Microarray analysis of the in vivo sequence preferences of a minor groove binding drug

<p>Abstract</p> <p>Background</p> <p>Minor groove binding drugs (MGBDs) interact with DNA in a sequence-specific manner and can cause changes in gene expression at the level of transcription. They serve as valuable models for protein interactions with DNA and form an important class of antitumor, antiviral, antitrypanosomal and antibacterial drugs. There is a need to extend knowledge of the sequence requirements for MGBDs from <it>in vitro </it>DNA binding studies to living cells.</p> <p>Results</p> <p>Here we describe the use of microarray analysis to discover yeast genes that are affected by treatment with the MGBD berenil, thereby allowing the investigation of its sequence requirements for binding <it>in vivo</it>. A novel approach to sequence analysis allowed us to address hypotheses about genes that were directly or indirectly affected by drug binding. The results show that the sequence features of A/T richness and heteropolymeric character discovered by <it>in vitro </it>berenil binding studies are found upstream of genes hypothesized to be directly affected by berenil but not upstream of those hypothesized to be indirectly affected or those shown to be unaffected.</p> <p>Conclusion</p> <p>The data support the conclusion that effects of berenil on gene expression in yeast cells can be explained by sequence patterns discovered by <it>in vitro </it>binding experiments. The results shed light on the sequence and structural rules by which berenil binds to DNA and affects the transcriptional regulation of genes and contribute generally to the development of MGBDs as tools for basic and applied research.</p

Reducing drug related deaths : a pre-implementation assessment of knowledge,barriers and enablers for naloxone distribution through general practice

Peer reviewedPublisher PD

Angiographically silent atherosclerosis detected by intravascular ultrasound in patients with familial hypercholesterolemia and familial combined hyperlipidemia: Correlation with high density lipoproteins

AbstractObjectives. This study sought to evaluate the extent of atherosclerosis in coronary and iliac arteries in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia, using intravascular ultraound imaging.Background. Intravascular ultrasound imaging provides cross-sectional tomographic views of the vessel wall and allows quantitative assessment of atherosclerosis.Methods. Forty-eight nonsmoking, asymptomatic patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia underwent intravascular ultrasound imaging of the left anterior descending coronary, left main coronary and common iliac arteries. Angiography showed only minimal or no narrowing in these vessels. Intravascular ultrasound images obtained during catheter pullback underwent morphometric analysis. Plaque burden was expressed as the mean and maximal intimal index (ratio of plaque area and area within the internal elastic lamina) and as the percent of vessel surface covered by plaque.Results. Intravascular ultrasound detected plaque more frequently than angiography in the left anterior descending (80% vs. 29%, respectively), left main (44% vs. 16%) and iliac arteries (33% vs. 27%). Plaque burden was higher in the left anterior descending (mean intimal index [±SD] 0.25 ± 0.16) than in the left main (0.11 ± 0.16, p < 0.001) and iliac arteries (0.02 ± 0.04, p < 0.001). Angiography detected lumen narrowing only in coronary arteries with a maximal intimal index ⪰0.42 (left anterior descending artery) and ⪰0.43 (left main artery). The area within the internal elastic lamina increased with plaque area in the left anterior descending (r = 0.82, p < 0.001) and left main arteries (r = 0.53, p < 0.001). By stepwise multiple regression analysis, the strongest predictor for plaque burden in the left anterior descending artery was the level of high density lipoprotein (HDL) cholesterol and total/HDL cholesterol ratio for the left main artery.Conclusions. In patients with heterozygous familial hypercholesterolemia and familial combined hyperlipidemia, extensive coronary plaque is present despite minimal or no angiographic changes. Compensatory vessel enlargement and diffuse involvement with eccentric plaque may account for the lack of angiographic changes. Levels of HDL cholesterol and total/HDL cholesterol ratio are far more powerful predictors of coronary plaque burden than are low density lipoprotein cholesterol levels in these patients with early, asymptomatic disease

