Bcr/Abl interferes with the Fanconi anemia/BRCA pathway: implications in the chromosomal instability of chronic myeloid leukemia cells

Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. Although it is well known that CML cells are genetically unstable, the mechanisms accounting for this genomic instability are still poorly understood. Because the Fanconi anemia (FA) pathway is believed to control several mechanisms of DNA repair, we investigated whether this pathway was disrupted in CML cells. Our data show that CML cells have a defective capacity to generate FANCD2 nuclear foci, either in dividing cells or after DNA damage. Similarly, human cord blood CD34(+) cells transduced with BCR/ABL retroviral vectors showed impaired FANCD2 foci formation, whereas FANCD2 monoubiquitination in these cells was unaffected. Soon after the transduction of CD34(+) cells with BCR/ABL retroviral vectors a high proportion of cells with supernumerary centrosomes was observed. Similarly, BCR/ABL induced a high proportion of chromosomal abnormalities, while mediated a cell survival advantage after exposure to DNA cross-linking agents. Significantly, both the impaired formation of FANCD2 nuclear foci, and also the predisposition of BCR/ABL cells to develop centrosomal and chromosomal aberrations were reverted by the ectopic expression of BRCA1. Taken together, our data show for the first time a disruption of the FA/BRCA pathway in BCR/ABL cells, suggesting that this defective pathway should play an important role in the genomic instability of CML by the co-occurrence of centrosomal amplification and DNA repair deficiencies.     

Nickel compound-induced DNA single-strand breaks in chromosomal and nuclear chromatin in human blood lymphocytes in vitro: role of oxidative stress and intracellular calcium

The effects of nickel sulfate, and soluble forms of nickel carbonate hydroxide (NiCH), nickel subsulfide, and nickel oxide on delayed induction of DNA single-strand breaks (DNA SSBs) in chromosomal and nuclear chromatin of human blood lymphocytes in culture were studied. After 46 h of initial culture in supplemented RPMI-1640 media at 37 degrees C, human whole blood lymphocytes in culture were exposed to low concentrations (0-15 microM) of different nickel (Ni) compounds for 2 h, whereas only RPMI-1640 medium served as control. Immediately after 2 h of such exposure, both control and Ni-treated cells were washed with the same medium and incubated further in fresh complete RPMI-1640 culture medium for another 24h. After a total 70 h of incubation, cells were then arrested at metaphase. Two hours later, the induction of DNA SSBs involving both metaphase chromosomal and interphase nuclear chromatin was measured using the method of electron microscopy in situ end-labeling. The metaphase chromosomal chromatin showed significantly higher DNA SSBs (as measured by an increase in immunogold particles per microm2 chromatin) due to 15 microM NiCH and NiO when compared to the corresponding control value. Both NiCH and nickel oxide produced significantly higher induction of DNA SSBs than those of nickel subsulfide and nickel sulfate in chromosomal chromatin. The DNA SSBs in chromosomal chromatin were found to be significantly higher than those in nuclear chromatin due to different Ni compounds. Overall, the genotoxic potency seems to be decreased as follows: NiCH>nickel oxide>or=nickel subsulfide>nickel sulfate. Pretreatment of human blood lymphocytes with either catalase (a H2O2 scavenger), or superoxide dismutase (a scavenger of O2- radical) or dimethylthiourea (a hydroxyl radical scavenger), or N-acetylcysteine (GSH precursor) significantly reduced DNA SSBs in both chromosomal and nuclear chromatin induced by NiCH, suggesting the involvement of different types of oxidative stress in such genotoxicity. Deferoxamine (a highly specific iron chelator) pretreatment prevented NiCH-induced DNA SSBs in both chromosomal and nuclear chromatin suggesting a role of iron-mediated oxidative stress generating hydroxyl radical in such genotoxicity. Simultaneous treatment with either verapamil (an inhibitor of Ca 2+ through plasma membranes), or dantrolene (an inhibitor of mobilization of [Ca2+]i from endoplasmic reticulum), or BAPTA (a Ca2+ chelator) significantly reduced Ni compound-induced DNA SSBs in both chromosomal and nuclear chromatin, suggesting that Ni compound-induced destabilization of calcium homeostasis may also involved in the induction of such DNA SSBs.     

