Full Counting Statistics of Superconductor--Normal-Metal Heterostructures

The article develops a powerful theoretical tool to obtain the full counting statistics. By a slight extension of the standard Keldysh method we can access immediately all correlation functions of the current operator. Embedded in a quantum generalization of the circuit theory of electronic transport, we are able to study the full counting statistics of a large class of two-terminal contacts and multi-terminal structures, containing superconductors and normal metals as elements. The practical use of the method is demonstrated in many examples.Comment: 35 pages, contribution to "Quantum Noise", ed. by Yu.V. Nazarov and Ya.M. Blanter, minor changes in text, references adde

Silent chromatin at the middle and ends: lessons from yeasts

Eukaryotic centromeres and telomeres are specialized chromosomal regions that share one common characteristic: their underlying DNA sequences are assembled into heritably repressed chromatin. Silent chromatin in budding and fission yeast is composed of fundamentally divergent proteins tat assemble very different chromatin structures. However, the ultimate behaviour of silent chromatin and the pathways that assemble it seem strikingly similar among Saccharomyces cerevisiae (S. cerevisiae), Schizosaccharomyces pombe (S. pombe) and other eukaryotes. Thus, studies in both yeasts have been instrumental in dissecting the mechanisms that establish and maintain silent chromatin in eukaryotes, contributing substantially to our understanding of epigenetic processes. In this review, we discuss current models for the generation of heterochromatic domains at centromeres and telomeres in the two yeast species

A Major Role for the Plasmodium falciparum ApiAP2 Protein PfSIP2 in Chromosome End Biology

The heterochromatic environment and physical clustering of chromosome ends at the nuclear periphery provide a functional and structural framework for antigenic variation and evolution of subtelomeric virulence gene families in the malaria parasite Plasmodium falciparum. While recent studies assigned important roles for reversible histone modifications, silent information regulator 2 and heterochromatin protein 1 (PfHP1) in epigenetic control of variegated expression, factors involved in the recruitment and organization of subtelomeric heterochromatin remain unknown. Here, we describe the purification and characterization of PfSIP2, a member of the ApiAP2 family of putative transcription factors, as the unknown nuclear factor interacting specifically with cis-acting SPE2 motif arrays in subtelomeric domains. Interestingly, SPE2 is not bound by the full-length protein but rather by a 60kDa N-terminal domain, PfSIP2-N, which is released during schizogony. Our experimental re-definition of the SPE2/PfSIP2-N interaction highlights the strict requirement of both adjacent AP2 domains and a conserved bipartite SPE2 consensus motif for high-affinity binding. Genome-wide in silico mapping identified 777 putative binding sites, 94% of which cluster in heterochromatic domains upstream of subtelomeric var genes and in telomere-associated repeat elements. Immunofluorescence and chromatin immunoprecipitation (ChIP) assays revealed co-localization of PfSIP2-N with PfHP1 at chromosome ends. Genome-wide ChIP demonstrated the exclusive binding of PfSIP2-N to subtelomeric SPE2 landmarks in vivo but not to single chromosome-internal sites. Consistent with this specialized distribution pattern, PfSIP2-N over-expression has no effect on global gene transcription. Hence, contrary to the previously proposed role for this factor in gene activation, our results provide strong evidence for the first time for the involvement of an ApiAP2 factor in heterochromatin formation and genome integrity. These findings are highly relevant for our understanding of chromosome end biology and variegated expression in P. falciparum and other eukaryotes, and for the future analysis of the role of ApiAP2-DNA interactions in parasite biology

Fatores associados à interrupção precoce do aleitamento materno: um estudo de coorte de nascimento em dois municípios do Recôncavo da Bahia, Brasil

Este estudo objetivou identificar a duração mediana e os fatores associados à interrupção precoce do aleitamento materno. Envolveu uma coorte de nascimento de 531 crianças acompanhadas até os dois anos de idade em dois municípios do Recôncavo da Bahia, Brasil. Utilizaram-se a análise de sobrevivência e o modelo multivariado de Cox. A duração mediana foi de 74,73, 211,25 e 432,63 dias, respectivamente, para o aleitamento materno exclusivo, misto complementado e total. A ausência materna ao pré-natal elevou em 173% (HR = 2,73; IC95%: 1,89-3,93) o risco de diminuir a duração do aleitamento materno exclusivo, em 83% (HR = 1,83; IC95%: 1,06-3,16) o risco da adoção do aleitamento misto complementado e em 38% (HR = 1,38; IC95%: 1,06-1,81) o risco da descontinuidade do aleitamento materno. O trabalho materno fora do domicílio e a área de residência urbana aumentaram o risco para interrupção precoce do aleitamento materno. A ampliação do acesso ao pré-natal e da rede de proteção às mães que trabalham fora do domicilio e àquelas que residem na área urbana poderia aumentar a duração da amamentação no Recôncavo da Bahia.This study aimed to identify the median duration of breastfeeding and associated factors in a cohort of 531 infants in two municipalities in the Recôncavo region, Bahia State, Brazil. Breastfeeding duration was estimated by survival analysis and its associations by the Cox ultivariate model. Median duration of exclusive breastfeeding, mixed breastfeeding with complementary feeding, and total breastfeeding was 74.73, 211.25, and 432.63 days, respectively. Lack of prenatal care increased the risk of shortening exclusive breastfeeding by 173% (HR = 2.73; 95%CI: 1.89-3.93), of adopting mixed breastfeeding with complementary feeding by 83% (HR = 1.83; 95%CI: 1.06-3.16), and of discontinuing breastfeeding entirely by 38% (HR = 1.38; 95%CI: 1.06-1.81). Both maternal employment and residence in an urban area increased the risk of early breastfeeding cessation. Expansion of access to prenatal care and the safety network for employed mothers living in urban areas could increase breastfeeding duration in the target region

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity