Role of antimutagens/anticarcinogens in cancer prevention

Recently it has become increasingly clear that chemicals found in our foods and beverages can prevent the genetic damage that leads to cancer initiation. Such substances may also affect subsequent events in the pathways that lead to cancer, and may have the potential to inhibit the mutations that allow tumor cells to become resistant to antitumor agents. We describe here the antimutagenic potential of Glabrene analogs against EMS-induced mutations utilizing modified Ames tests in S. typhimurium TA 100 and E. coli JC 5088. Results of studies of the ability of well-known antioxidants such as EGCG and related compounds to prevent drug resistance mutations in microorganisms are described, and their possible significance in the prevention of chemotherapeutic drug-resistance in tumor cells is discussed.     

Maintenance of Nef-mediated modulation of major histocompatibility complex class I and CD4 after sexual transmission of human immunodeficiency virus type 1

Viruses encounter changing selective pressures during transmission between hosts, including host-specific immune responses and potentially varying functional demands on specific proteins. The human immunodeficiency virus type 1 Nef protein performs several functions potentially important for successful infection, including immune escape via down-regulation of class I major histocompatibility complex (MHC-I) and direct enhancement of viral infectivity and replication. Nef is also a major target of the host cytotoxic T-lymphocyte (CTL) response. To examine the impact of changing selective pressures on Nef functions following sexual transmission, we analyzed genetic and functional changes in nef clones from six transmission events. Phylogenetic analyses indicated that the diversity of nef was similar in both sources and acutely infected recipients, the patterns of selection across transmission were variable, and regions of Nef associated with distinct functions evolved similarly in sources and recipients. These results weighed against the selection of specific Nef functions by transmission or during acute infection. Measurement of Nef function provided no evidence that the down-regulation of either CD4 or MHC-I was optimized by transmission or during acute infection, although rare nef clones from sources that were impaired in these activities were not detected in recipients. Nef-specific CTL activity was detected as early as 3 weeks after infection and appeared to be an evolutionary force driving the diversification of nef. Despite the change in selective pressure between the source and recipient immune systems and concomitant genetic diversity, the majority of Nef proteins maintained robust abilities to down-regulate MHC-I and CD4. These data suggest that both functions are important for the successful establishment of infection in a new host.     

Guanidinylated neomycin delivers large, bioactive cargo into cells through a heparan sulfate-dependent pathway

Facilitating the uptake of molecules into living cells is of substantial interest for basic research and drug delivery applications. Arginine-rich peptides have been shown to facilitate uptake of high molecular mass cargos into cells, but the mechanism of uptake is complex and may involve multiple receptors. In this report, we show that a derivative of the aminoglycoside antibiotic neomycin, in which all of the ammonium groups have been converted into guanidinium groups, can carry large (>300 kDa) bioactive molecules across cell membranes. Delivery occurs at nanomolar transporter concentrations and under these conditions depends entirely on cell surface heparan sulfate proteoglycans. Conjugation of guanidinoneomycin to the plant toxin saporin, a ribosome-inactivating agent, results in proteoglycan-dependent cell toxicity. In contrast, an arginine-rich peptide shows both heparan sulfate-dependent and -independent cellular uptake. The high selectivity of guanidinoneomycin for heparan sulfate suggests the possibility of exploiting differences in proteoglycan compositions to target delivery to different cell types.     

Physical spousal violence against women in India: some risk factors

Domestic spousal violence against women in developing countries like India, is now beginning to be recognized as a widespread health problem impeding development. This study aimed to explore the risk and protective factors for lifetime spousal physical violence. A cross-sectional household survey was carried out in rural, urban and urban-slum areas across seven sites in India, among women aged 15-49 years, living with a child less than 18 years of age. The sample was selected using the probability proportionate to size method. Trained field workers administered a structured questionnaire to elicit information on spousal physical violence. The main hypothesized variables were social support, witnessed father beating mother and experience of harsh physical violence during childhood, alcohol abuse by spouse and socioeconomic variables. The outcome variables included three physical violence behaviours of hit, kick and beat. Odds ratios were calculated for risk and protective factors of violence using logistic regression. Of 9938 women surveyed, 26% reported experiencing spousal physical violence during the lifetime of their marriage. Adjusted odds ratios calculated using multiple logistic regression analysis suggest that women whose husbands regularly consumed alcohol (OR 5.6; 95% CI 4.7-6.6); who experienced dowry harassment (OR 3.2; 95% CI 2.7-3.8); had reported experiencing harsh physical punishment during childhood (OR 1.6; 95% CI 1.4-1.8) and had witnessed their fathers beat their mothers (OR 1.9; 95% CI 1.6-2.1), were at increased risk of spousal physical violence (beat, hit and kick). Higher socioeconomic status and good social support acted as protective buffers against spousal physical violence. The findings provide compelling evidence of the potential risk factors for spousal physical violence, which in turn could help in planning interventions.     