Engineering bacteria to solve the Burnt Pancake Problem

<p>Abstract</p> <p>Background</p> <p>We investigated the possibility of executing DNA-based computation in living cells by engineering <it>Escherichia coli </it>to address a classic mathematical puzzle called the Burnt Pancake Problem (BPP). The BPP is solved by sorting a stack of distinct objects (pancakes) into proper order and orientation using the minimum number of manipulations. Each manipulation reverses the order and orientation of one or more adjacent objects in the stack. We have designed a system that uses site-specific DNA recombination to mediate inversions of genetic elements that represent pancakes within plasmid DNA.</p> <p>Results</p> <p>Inversions (or "flips") of the DNA fragment pancakes are driven by the <it>Salmonella typhimurium </it>Hin/<it>hix </it>DNA recombinase system that we reconstituted as a collection of modular genetic elements for use in <it>E. coli</it>. Our system sorts DNA segments by inversions to produce different permutations of a promoter and a tetracycline resistance coding region; <it>E. coli </it>cells become antibiotic resistant when the segments are properly sorted. Hin recombinase can mediate all possible inversion operations on adjacent flippable DNA fragments. Mathematical modeling predicts that the system reaches equilibrium after very few flips, where equal numbers of permutations are randomly sorted and unsorted. Semiquantitative PCR analysis of <it>in vivo </it>flipping suggests that inversion products accumulate on a time scale of hours or days rather than minutes.</p> <p>Conclusion</p> <p>The Hin/<it>hix </it>system is a proof-of-concept demonstration of <it>in vivo </it>computation with the potential to be scaled up to accommodate larger and more challenging problems. Hin/<it>hix </it>may provide a flexible new tool for manipulating transgenic DNA <it>in vivo</it>.</p

A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric <em>DISC1</em> transcripts that encode structurally altered, deleterious mitochondrial proteins

Disrupted-In-Schizophrenia 1 (DISC1) was identified as a risk factor for psychiatric illness through its disruption by a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), that co-segregates with schizophrenia, bipolar disorder and depression. We previously reported that the translocation reduces DISC1 expression, consistent with a haploinsufficiency disease model. Here we report that, in lymphoblastoid cell lines, the translocation additionally results in the production of abnormal transcripts due to the fusion of DISC1 with a disrupted gene on chromosome 11 (DISC1FP1/Boymaw). These chimeric transcripts encode abnormal proteins, designated CP1, CP60 and CP69, consisting of DISC1 amino acids 1–597 plus 1, 60 or 69 amino acids, respectively. The novel 69 amino acids in CP69 induce increased α-helical content and formation of large stable protein assemblies. The same is predicted for CP60. Both CP60 and CP69 exhibit profoundly altered functional properties within cell lines and neurons. Both are predominantly targeted to mitochondria, where they induce clustering and loss of membrane potential, indicative of severe mitochondrial dysfunction. There is currently no access to neural material from translocation carriers to confirm these findings, but there is no reason to suppose that these chimeric transcripts will not also be expressed in the brain. There is thus potential for the production of abnormal chimeric proteins in the brains of translocation carriers, although at substantially lower levels than for native DISC1. The mechanism by which inheritance of the translocation increases risk of psychiatric illness may therefore involve both DISC1 haploinsufficiency and mitochondrial deficiency due to the effects of abnormal chimeric protein expression. GenBank accession numbers: DISC1FP1 (EU302123), Boymaw (GU134617), der 11 chimeric transcript DISC1FP1 exon 2 to DISC1 exon 9 (JQ650115), der 1 chimeric transcript DISC1 exon 4 to DISC1FP1 exon 4 (JQ650116), der 1 chimeric transcript DISC1 exon 6 to DISC1FP1 exon 3a (JQ650117)

Family-centred music therapy with preterm infants and their parents in the Neonatal Intensive Care Unit (NICU) in Colombia – A mixed-methods study

