Overview of Genetic-epidemiological Studies in Ethnically and Demographically Diverse Isolates of Dagestan, Northern Caucasus, Russia

Aim: To assess genetic diversity and genetic distances among isolated populations from Dagestan. Methods: A cross-population genetic epidemiology design was applied in ethnically and demographically diverse isolates from Dagestan, some with more than 200 and some with less than 100 generations of demographical history since their founding. Results: The analysis of genetic diversity showed that Dagestan ethnic populations are clearly close to European ethnic populations. The genetic data support the view of them as ancient, highly isolated populations 85%-97% the rate of the endogamy and inbreeding coefficient F=0.010-0.015. Many Dagestan populations have very high prevalence of certain complex diseases such as cardiovascular illnesses, cancer, schizophrenia, mental retardation, and progressive muscular dystrophy. Lifetime morbid risk for schizophrenia in the isolates varied from 0 to 5%. Among the relatives, the number of men with chronic schizophrenia was at least twice as high as women. The average age of onset of schizophrenia was 21.2 years for offspring of consanguineous marriages and 17.4 years for offspring of non-consanguineous marriages (P=0.033). Conclusion: The results support the hypothesis that cross-population design provides unique opportunities for observing reliable ancestral haplotypes with disease predisposing loci, as well as population-specific linked loci

Estrogens and genomic instability in human cancer cells-involvement of Src/Raf/Erk signaling in micronucleus formation by estrogenic chemicals

This article is available open access through the publisher’s website. Copyright @ 2008 The Authors.Reports of the ability of estrogenic agents such as 17β-estradiol (E2), estriol (E3) and bisphenol A (BPA) to induce micronuclei (MN) in MCF-7 breast cancer cells have prompted us to investigate whether these effects are linked to activation of the estrogen receptor (ER) α. Coadministration of tamoxifen and the pure ER antagonist ICI 182 780 to cells treated with E2 and E3 did not lead to significant reductions in micronucleus frequencies. Since these antiestrogens interfere with the transcriptional activity of the ER and block promotion of ER-dependent gene expression, it appears that this process is not involved in micronucleus formation. However, ER activation also triggers rapid signaling via the Src/Raf/extracellular signal-regulated kinase (Erk) pathway. When MCF-7 cells were exposed to E2 and BPA in combination with the specific kinase inhibitors pyrazolopyrimidine and 2′-amino-3′-methoxyflavone, reductions in micronucleus frequencies occurred. These findings suggest that the Src/Raf/Erk pathway plays a role in micronucleus formation by estrogenic agents. Enhanced activation of the Src/Raf/Erk cascade disturbs the localization of Aurora B kinase to kinetochores, leading to a defective spindle checkpoint with chromosome malsegregation. Using antikinetochore CREST antibody staining, a high proportion of micronucleus containing kinetochores was observed, indicating that such processes are relevant to the induction of MN by estrogens. Our results suggest that estrogens induce MN by causing improper chromosome segregation, possibly by interfering with kinase signaling that controls the spindle checkpoint, or by inducing centrosome amplification. Our findings may have some relevance in explaining the effects of estrogens in the later stages of breast carcinogenesis.European Commissio

Culture creates genetic structure in the Caucasus: Autosomal, mitochondrial, and Y-chromosomal variation in Daghestan

