Molecular and cellular mechanisms in nervous system-specific carcinogenesis by N-ethyl-N-nitrosourea

A single pulse of N-ethyl-N-nitrosourea (ENU), applied to BDIX rats during the perinatal age, specifically results in a high incidence of neuroectodermal neoplasms in the central and peripheral nervous system (NS). The pronounced sensitivity of the developing NS suggests a dependence of the carcinogenic effect on the proliferative and/or differentiative state of the target cells at the time of the ENU pulse. The specificity of ENU for the NS cannot be due to tissue variations in the degree of carcinogen-cell interactions, since the reactive, electrophilic ethyl cation is produced by rapid, nonenzymatic decomposition of ENU indiscriminately in all tissues. Correspondingly, the initial molar fractions of ethylated purine bases are similar in the DNA of "high-risk" (perinatal brain) and "low-risk" tissues (e.g., liver; adult brain). However, while the respective half lives in DNA of N7-ethylguanine and N3-ethyladenine show only minor differences for both types of tissues, the mutagenic ethylation product 06-ethylguanine is removed from brain DNA very much more slowly than from the DNA of other tissues. Together with their high rate of DNA replication during the perinatal age, the incapacity of rat brain cells for enzymatic elimination of 06-alkylguanine from their DNA could account for an increased probability of neoplastic conversion, and hence for the NS specificity of ENU in the rat

The Anopheles gambiae Odorant Binding Protein 1 (AgamOBP1) Mediates Indole Recognition in the Antennae of Female Mosquitoes

Haematophagous insects are frequently carriers of parasitic diseases, including malaria. The mosquito Anopheles gambiae is the major vector of malaria in sub-Saharan Africa and is thus responsible for thousands of deaths daily. Although the role of olfaction in A. gambiae host detection has been demonstrated, little is known about the combinations of ligands and odorant binding proteins (OBPs) that can produce specific odor-related responses in vivo. We identified a ligand, indole, for an A. gambiae odorant binding protein, AgamOBP1, modeled the interaction in silico and confirmed the interaction using biochemical assays. RNAi-mediated gene silencing coupled with electrophysiological analyses confirmed that AgamOBP1 binds indole in A. gambiae and that the antennal receptor cells do not respond to indole in the absence of AgamOBP1. This case represents the first documented instance of a specific A. gambiae OBP–ligand pairing combination, demonstrates the significance of OBPs in odor recognition, and can be expanded to the identification of other ligands for OBPs of Anopheles and other medically important insects

Nervous-system-specific carcinogenesis by ethylnitrosourea in the rat: molecular and cellular aspects

A lead in the search for cellular determinants favoring neoplastic transformation may be provided by the pronounced tissue specificity of the oncogenic effect of certain carcinogens which do not require enzymatic metabolic activation, i.e., in cases where this specificity cannot be due to tissue differences in the activity of enzymes involved in the formation of the ultimate reactants. A carcinogen that fulfills this condition is the ethylating agent N-ethyl-N-nitrosourea (EtNU). Alkylation of nucleic acid constituents by N-nitroso compounds in relation to mutagenesis and carcinogenesis has received considerable attention recently

The Ku Protein Complex Is Involved in Length Regulation of Drosophila Telomeres

Chromosome ends in Drosophila melanogaster can be elongated either by terminal attachment of the telomere-specific retrotransposons HeT-A and TART or by terminal gene conversion. Here we show that a decrease in Ku70 or Ku80 gene dosage causes a sharp increase in the frequency of HeT-A and TART attachments to a broken chromosome end and in terminal DNA elongation by gene conversion. Loss of Ku80 has more pronounced effects than loss of Ku70. However, lower Ku70 concentration reduces the stability of terminally deficient chromosomes. Our results suggest a role of the end-binding Ku complex in the accessibility and length regulation of Drosophila telomeres

Regularized linear discriminant analysis of EEG features in dementia patients

The present study explores if EEG spectral parameters can discriminate between healthy elderly controls (HC), Alzheimer’s disease (AD) and vascular dementia (VaD) using. We considered EEG data recorded during normal clinical routine with 114 healthy controls (HC), 114 AD, and 114 VaD patients. The spectral features extracted from the EEG were the absolute delta power, decay from lower to higher frequencies, amplitude, center and dispersion of the alpha power and baseline power of the entire frequency spectrum. For discrimination, we submitted these EEG features to regularized linear discriminant analysis algorithm with a 10-fold cross-validation. To check the consistency of the results obtained by our classifiers, we applied bootstrap statistics. Four binary classifiers were used to discriminate HC from AD, HC from VaD, AD from VaD, and HC from dementia patients (AD or VaD). For each model, we measured the discrimination performance using the area under curve (AUC) and the accuracy of the cross-validation (cv-ACC). We applied this procedure using two different sets of predictors. The first set considered all the features extracted from the 22 channels. For the second set of features, we automatically rejected features poorly correlated with their labels. Fairly good results were obtained when discriminating HC from dementia patients with AD or VaD (AUC = 0.84). We also obtained AUC = 0.74 for discrimination of AD from HC, AUC = 0.77 for discrimination of VaD from HC, and finally AUC = 0.61 for discrimination of AD from VaD. Our models were able to separate HC from dementia patients, and also and to discriminate AD from VaD above chance. Our results suggest that these features may be relevant for the clinical assessment of patients with dementia

Protein Interactions on Telomeric Retrotransposons in Drosophila

Telomere length in Drosophila is maintained by targeted transposition of three non-LTR retrotransposons: HeT-A, TART and TAHRE (HTT), but understanding the regulation of this process is hindered by our poor knowledge of HTT associated proteins. We have identified new protein components of the HTT array: Chromator (Chro), the TRF2/DREF complex and the sumoylation machinery. Chro was localized on telomeric HTT arrays by immunostaining, where it may interact with Prod directly, as indicated by yeast two-hybrid interaction, co-IP, and colocalization on polytene chromosomes. The TRF2/DREF complex may promote the open structure of HTT chromatin. The protein interactions controlling HTT chromatin structure and telomere length may be modulated by sumoylation