Sen1 is recruited to replication forks via Ctf4 and Mrc1 and promotes genome stability

DNA replication and RNA transcription compete for the same substrate during S phase. Cells have evolved several mechanisms to minimize such conflicts. Here, we identify the mechanism by which the transcription termination helicase Sen1 associates with replisomes. We show that the N terminus of Sen1 is both sufficient and necessary for replisome association and that it binds to the replisome via the components Ctf4 and Mrc1. We generated a separation of function mutant, sen1-3, which abolishes replisome binding without affecting transcription termination. We observe that the sen1-3 mutants show increased genome instability and recombination levels. Moreover, sen1-3 is synthetically defective with mutations in genes involved in RNA metabolism and the S phase checkpoint. RNH1 overexpression suppresses defects in the former, but not the latter. These findings illustrate how Sen1 plays a key function at replication forks during DNA replication to promote fork progression and chromosome stability

Bayesian Centroid Estimation for Motif Discovery

Biological sequences may contain patterns that are signal important biomolecular functions; a classical example is regulation of gene expression by transcription factors that bind to specific patterns in genomic promoter regions. In motif discovery we are given a set of sequences that share a common motif and aim to identify not only the motif composition, but also the binding sites in each sequence of the set. We present a Bayesian model that is an extended version of the model adopted by the Gibbs motif sampler, and propose a new centroid estimator that arises from a refined and meaningful loss function for binding site inference. We discuss the main advantages of centroid estimation for motif discovery, including computational convenience, and how its principled derivation offers further insights about the posterior distribution of binding site configurations. We also illustrate, using simulated and real datasets, that the centroid estimator can differ from the maximum a posteriori estimator.Comment: 24 pages, 9 figure

A New Evolutionary Algorithm-Based Home Monitoring Device for Parkinson’s Dyskinesia

Parkinson’s disease (PD) is a neurodegenerative movement disorder. Although there is no cure, symptomatic treatments are available and can significantly improve quality of life. The motor, or movement, features of PD are caused by reduced production of the neurotransmitter dopamine. Dopamine deficiency is most often treated using dopamine replacement therapy. However, this therapy can itself lead to further motor abnormalities referred to as dyskinesia. Dyskinesia consists of involuntary jerking movements and muscle spasms, which can often be violent. To minimise dyskinesia, it is necessary to accurately titrate the amount of medication given and monitor a patient’s movements. In this paper, we describe a new home monitoring device that allows dyskinesia to be measured as a patient goes about their daily activities, providing information that can assist clinicians when making changes to medication regimens. The device uses a predictive model of dyskinesia that was trained by an evolutionary algorithm, and achieves AUC>0.9 when discriminating clinically significant dyskinesia

Rationale Marktübertreibungen im Zusammenhang der aktuellen Finanzmarktkrise

Der Untersuchungsgegenstand der Arbeit ist die Darstellung der wichtigsten Anlegermotive bei Marktübertreibungen. Es wird dabei auf Konzepte der verhaltensorientierten Kapitalmarktforschung zurückgegriffen. Basierend auf den gewonnenen Erkenntnissen werden Lösungsansätze zur Vermeidung von Marktübertreibungen abgeleitet. Untersuchungen, beispielsweise durch Bikhchandani und Sharma (2000), haben gezeigt, dass Herdenverhalten eine wichtige Rolle bei der Erklärung von Preisübertreibungen spielt. Dabei kann es rational sein, sich konform zur Masse der Marktteilnehmer zu verhalten. Neben dem Konzept des Herdenverhaltens kann Konservatismus unter Marktteilnehmern zur Bestätigung vorherrschender Trends beitragen. Heuristiken werden angewandt, um komplexe Sachverhalte zu vereinfachen. Insbesondere die Repräsentativitätsheuristik kann zu einer Verstärkung bestehender Preisübertreibungen führen. Die Autoren sind der Ansicht, dass vor allem eine Verbesserung der Informationsbasis zur Reduzierung von Fehleinschätzungen durch Marktteilnehmer beitragen kann. Sowohl die Verfügbarkeit als auch die Qualität der Informationen spielen dabei eine Rolle. Ein weiterer Lösungsansatz betrifft die Risikoeinstellung und Kreditvergabe der Banken. In Boomphasen sollte das Risiko eines Crashs berücksichtigt werden.The paper deals with the motives of people to invest in overvalued markets. We resort to the concepts of behavioural finance to describe the most important factors. Based on these findings we deduct measures to avoid misjudgement of markets participants. As Bikhchandani and Sharma (2000) show, the concept of herd behaviour plays a decisive role in explaining exuberance in markets. There are incentives for investors, money managers and analysts to imitate other's actions. Furthermore, conservatism as well as heuristics like representativeness may also lead to a confirmation of prevailing trends. Another driver of misjudgement is the usage of heuristics like representativeness. The authors consider that the provision of information may substantially contribute to the reduction of misjudgement and exuberance in markets. Both availability and quality of information are important. Another approach aims at the regulation of bank lending, which should be limited particularly during a booming economy

Raman spectroscopy in head and neck cancer

In recent years there has been much interest in the use of optical diagnostics in cancer detection. Early diagnosis of cancer affords early intervention and greatest chance of cure. Raman spectroscopy is based on the interaction of photons with the target material producing a highly detailed biochemical 'fingerprint' of the sample. It can be appreciated that such a sensitive biochemical detection system could confer diagnostic benefit in a clinical setting. Raman has been used successfully in key health areas such as cardiovascular diseases, and dental care but there is a paucity of literature on Raman spectroscopy in Head and Neck cancer. Following the introduction of health care targets for cancer, and with an ever-aging population the need for rapid cancer detection has never been greater. Raman spectroscopy could confer great patient benefit with early, rapid and accurate diagnosis. This technique is almost labour free without the need for sample preparation. It could reduce the need for whole pathological specimen examination, in theatre it could help to determine margin status, and finally peripheral blood diagnosis may be an achievable target

SREB, a GATA Transcription Factor That Directs Disparate Fates in Blastomyces dermatitidis Including Morphogenesis and Siderophore Biosynthesis

Blastomyces dermatitidis belongs to a group of human pathogenic fungi that exhibit thermal dimorphism. At 22°C, these fungi grow as mold that produce conidia or infectious particles, whereas at 37°C they convert to budding yeast. The ability to switch between these forms is essential for virulence in mammals and may enable these organisms to survive in the soil. To identify genes that regulate this phase transition, we used Agrobacterium tumefaciens to mutagenize B. dermatitidis conidia and screened transformants for defects in morphogenesis. We found that the GATA transcription factor SREB governs multiple fates in B. dermatitidis: phase transition from yeast to mold, cell growth at 22°C, and biosynthesis of siderophores under iron-replete conditions. Insertional and null mutants fail to convert to mold, do not accumulate significant biomass at 22°C, and are unable to suppress siderophore biosynthesis under iron-replete conditions. The defect in morphogenesis in the SREB mutant was independent of exogenous iron concentration, suggesting that SREB promotes the phase transition by altering the expression of genes that are unrelated to siderophore biosynthesis. Using bioinformatic and gene expression analyses, we identified candidate genes with upstream GATA sites whose expression is altered in the null mutant that may be direct or indirect targets of SREB and promote the phase transition. We conclude that SREB functions as a transcription factor that promotes morphogenesis and regulates siderophore biosynthesis. To our knowledge, this is the first gene identified that promotes the conversion from yeast to mold in the dimorphic fungi, and may shed light on environmental persistence of these pathogens