How high is the level of technical noise in microarray data?

Background  

Microarray gene expression data are commonly perceived as being extremely noisy because of many imperfections inherent in the current technology. A recent study conducted by the MicroArray Quality Control (MAQC) Consortium and published in Nature Biotechnology provides a unique opportunity to probe into the true level of technical noise in such data.     

NMR assignments of the C-terminal domain of human polypeptide release factor eRF1

We report NMR assignments of the protein backbone of the C-terminal domain (163 a.a.) of human class 1 translation termination factor eRF1. It was found that several protein loop residues exist in two slowly interconverting conformational states.     

Bayesian model selection for spatial capture–recapture models

A vast amount of ecological knowledge generated over the past two decades has hinged upon the ability of model selection methods to discriminate among various ecological hypotheses. The last decade has seen the rise of Bayesian hierarchical models in ecology. Consequently, commonly used tools, such as the AIC, become largely inapplicable and there appears to be no consensus about a particular model selection tool that can be universally applied. We focus on a specific class of competing Bayesian spatial capture–recapture (SCR) models and apply and evaluate some of the recommended Bayesian model selection tools: (1) Bayes Factor—using (a) Gelfand‐Dey and (b) harmonic mean methods, (2) Deviance Information Criterion (DIC), (3) Watanabe‐Akaike's Information Criterion (WAIC) and (4) posterior predictive loss criterion. In all, we evaluate 25 variants of model selection tools in our study. We evaluate these model selection tools from the standpoint of selecting the “true” model and parameter estimation. In all, we generate 120 simulated data sets using the true model and assess the frequency with which the true model is selected and how well the tool estimates N (population size), a parameter of much importance to ecologists. We find that when information content is low in the data, no particular model selection tool can be recommended to help realize, simultaneously, both the goals of model selection and parameter estimation. But, in general (when we consider both the objectives together), we recommend the use of our application of the Bayes Factor (Gelfand‐Dey with MAP approximation) for Bayesian SCR models. Our study highlights the point that although new model selection tools are emerging (e.g., WAIC) in the applied statistics literature, those tools based on sound theory even under approximation may still perform much better.     

Pseudogamous Apomixis in Maize and Sorghum in Diploid-Tetraploid Crosses

Apomictic seed development is a complex process including formation of unreduced embryo sac, parthenogenetic embryo development from the egg cell, and endosperm formation either autonomously, or due to fertilization of polar nuclei by the sperm (under pseudogamous form of apomixis). In the latter case, an obstacle to the normal endosperm development is disturbance of maternal (m) -to-paternal (p) genomic ratio 2m: 1p that occurs in the cases of pollination of unreduced embryo sac with haploid sperms. Usage of tetraploid pollinators can overcome this problem because in such crosses maternal-to-paternal genomic ratio is 4m: 2p that provides formation of kernels with plump endosperm. Using tetraploid lines as pollen parents we observed formation of plump kernels on the ears and panicles of diploid maize and sorghum accessions. These kernels had hybrid endosperm and diploid maternaltype embryo or hybrid embryo with different ploidy level (2n, 3n, 4n). The frequencies of plump kernels on the ear ranged from 0.2-0.3% to 5.7-6.2% counting from the number of ovaries. Maternal-type plants were found in two maize lines, their frequency varying from 10.7 to 37.5% of the progeny plants. In CMS-lines of sorghum pollinated with tetraploid sorghum accessions, the frequency of plump kernels ranged from 0.6 to 14.0% counting from the number of ovaries; the frequency of maternal-type plants varied from 33.0 up to 96.1%. The hybrid nature of endosperm of the kernels that gave rise to maternal-type plants has been proved by marker gene expression and by SDS-electrophoresis of endosperm proteins. These data testify to variable modes of seed formation under diploid × tetraploid crosses in maize and sorghum both by amphi- and by apomixis. Therefore, usage of tetraploid pollinators might be a promising approach for isolation of apomixis in maize and sorghum accessions.