1,551 research outputs found
Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival
MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over-or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics
Thermal Degradation of Adsorbed Bottle-Brush Macromolecules: Molecular Dynamics Simulation
The scission kinetics of bottle-brush molecules in solution and on an
adhesive substrate is modeled by means of Molecular Dynamics simulation with
Langevin thermostat. Our macromolecules comprise a long flexible polymer
backbone with segments, consisting of breakable bonds, along with two side
chains of length , tethered to each segment of the backbone. In agreement
with recent experiments and theoretical predictions, we find that bond cleavage
is significantly enhanced on a strongly attractive substrate even though the
chemical nature of the bonds remains thereby unchanged.
We find that the mean bond life time decreases upon adsorption by
more than an order of magnitude even for brush molecules with comparatively
short side chains $N=1 \div 4$. The distribution of scission probability along
the bonds of the backbone is found to be rather sensitive regarding the
interplay between length and grafting density of side chains. The life time
declines with growing contour length as ,
and with side chain length as . The probability
distribution of fragment lengths at different times agrees well with
experimental observations. The variation of the mean length of the
fragments with elapsed time confirms the notion of the thermal degradation
process as a first order reaction.Comment: 15 pages, 7 figure
Kinetics of fragmentation-annihilation processes
We investigate the kinetics of systems in which particles of one species
undergo binary fragmentation and pair annihilation. In the latter, nonlinear
process, fragments react at collision to produce an inert species, causing loss
of mass. We analyse these systems in the reaction-limited regime by solving a
continuous model within the mean-field approximation. The rate of
fragmentation, for a particle of mass to break into fragments of masses
and , has the form (), and the annihilation
rate is constant and independent of the masses of the reactants. We find that
the asymptotic regime is characterized by the annihilation of small-mass
clusters. The results are compared with those for a model with linear mass-loss
(i.e.\ with a sink). We also study more complex models, in which the processes
of fragmentation and annihilation are controlled by mutually-reacting
catalysts. Both pair- and linear-annihilation are considered. Depending on the
specific model and initial densities of the catalysts, the time-decay of the
cluster-density can now be very unconventional and even non-universal. The
interplay between the intervening processes and the existence of a scaling
regime are determined by the asymptotic behaviour of the average-mass and of
the mass-density, which may either decay indefinitely or tend to a constant
value. We discuss further developments of this class of models and their
potential applications.Comment: 16 pages(LaTeX), submitted to Phys. Rev.
TEXT messages to improve MEDication adherence and Secondary prevention (TEXTMEDS) after acute coronary syndrome: A randomised clinical trial protocol
Background: Identifying simple, low-cost and scalable means of supporting lifestyle change and medication adherence for patients following a cardiovascular (CV) event is important. Objective: The TEXTMEDS (TEXT messages to improve MEDication adherence and Secondary prevention) study aims to investigate whether a cardiac education and support programme sent via mobile phone text message improves medication adherence and risk factor levels in patients following an acute coronary syndrome (ACS). Study design: A single-blind, multicentre, randomised clinical trial of 1400 patients after an ACS with 12 months follow-up. The intervention group will receive multiple weekly text messages that provide information, motivation, support to adhere to medications, quit smoking (if relevant) and recommendations for healthy diet and exercise. The primary endpoint is the percentage of patients who are adherent to cardioprotective medications and the key secondary outcomes are mean systolic blood pressure (BP) and low-density lipoprotein cholesterol. Secondary outcomes will also include total cholesterol, mean diastolic BP, the percentage of participants who are adherent to each cardioprotective medication class, the percentage of participants who achieve target levels of CV risk factors, major vascular events, hospital readmissions and all-cause mortality. The study will be augmented by formal economic and process evaluations to assess acceptability, utility and cost-effectiveness. Summary: The study will provide multicentre randomised trial evidence of the effects of a text message-based programme on cardioprotective medication adherence and levels of CV risk factors. Ethics and dissemination: Primary ethics approval was received from Western Sydney Local Health District Human Research Ethics Committee (HREC2012/12/4.1 (3648) AU RED HREC/13/WMEAD/15). Results will be disseminated via peer-reviewed publications and presentations at international conferences. Trial registration number ACTRN12613000793718; Pre-results
