Down's syndrome, five being unique to the parents of children with trisomy 21 and CHD. There were no unusual genotypes associated with other chromosome 21 loci. No single COL6A1 genotype was associated with CHD. Thus, the unusual genotypes unique to parents of affected children suggest that genetic variation in the COL6A1 gene region contributes to the pathogenesis of CHD in Down's syndrome.     

An alpha satellite DNA polymorphism specific for the centromeric region of chromosome 13

Alpha satellite DNA is composed of variants of a short consensus sequence that are repeated in tandem arrays in the centromeric heterochromatin of each human chromosome. To define centromeric markers for linkage studies, we screened human genomic DNA for restriction fragment length polymorphisms using a probe detecting alphoid sequences on chromosomes 13 and 21. We describe one such DNA polymorphism. Analysis of linkage of this DNA marker to other polymorphic markers in the CEPH pedigrees demonstrates linkage to markers on the proximal long arm of chromosome 13 and defines the centromeric end of the linkage map of this chromosome.     

A test of the hypothesis that age at onset in Huntington disease is controlled by an X-linked recessive modifier.

Data from the Research Roster for Huntington Disease Patients and Families were used to assess the hypothesis that juvenile onset in Huntington disease is determined by an X-linked recessive modifying gene in the affected parent. The observed proportion of affected fathers to affected mothers who had such offspring was not compatible with this hypothesis. Furthermore, neither the excess of affected grandfathers nor the existence of juvenile-onset and adult-onset cases within a sibship would be predicted by this model. We also rejected a more general hypothesis that a major change in gene expression across generations, measured by the presence of juvenile onset and/or major anticipation, is determined by an X-linked modifier. However, the inheritance of a propensity toward juvenile onset via the affected male line could be due to an abnormal pattern of paternal genomic imprinting.     

Performance of random forest when SNPs are in linkage disequilibrium

Background

Proteases of human pathogens are becoming increasingly important drug targets, hence it is necessary to understand their substrate specificity and to interpret this knowledge in practically useful ways. New methods are being developed that produce large amounts of cleavage information for individual proteases and some have been applied to extract cleavage rules from data. However, the hitherto proposed methods for extracting rules have been neither easy to understand nor very accurate. To be practically useful, cleavage rules should be accurate, compact, and expressed in an easily understandable way.

Results

A new method is presented for producing cleavage rules for viral proteases with seemingly complex cleavage profiles. The method is based on orthogonal search-based rule extraction (OSRE) combined with spectral clustering. It is demonstrated on substrate data sets for human immunodeficiency virus type 1 (HIV-1) protease and hepatitis C (HCV) NS3/4A protease, showing excellent prediction performance for both HIV-1 cleavage and HCV NS3/4A cleavage, agreeing with observed HCV genotype differences. New cleavage rules (consensus sequences) are suggested for HIV-1 and HCV NS3/4A cleavages. The practical usability of the method is also demonstrated by using it to predict the location of an internal cleavage site in the HCV NS3 protease and to correct the location of a previously reported internal cleavage site in the HCV NS3 protease. The method is fast to converge and yields accurate rules, on par with previous results for HIV-1 protease and better than previous state-of-the-art for HCV NS3/4A protease. Moreover, the rules are fewer and simpler than previously obtained with rule extraction methods.

Conclusion

A rule extraction methodology by searching for multivariate low-order predicates yields results that significantly outperform existing rule bases on out-of-sample data, but are more transparent to expert users. The approach yields rules that are easy to use and useful for interpreting experimental data.     

Intestinal barrier function in response to abundant or depleted mucosal glutathione in Salmonella-infected rats

Background  

Glutathione, the main antioxidant of intestinal epithelial cells, is suggested to play an important role in gut barrier function and prevention of inflammation-related oxidative damage as induced by acute bacterial infection. Most studies on intestinal glutathione focus on oxidative stress reduction without considering functional disease outcome. Our aim was to determine whether depletion or maintenance of intestinal glutathione changes susceptibility of rats to Salmonella infection and associated inflammation.     

Anti-Angiogenic/Vascular Effects of the mTOR Inhibitor Everolimus Are Not Detectable by FDG/FLT-PET

Noninvasive functional imaging of tumors can provide valuable early-response biomarkers, in particular, for targeted chemotherapy. Using various experimental tumor models, we have investigated the ability of positron emission tomography (PET) measurements of 2-deoxy-2-[¹⁸F]fluoro-glucose (FDG) and 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) to detect response to the allosteric mammalian target of rapamycin (mTOR) inhibitor everolimus. Tumor models were declared sensitive (murine melanoma B16/BL6 and human lung H596) or relatively insensitive (human colon HCT116 and cervical KB31), according to the IC₅₀ values (concentration inhibiting cell growth by 50%) for inhibition of proliferation in vitro (<10 nM and >1 µM, respectively). Everolimus strongly inhibited growth of the sensitive models in vivo but also significantly inhibited growth of the insensitive models, an effect attributable to its known anti-angiogenic/vascular properties. However, although tumor FDG and FLT uptake was significantly reduced in the sensitive models, it was not affected in the insensitive models, suggesting that endothelial-directed effects could not be detected by these PET tracers. Consistent with this hypothesis, in a well-vascularized orthotopic rat mammary tumor model, other antiangiogenic agents also failed to affect FDG uptake, despite inhibiting tumor growth. In contrast, the cytotoxic patupilone, a microtubule stabilizer, blocked tumor growth, and markedly reduced FDG uptake. These results suggest that FDG/FLT-PET may not be a suitable method for early markers of response to antiangiogenic agents and mTOR inhibitors in which anti-angiogenic/vascular effects predominate because the method could provide false-negative responses. These conclusions warrant clinical testing.