This article reports a mixed-methods study of Music Therapy (MT) with preterm infants and their parents in a neonatal intensive care unit (NICU) in Colombia. The aim was to find out whether live MT during kangaroo care had an effect on the physiological outcomes of the neonates and would help parents to decrease their anxiety levels and improve parent–infant bonding. The participants were 36 medically stable neonates born between the 28th and 34th week of gestation and their parents. The quantitative data collection included heart rate, oxygen saturation, weight gain, length of hospitalization and re-hospitalization rate. The assessment measures for anxiety and bonding were the State-Trait Anxiety Inventory (STAI) and the Mother-to-Infant-Bonding Scale (MIBS). Thematic analysis was used to analyse the qualitative data collected with semi-structured interviews and questionnaires. The quantitative results showed statistically significant improvements in maternal state-anxiety (p = .007) and in the babies weight gain per day during the intervention period (p = .036). Positive trends were found regarding the babies’ length of hospitalization and re-hospitalization rate. Both parents improved their scores with the MIBS, but this was not statistically significant. The qualitative analysis showed that MT was important for parental well-being, for bonding and for fostering the development of the neonates. Interacting musically with their babies helped parents to experience feelings of connectedness and to distract themselves from their difficulties and from the noisy hospital environment

GT2006-90165 GROUND TEST DATA VALIDATION USING A SUBSCALE F/A-22 ENGINE INLET EMPIRICAL MODEL

ABSTRACT The US Air Force&apos;s two main aeropropulsion test centers, Arnold Engineering Development Center and the Air Force Flight Test Center, are developing a common suite of modeling and simulation tools employing advanced predictive modeling technologies. These modeling and simulation tools incorporate real-time data validation, system identification, parameter estimation, model calibration, and automated model updating as new test results or operational data become available. The expected benefit is improved efficiency and accuracy for online diagnostic monitoring of Air Force assets. This paper describes the integrated approach to real-time data validation. Implementation of a software package to enable efficient model handoff between test groups and centers and extension of the capability to aeropropulsion models is discussed. An F/A-22 inlet model is used to demonstrate the approach. Compact polynomial function models of the distortion and recovery flow descriptors and 40-probe pressure values are derived from quasisteady and instantaneous subscale wind tunnel data. The total-pressure inlet distortion and recovery models are integrated in a real-time equipment health monitoring system designed to support test operations, and preliminary results are given. A companion paper describes the integrated approach to system identification, parameter estimation, and model updating

Momentum meets value investing in a small European market

In this paper, we investigate two prominent market anomalies documented in the finance literature – the momentum effect and value-growth effect. We conduct an out- of-sample test to the link between these two anomalies recurring to a sample of Portuguese stocks during the period 1988–2015. We find that the momentum of value and growth stocks is significantly different: growth stocks exhibit a much larger momentum than value stocks. A combined value and momentum strategy can generate statistically significant excess annual returns of 10.8%. These findings persist across several holding periods up to a year. Moreover, we show that macroeconomic variables fail to explain value and momentum of individual and combined returns. Collectively, our results contradict market efficiency at the weak form and pose a challenge to existing asset pricing theories.info:eu-repo/semantics/publishedVersio

Long-Horizon Consumption Risk and the Cross-Section of Returns: New Tests and International Evidence

This paper investigates whether measuring consumption risk over long horizons can improve the empirical performance of the Consumption CAPM for size and value premia in international stock markets (US, UK, and Germany). In order to account for commonalities in size and book-tomarket sorted portfolios, we also include industry portfolios in our set of test assets. Our results show that, contrary to the findings of Parker and Julliard (2005), the model falls short of providing an accurate description of the cross-section of returns under our modified empirical approach. At the same time, however, measuring consumption risk over longer horizons typically yields lower risk-aversion estimates. Thus, our results suggest that more plausible parameter estimates - as opposed to lower pricing errors - can be regarded as the main achievement of the long-horizon Consumption CAPM

One-Year Treatment With Exenatide Improves β-Cell Function, Compared With Insulin Glargine, in Metformin-Treated Type 2 Diabetic Patients: A randomized, controlled trial

0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS: Exenatide significantly improves beta-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, beta-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therap