<p>Abstract</p> <p>Background</p> <p>Near the junction of three major continents, the Caucasus region has been an important thoroughfare for human migration. While the Caucasus Mountains have diverted human traffic to the few lowland regions that provide a gateway from north to south between the Caspian and Black Seas, highland populations have been isolated by their remote geographic location and their practice of patrilocal endogamy. We investigate how these cultural and historical differences between highland and lowland populations have affected patterns of genetic diversity. We test 1) whether the highland practice of patrilocal endogamy has generated sex-specific population relationships, and 2) whether the history of migration and military conquest associated with the lowland populations has left Central Asian genes in the Caucasus, by comparing genetic diversity and pairwise population relationships between Daghestani populations and reference populations throughout Europe and Asia for autosomal, mitochondrial, and Y-chromosomal markers.</p> <p>Results</p> <p>We found that the highland Daghestani populations had contrasting histories for the mitochondrial DNA and Y-chromosome data sets. Y-chromosomal haplogroup diversity was reduced among highland Daghestani populations when compared to other populations and to highland Daghestani mitochondrial DNA haplogroup diversity. Lowland Daghestani populations showed Turkish and Central Asian affinities for both mitochondrial and Y-chromosomal data sets. Autosomal population histories are strongly correlated to the pattern observed for the mitochondrial DNA data set, while the correlation between the mitochondrial DNA and Y-chromosome distance matrices was weak and not significant.</p> <p>Conclusion</p> <p>The reduced Y-chromosomal diversity exhibited by highland Daghestani populations is consistent with genetic drift caused by patrilocal endogamy. Mitochondrial and Y-chromosomal phylogeographic comparisons indicate a common Near Eastern origin of highland populations. Lowland Daghestani populations show varying influence from Near Eastern and Central Asian populations.</p

Xenoestrogen-Induced ERK-1 and ERK-2 Activation via Multiple Membrane-Initiated Signaling Pathways

Xenoestrogens can mimic or antagonize the activity of physiological estrogens, and the suggested mechanism of xenoestrogen action involves binding to estrogen receptors (ERs). However, the failure of various in vitro or in vivo assays to show strong genomic activity of xenoestrogens compared with estradiol (E(2)) makes it difficult to explain their ability to cause abnormalities in animal (and perhaps human) reproductive functions via this pathway of steroid action. E(2) has also been shown to initiate rapid intracellular signaling, such as changes in levels of intracellular calcium, cAMP, and nitric oxide, and activations of a variety of kinases, via action at the membrane. In this study, we demonstrate that several xenoestrogens can rapidly activate extracellular-regulated kinases (ERKs) in the pituitary tumor cell line GH(3)/B6/F10, which expresses high levels of the membrane receptor for ER-α(mER). We tested a phytoestrogen (coumestrol), organochlorine pesticides or their metabolites (endosulfan, dieldrin, and DDE), and detergent by-products of plastics manufacturing (p-nonylphenol and bisphenol A). These xenoestrogens (except bisphenol A) produced rapid (3–30 min after application), concentration (10(−14)–10(−8) M)-dependent ERK-1/2 phosphorylation but with distinctly different activation patterns. To identify signaling pathways involved in ERK activation, we used specific inhibitors of ERs, epidermal growth factor receptors, Ca(2+) signaling, Src and phosphoinositide-3 kinases, and a membrane structure disruption agent. Multiple inhibitors blocked ERK activation, suggesting simultaneous use of multiple pathways and complex signaling web interactions. However, inhibitors differentially affected each xenoestrogen response examined. These actions may help to explain the distinct abilities of xenoestrogens to disrupt reproductive functions at low concentrations

Uso de tecnologia de treinamento na preparação de estudantes de especialidades de engenharia