In vitro antioxidant properties,free radicals scavenging activities of extracts and polyphenol composition of a non-timber forest product used as spice: Monodora myristica

Background

Excessive production of free radicals causes direct damage to biological molecules such as DNA, proteins, lipids, carbohydrates leading to tumor development and progression. Natural antioxidant molecules from phytochemicals of plant origin may directly inhibit either their production or limit their propagation or destroy them to protect the system. In the present study, Monodora myristica a non-timber forest product consumed in Cameroon as spice was screened for its free radical scavenging properties, antioxidant and enzymes protective activities. Its phenolic compound profile was also realized by HPLC.

Results

This study demonstrated that M. myristica has scavenging properties against DPPH^•, OH^•, NO^•, and ABTS^• radicals which vary in a dose depending manner. It also showed an antioxidant potential that was comparable with that of Butylated Hydroxytoluene (BHT) and vitamin C used as standard. The aqueous ethanol extract of M. myristica barks (AEH); showed a significantly higher content in polyphenolic compounds (21.44 ± 0.24 mg caffeic acid/g dried extract) and flavonoid (5.69 ± 0.07 quercetin equivalent mg/g of dried weight) as compared to the other studied extracts. The HPLC analysis of the barks and leaves revealed the presence of several polyphenols. The acids (3,4-OH-benzoic, caffeic, gallic, O- and P- coumaric, syringic, vanillic), alcohols (tyrosol and OH-tyrosol), theobromine, quercetin, rutin, catechine and apigenin were the identified and quantified polyphenols. All the tested extracts demonstrated a high protective potential on the superoxide dismutase (SOD), catalase and peroxidase activities.

Conclusion

Finally, the different extracts from M. myristica and specifically the aqueous ethanol extract reveal several properties such as higher free radical scavenging properties, significant antioxidant capacities and protective potential effects on liver enzymes.     

Place-Based Attributes Predict Community Membership in a Mobile Phone Communication Network

Social networks can be organized into communities of closely connected nodes, a property known as modularity. Because diseases, information, and behaviors spread faster within communities than between communities, understanding modularity has broad implications for public policy, epidemiology and the social sciences. Explanations for community formation in social networks often incorporate the attributes of individual people, such as gender, ethnicity or shared activities. High modularity is also a property of large-scale social networks, where each node represents a population of individuals at a location, such as call flow between mobile phone towers. However, whether or not place-based attributes, including land cover and economic activity, can predict community membership for network nodes in large-scale networks remains unknown. We describe the pattern of modularity in a mobile phone communication network in the Dominican Republic, and use a linear discriminant analysis (LDA) to determine whether geographic context can explain community membership. Our results demonstrate that place-based attributes, including sugar cane production, urbanization, distance to the nearest airport, and wealth, correctly predicted community membership for over 70% of mobile phone towers. We observed a strongly positive correlation (r = 0.97) between the modularity score and the predictive ability of the LDA, suggesting that place-based attributes can accurately represent the processes driving modularity. In the absence of social network data, the methods we present can be used to predict community membership over large scales using solely place-based attributes.     

Unmanned Aerial Survey of Elephants

The use of a UAS (Unmanned Aircraft System) was tested to survey large mammals in the Nazinga Game Ranch in the south of Burkina Faso. The Gatewing ×100™ equipped with a Ricoh GR III camera was used to test animal reaction as the UAS passed, and visibility on the images. No reaction was recorded as the UAS passed at a height of 100 m. Observations, made on a set of more than 7000 images, revealed that only elephants (Loxodonta africana) were easily visible while medium and small sized mammals were not. The easy observation of elephants allows experts to enumerate them on images acquired at a height of 100 m. We, therefore, implemented an aerial strip sample count along transects used for the annual wildlife foot count. A total of 34 elephants were recorded on 4 transects, each overflown twice. The elephant density was estimated at 2.47 elephants/km² with a coefficient of variation (CV%) of 36.10%. The main drawback of our UAS was its low autonomy (45 min). Increased endurance of small UAS is required to replace manned aircraft survey of large areas (about 1000 km of transect per day vs 40 km for our UAS). The monitoring strategy should be adapted according to the sampling plan. Also, the UAS is as expensive as a second-hand light aircraft. However the logistic and flight implementation are easier, the running costs are lower and its use is safer. Technological evolution will make civil UAS more efficient, allowing them to compete with light aircraft for aerial wildlife surveys.     

