MYCN-targeting miRNAs are predominantly downregulated during MYCN-driven neuroblastoma tumor formation

MYCN is a transcription factor that plays key roles in both normal development and cancer. In neuroblastoma, MYCN acts as a major oncogenic driver through pleiotropic effects controlled by multiple protein encoding genes as well as microRNAs (miRNAs). MYCN activity is tightly regulated at the level of transcription and protein stability through various mechanisms. Like most genes, MYCN is further controlled by miRNAs, but the full complement of all miRNAs implicated in this process has not been determined through an unbiased approach. To elucidate the role of miRNAs in regulation of MYCN, we thus explored the MYCN-miRNA interactome to establish miRNAs controlling MYCN expression levels. We combined results from an unbiased and genome-wide high-throughput miRNA target reporter screen with miRNA and mRNA expression data from patients and a murine neuroblastoma progression model. We identified 29 miRNAs targeting MYCN, of which 12 miRNAs are inversely correlated with MYCN expression or activity in neuroblastoma tumor tissue. The majority of MYCN-targeting miRNAs in neuroblastoma showed a decrease in expression during murine MYCN-driven neuroblastoma tumor development. Therefore, we provide evidence that MYCN-targeting miRNAs are preferentially downregulated in MYCN-driven neuroblastoma, suggesting that MYCN negatively controls the expression of these miRNAs, to safeguard its expression

The effect of cardiac resynchronization without a defibrillator on morbidity and mortality: an individual patient data meta-analysis of COMPANION and CARE-HF

AIMS: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality for patients with heart failure, reduced left ventricular ejection fraction, QRS duration >130 ms and in sinus rhythm. The aim of this study was to identify patient characteristics that predict the effect, specifically, of CRT pacemakers (CRT-P) on all-cause mortality or the composite of hospitalization for heart failure or all-cause mortality. METHODS AND RESULTS: We conducted an individual patient data meta-analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization-Heart Failure (CARE-HF) trials. Only patients assigned to CRT-P or control (n = 1738) were included in order to avoid confounding from concomitant defibrillator therapy. The influence of baseline characteristics on treatment effects was investigated. Median age was 67 (59-73) years, most patients were men (70%), 68% had a QRS duration of 150-199 ms and 80% had left bundle branch block. Patients assigned to CRT-P had lower rates for all-cause mortality (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.56-0.81; p < 0.0001) and the composite outcome (HR 0.67, 95% CI 0.58-0.78; p < 0.0001). No pre-specified characteristic, including sex, aetiology of ventricular dysfunction, QRS duration (within the studied range) or morphology or PR interval significantly influenced the effect of CRT-P on all-cause mortality or the composite outcome. However, CRT-P had a greater effect on the composite outcome for patients with lower body surface area and those prescribed beta-blockers. CONCLUSIONS: Cardiac resynchronization therapy-pacemaker reduces morbidity and mortality in appropriately selected patients with heart failure. Benefits may be greater in smaller patients and in those receiving beta-blockers. Neither QRS duration nor morphology independently predicted the benefit of CRT-P. CLINICAL TRIAL REGISTRATION: COMPANION, NCT00180258; CARE-HF, NCT00170300

A Multi-Modal Public Transport Solution For Male, Maldives

Male, the island capital of the Maldives, an archipelago of over 1000 islands in the Indian Ocean faces chronic traffic congestion. This 2 sq km island is home to over 100,000 people. There is a taxi service comprising of around 450 vehicles and a dhoni (ferry) service amounting to over 100 vessels to neighbouring islands. Male, which is fast becoming a small urban centre faces typical peak period traffic issues. The vehicle fleet is dominated by motor cycles which still contribute to traffic congestion in narrow streets. The taxi system which comprises of individually owned taxis registered with a ‘call centre’, provide limited services but fails during peak demand periods especially on rainy days. There is very little coordination between the ferry and taxi services. The paper is based on the results of a detailed urban transport planning study carried out in Male Urban Area which included passenger interviews, vehicle counts and travel time surveys covering all modes of motorized and non-motorized travel. This paper investigates the introduction of a mini-bus transport system that would provide easy transfers between ferries and major traffic generators and attractors. The contribution of a mini-bus service in the long-term is also discussed with respect to implementation of traffic demand management measures. This paper discuses the most appropriate type of vehicle that could be used and the potential framework for ownership and management of such a system taking in to consideration the multi-modal connectivity and also the service parameters for the operation of a successful minibus service. The paper also analyses the present operation of the ferry services and investigates its ownership and operation parameters for efficiency and cost effectiveness. The paper reports reasons for the varied efficiencies seen on the different routes and the impact the informal and loosely regulated service providers have on the key performance indicators of these services. It also compares cost between different ferry services and studies the relationship between the ownership structure, technology levels, productivity and fare.Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Head-Tail Clouds: Drops to Probe the Diffuse Galactic Halo