The content of higher education is influenced by the market economy, computerization and technological development of society. To discover the potential of students, new approaches to learning are required. In Russia, in the field of vocational education, the technology of project training is implemented, which meets the new emerging requirements of the state and society. Project training technology contributes to the most productive training of students as highly qualified specialists, and also allows them to consciously address their activities, establish professional tasks and perform them independently. The purpose of the article is to consider the experience of using technology in the training of projects in graduates of engineering specialties. As a result of the theoretical analysis of the pedagogical literature, we selected the pedagogical conditions for the implementation of these technologies (didactic, psychological, social, pedagogical, organizational and pedagogical). At the Nizhny Novgorod State Pedagogical University named after Kozma Minin, the study was conducted among the students on the "Construction" and "Technology" training profiles. The total number of respondents was 212 people. According to the data received, 88% of the students noticed the effectiveness of the application of the project method in the study of the graphic disciplines, 72% indicated that the design method promotes a deeper study of the material. In general, the experiment showed that the level of training using the project's training technology was significantly higher.El contenido de la educación superior está influenciado por la economía de Mercado, la informatización y el desarrollo tecnológico de la sociedad. Para descubrir el potencial de los estudiantes, se requieren nuevos enfoques para el aprendizaje. En Rusia, en el campo de la educación vocacional, se implementa la tecnología de capacitación de proyectos, que cumple con los nuevos requisitos emergentes del estado y la sociedad. La tecnología de capacitación en proyectos contribuye a la formación más productiva de los estudiantes como especialistas altamente calificados, y también les permite abordar conscientemente sus actividades, poder establecer tareas profesionales y realizarlas de manera independiente. El propósito del artículo es considerar la experiencia de utilizar la tecnología en la capacitación de proyectos en graduados de especialidades de ingeniería. Como resultado del análisis teórico de la literatura pedagógica, seleccionamos las condiciones pedagógicas para la implementación de estas tecnologías (didáctica, psicológica, social, pedagógica, organizativa y pedagógica). En la Universidad Pedagógica Estatal de Nizhny Novgorod que lleva el nombre de Kozma Minin, el estudio se realizó entre los estudiantes sobre los perfiles de capacitación "Construcción" y "Tecnología". El número total de encuestados fue de 212 personas. De acuerdo con los datos recibidos, el 88% de los estudiantes notó la efectividad de la aplicación del método del proyecto en el estudio de las disciplinas gráficas, el 72% indicó que el método de diseño promueve un estudio más profundo del material. En general, el experimento mostró que el nivel de capacitación utilizando la tecnología de capacitación del proyecto fue significativamente mayor.O conteúdo do ensino superior é influenciado pela economia de mercado, informatização e desenvolvimento tecnológico da sociedade. Para descobrir o potencial dos estudantes, novas abordagens para a aprendizagem são necessárias. Na Rússia, no campo da educação profissional, implementa-se a tecnologia de treinamento em projetos, que atende às novas exigências emergentes do estado e da sociedade. A tecnologia de treinamento do projeto contribui para a formação mais produtiva dos alunos como especialistas altamente qualificados, e também permite que eles abordem conscientemente suas atividades, estabeleçam tarefas profissionais e as executem de forma independente. O objetivo do artigo é considerar a experiência de usar a tecnologia na formação de projetos em graduados de especialidades de engenharia. Como resultado da análise teórica da literatura pedagógica, selecionamos as condições pedagógicas para a implementação dessas tecnologias (didáticas, psicológicas, sociais, pedagógicas, organizacionais e pedagógicas). Na Universidade Pedagógica do Estado de Nizhny Novgorod, em homenagem a Kozma Minin, o estudo foi conduzido entre os estudantes nos perfis de treinamento "Construção" e "Tecnologia". O número total de entrevistados foi de 212 pessoas. De acordo com os dados recebidos, 88% dos estudantes notaram a eficácia da aplicação do método de projeto no estudo das disciplinas gráficas, 72% indicaram que o método de projeto promove um estudo mais profundo do material. Em geral, o experimento mostrou que o nível de treinamento usando a tecnologia de treinamento do projeto foi significativamente maior

Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux

<p>Abstract</p> <p>Background</p> <p>Neurological diseases and neuropsychiatric disorders that vary depending on female life stages suggest that sex hormones may influence the function of neurotransmitter regulatory machinery such as the dopamine transporter (DAT).</p> <p>Results</p> <p>In this study we tested the rapid nongenomic effects of several physiological estrogens [estradiol (E₂), estrone (E₁), and estriol (E₃)] on dopamine efflux via the DAT in a non-transfected, NGF-differentiated, rat pheochromocytoma (PC12) cell model that expresses membrane estrogen receptors (ERs) α, β, and GPR30. We examined kinase, ionic, and physical interaction mechanisms involved in estrogenic regulation of the DAT function. E₂-mediated dopamine efflux is DAT-specific and not dependent on extracellular Ca²⁺-mediated exocytotic release from vesicular monoamine transporter vesicles (VMATs). Using kinase inhibitors we also showed that E₂-mediated dopamine efflux is dependent on protein kinase C and MEK activation, but not on PI3K or protein kinase A. In plasma membrane there are ligand-independent associations of ERα and ERβ (but not GPR30) with DAT. Conditions which cause efflux (a 9 min 10^-9M E₂treatment) cause trafficking of ERα (stimulatory) to the plasma membrane and trafficking of ERβ (inhibitory) away from the plasma membrane. In contrast, E₁and E₃can inhibit efflux with a nonmonotonic dose pattern, and cause DAT to leave the plasma membrane.</p> <p>Conclusion</p> <p>Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.</p