Variance in the reproductive success of dominant male mountain gorillas

Using 30 years of demographic data from 15 groups, this study estimates how harem size, female fertility, and offspring survival may contribute to variance in the siring rates of dominant male mountain gorillas throughout the Virunga Volcano Region. As predicted for polygynous species, differences in harem size were the greatest source of variance in the siring rate, whereas differences in female fertility and offspring survival were relatively minor. Harem size was positively correlated with offspring survival, even after removing all known and suspected cases of infanticide, so the correlation does not seem to reflect differences in the ability of males to protect their offspring. Harem size was not significantly correlated with female fertility, which is consistent with the hypothesis that mountain gorillas have minimal feeding competition. Harem size, offspring survival, and siring rates were not significantly correlated with the proportion of dominant tenures that occurred in multimale groups versus one-male groups; even though infanticide is less likely when those tenures end in multimale groups than one-male groups. In contrast with the relatively small contribution of offspring survival to variance in the siring rates of this study, offspring survival is a major source of variance in the male reproductive success of western gorillas, which have greater predation risks and significantly higher rates of infanticide. If differences in offspring protection are less important among male mountain gorillas than western gorillas, then the relative importance of other factors may be greater for mountain gorillas. Thus, our study illustrates how variance in male reproductive success and its components can differ between closely related species.     

The diet of the mud clam Geloina coaxans (Mollusca, Bivalvia) as indicated by fatty acid markers in a subtropical mangrove forest of Okinawa, Japan

Fatty acid compositions in the tissues of the clam Geloina coaxans collected from Oura mangal, Okinawa, Japan, during the cold and warm seasons (January and July 2001, respectively) were compared with those in suspended materials (SM) in order to assess the clams' diet. In both seasons, the suspended mangrove detritus at the sediment-water interface was high as indicated by the mean percentage of even-numbered long-chain fatty acids in SM (12.8-18.4%). The contribution of this marker in the clam tissues, especially during the cold season (3.9%), indicates the consumption of mangrove detritus in considerable amounts by the clams. The occurrence of the fatty acids 16:1ω7, 18:1ω9, 18:2ω6 and 18:3ω3 in SM was most likely due to the mangrove detritus sources, whereas in the SM they together constituted 12.9% and 23.9% of total fatty acid contents during the cold and warm seasons, respectively. As a result, their contribution in the clam tissues was high in the cold (15.4%) and warm seasons (19.0%). These results indicate that mangrove detritus play a significant role in the clams' diet. The mean percentages of bacterial markers (odd-numbered branched fatty acids and vaccenic acid, 18:1ω7) in the SM and tissues during both seasons ranged from 8.1% to 9.5%. This indicates that the clam diet is also dependent on the attached bacteria on the partially decomposed leaf detritus suspended at the sediment-water interface. The relative contribution by microalgae markers (18:4ω3, 20:5ω3 and 22:6ω3) in clam tissues ranged from 4.3% to 7.6%, suggesting considerable microalgae sources in the diets.     

Salmonella-mediated mucosal cell-mediated immunity.

Oral immunization with the recombinant Salmonella typhimurium strain (BRD 847) expressing the C fragment of tetanus toxin (TT) induces brisk Ag-specific mucosal S-IgA and serum Ab responses characterized by strong IgG2a Abs to the encoded antigen. We have constructed an attenuated Salmonella typhimurium (aroA- aroD-) strain that expresses chicken egg albumin (OVA) to further elucidate the role of Salmonella-induced Th1 cell phenotype on mucosal cell-mediated immunity (CMI). Peyer's patches and spleen lymphocytes from mice that received the oral Salmonella-OVA vaccine showed dramatic increases in the percent cell lysis of the H-2b restricted EG7.OVA tumor cell line. These results indicate that a single dose of rSalmonella vaccine antigen vector is required to illicit systemic and mucosal Th1-type responses and CTLs. These results also support the existence of a highly regulated relationship between specific cell-mediated immunity and a branch of the humoral immune system, i.e. mucosal IgA responses.