A head-tail high-velocity cloud (HVC) is a neutral hydrogen halo cloud that appears to be interacting with the diffuse halo medium as evident by its compressed head trailed by a relatively diffuse tail. This paper presents a sample of 116 head-tail HVCs across the southern sky (d < 2 deg) from the HI Parkes All Sky Survey (HIPASS) HVC catalog, which has a spatial resolution of 15.5 arcmin (45 pc at 10 kpc) and a sensitivity of N_HI=2 x 10^(18) cm^(-2) (5 sigma). 35% of the HIPASS compact and semi-compact HVCs (CHVCs and :HVCs) can be classified as head-tail clouds from their morphology. The clouds have typical masses of 730 M_sun at 10 kpc (26,000 M_sun at 60 kpc) and the majority can be associated with larger HVC complexes given their spatial and kinematic proximity. This proximity, together with their similar properties to CHVCs and :HVCs without head-tail structure, indicate the head-tail clouds have short lifetimes, consistent with simulation predictions. Approximately half of the head-tail clouds can be associated with the Magellanic System, with the majority in the region of the Leading Arm with position angles pointing in the general direction of the movement of the Magellanic System. The abundance in the Leading Arm region is consistent with this feature being closer to the Galactic disk than the Magellanic Stream and moving through a denser halo medium. The head-tail clouds will feed the multi-phase halo medium rather than the Galactic disk directly and provide additional evidence for a diffuse Galactic halo medium extending to at least the distance of the Magellanic Clouds.Comment: MNRAS Accepted, 10 figures, 7 in colo

Perspective: Chain dynamics of unfolded and intrinsically disordered proteins from nanosecond fluorescence correlation spectroscopy combined with single-molecule FRET

The dynamics of unfolded proteins are important both for the process of protein folding and for the behavior of intrinsically disordered proteins. However, methods for investigating the global chain dynamics of these structurally diverse systems have been limited. A versatile experimental approach is single-molecule spectroscopy in combination with Förster resonance energy transfer and nanosecond fluorescence correlation spectroscopy. The concepts of polymer physics offer a powerful framework both for interpreting the results and for understanding and classifying the properties of unfolded and intrinsically disordered proteins. This information on long-range chain dynamics can be complemented with spectroscopic techniques that probe different length scales and time scales, and integration of these results greatly benefits from recent advances in molecular simulations. This increasing convergence between the experiment, theory, and simulation is thus starting to enable an increasingly detailed view of the dynamics of disordered proteins

The relationship between lung function impairment and quantitative computed tomography in chronic obstructive pulmonary disease

Contains fulltext : 109919.pdf (Publisher’s version ) (Open Access)OBJECTIVES: To determine the relationship between lung function impairment and quantitative computed tomography (CT) measurements of air trapping and emphysema in a population of current and former heavy smokers with and without airflow limitation. METHODS: In 248 subjects (50 normal smokers; 50 mild obstruction; 50 moderate obstruction; 50 severe obstruction; 48 very severe obstruction) CT emphysema and CT air trapping were quantified on paired inspiratory and end-expiratory CT examinations using several available quantification methods. CT measurements were related to lung function (FEV(1), FEV(1)/FVC, RV/TLC, Kco) by univariate and multivariate linear regression analysis. RESULTS: Quantitative CT measurements of emphysema and air trapping were strongly correlated to airflow limitation (univariate r-squared up to 0.72, p < 0.001). In multivariate analysis, the combination of CT emphysema and CT air trapping explained 68-83% of the variability in airflow limitation in subjects covering the total range of airflow limitation (p < 0.001). CONCLUSIONS: The combination of quantitative CT air trapping and emphysema measurements is strongly associated with lung function impairment in current and former heavy smokers with a wide range of airflow limitation.01 januari 201

The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during<i> Caenorhabditis elegans</i> Meiosis

Meiotic recombination is essential for the repair of programmed double strand breaks (DSBs) to generate crossovers (COs) during meiosis. The efficient processing of meiotic recombination intermediates not only needs various resolvases but also requires proper meiotic chromosome structure. The Smc5/6 complex belongs to the structural maintenance of chromosome (SMC) family and is closely related to cohesin and condensin. Although the Smc5/6 complex has been implicated in the processing of recombination intermediates during meiosis, it is not known how Smc5/6 controls meiotic DSB repair. Here, using Caenorhabditis elegans we show that the SMC-5/6 complex acts synergistically with HIM-6, an ortholog of the human Bloom syndrome helicase (BLM) during meiotic recombination. The concerted action of the SMC-5/6 complex and HIM-6 is important for processing recombination intermediates, CO regulation and bivalent maturation. Careful examination of meiotic chromosomal morphology reveals an accumulation of inter-chromosomal bridges in smc-5; him-6 double mutants, leading to compromised chromosome segregation during meiotic cell divisions. Interestingly, we found that the lethality of smc-5; him-6 can be rescued by loss of the conserved BRCA1 ortholog BRC-1. Furthermore, the combined deletion of smc-5 and him-6 leads to an irregular distribution of condensin and to chromosome decondensation defects reminiscent of condensin depletion. Lethality conferred by condensin depletion can also be rescued by BRC-1 depletion. Our results suggest that SMC-5/6 and HIM-6 can synergistically regulate recombination intermediate metabolism and suppress ectopic recombination by controlling chromosome architecture during meiosis