Proliferative and anti-proliferative effects of dietary levels of phytoestrogens in rat pituitary GH3/B6/F10 cells - the involvement of rapidly activated kinases and caspases

<p>Abstract</p> <p>Background</p> <p>Phytoestogens are a group of lipophillic plant compounds that can have estrogenic effects in animals; both tumorigenic and anti-tumorigenic effects have been reported. Prolactin-secreting adenomas are the most prevalent form of pituitary tumors in humans and have been linked to estrogen exposures. We examined the proliferative effects of phytoestrogens on a rat pituitary tumor cell line, GH₃/B₆/F₁₀, originally subcloned from GH₃cells based on its ability to express high levels of the membrane estrogen receptor-α.</p> <p>Methods</p> <p>We measured the proliferative effects of these phytoestrogens using crystal violet staining, the activation of several mitogen-activated protein kinases (MAPKs) and their downstream targets via a quantitative plate immunoassay, and caspase enzymatic activities.</p> <p>Results</p> <p>Four phytoestrogens (coumestrol, daidzein, genistein, and <it>trans</it>-resveratrol) were studied over wide concentration ranges. Except <it>trans</it>-resveratrol, all phytoestrogens increased GH₃/B₆/F₁₀cell proliferation at some concentration relevant to dietary levels. All four phytoestrogens attenuated the proliferative effects of estradiol when administered simultaneously. All phytoestrogens elicited MAPK and downstream target activations, but with time course patterns that often differed from that of estradiol and each other. Using selective antagonists, we determined that MAPKs play a role in the ability of these phytoestrogens to elicit these responses. In addition, except for <it>trans</it>-resveratrol, a serum removal-induced extrinsic apoptotic pathway was blocked by these phytoestrogens.</p> <p>Conclusion</p> <p>Phytoestrogens can block physiological estrogen-induced tumor cell growth <it>in vitro </it>and can also stimulate growth at high dietary concentrations in the absence of endogenous estrogens; these actions are correlated with slightly different signaling response patterns. Consumption of these compounds should be considered in strategies to control endocrine tumor cell growth, such as in the pituitary.</p

High altitude adaptation in Daghestani populations from the Caucasus

We have surveyed 15 high-altitude adaptation candidate genes for signals of positive selection in North Caucasian highlanders using targeted re-sequencing. A total of 49 unrelated Daghestani from three ethnic groups (Avars, Kubachians, and Laks) living in ancient villages located at around 2,000 m above sea level were chosen as the study population. Caucasian (Adygei living at sea level, N = 20) and CEU (CEPH Utah residents with ancestry from northern and western Europe; N = 20) were used as controls. Candidate genes were compared with 20 putatively neutral control regions resequenced in the same individuals. The regions of interest were amplified by long-PCR, pooled according to individual, indexed by adding an eight-nucleotide tag, and sequenced using the Illumina GAII platform. 1,066 SNPs were called using false discovery and false negative thresholds of ~6%. The neutral regions provided an empirical null distribution to compare with the candidate genes for signals of selection. Two genes stood out. In Laks, a non-synonymous variant within HIF1A already known to be associated with improvement in oxygen metabolism was rediscovered, and in Kubachians a cluster of 13 SNPs located in a conserved intronic region within EGLN1 showing high population differentiation was found. These variants illustrate both the common pathways of adaptation to high altitude in different populations and features specific to the Daghestani populations, showing how even a mildly hypoxic environment can lead to genetic adaptation