Universal features of the order-parameter fluctuations : reversible and irreversible aggregation
We discuss the universal scaling laws of order parameter fluctuations in any
system in which the second-order critical behaviour can be identified. These
scaling laws can be derived rigorously for equilibrium systems when combined
with the finite-size scaling analysis. The relation between order parameter,
criticality and scaling law of fluctuations has been established and the
connexion between the scaling function and the critical exponents has been
found. We give examples in out-of-equilibrium aggregation models such as the
Smoluchowski kinetic equations, or of at-equilibrium Ising and percolation
models.Comment: 19 pages, 10 figure
Nature of the bonding in metal-silane σ-complexes
The nature of metal silane σ-bond interaction has been investigated in several key systems by a range of experimental and computational techniques. The structure of [Cp′Mn(CO)2(η2-HSiHPh2)] 1 has been determined by single crystal neutron diffraction, and the geometry at the Si atom is shown to approximate a trigonal bipyramid; salient bond distances and angles are Mn−H(1) 1.575(14), Si−H(1) 1.806(14), Si−H(2) 1.501(13) Å, and H(1)−Si−H(2) 148.5(8)°. This complex is similar to [Cp′Mn(CO)2(η2-HSiFPh2)] 2, whose structure and bonding characteristics have recently been determined by charge density studies based on high-resolution X-ray and neutron diffraction data. The geometry at the Si atom in these σ-bond complexes is compared with that in other systems containing hypercoordinate silicon. The Mn−H distances for 1 and 2 in solution have been estimated using NMR T1 relaxation measurements, giving a value of 1.56(3) Å in each case, in excellent agreement with the distances deduced from neutron diffraction. Density functional theory calculations have been employed to explore the bonding in the Mn−H−Si unit in 1 and 2 and in the related system [Cp′Mn(CO)2(η2-HSiCl3)] 3. These studies support the idea that the oxidative addition of a silane ligand to a transition metal center may be described as an asymmetric process in which the Mn−H bond is formed at an early stage, while both the establishment of the Mn−Si bond and also the activation of the η2-coordinated Si−H moiety are controlled by the extent of Mn → σ*(X−Si−H) back-donation, which increases with increasing electron-withdrawing character of the X substituent trans to the metal-coordinated Si−H bond. This delocalized molecular orbital (MO) approach is complemented and supported by combined experimental and theoretical charge density studies: the source function S(r,Ω), which provides a measure of the relative importance of each atom’s contribution to the density at a specific reference point r, clearly shows that all three atoms of the Mn(η2-SiH) moiety contribute to a very similar extent to the density at the Mn−Si bond critical point, in pleasing agreement with the MO model. Hence, we advance a consistent and unifying concept which accounts for the degree of Si−H activation in these silane σ-bond complexes
Contrasted Effects of Diversity and Immigration on Ecological Insurance in Marine Bacterioplankton Communities
The ecological insurance hypothesis predicts a positive effect of species richness on ecosystem functioning in a variable environment. This effect stems from temporal and spatial complementarity among species within metacommunities coupled with optimal levels of dispersal. Despite its importance in the context of global change by human activities, empirical evidence for ecological insurance remains scarce and controversial. Here we use natural aquatic bacterial communities to explore some of the predictions of the spatial and temporal aspects of the ecological insurance hypothesis. Addressing ecological insurance with bacterioplankton is of strong relevance given their central role in fundamental ecosystem processes. Our experimental set up consisted of water and bacterioplankton communities from two contrasting coastal lagoons. In order to mimic environmental fluctuations, the bacterioplankton community from one lagoon was successively transferred between tanks containing water from each of the two lagoons. We manipulated initial bacterial diversity for experimental communities and immigration during the experiment. We found that the abundance and production of bacterioplankton communities was higher and more stable (lower temporal variance) for treatments with high initial bacterial diversity. Immigration was only marginally beneficial to bacterial communities, probably because microbial communities operate at different time scales compared to the frequency of perturbation selected in this study, and of their intrinsic high physiologic plasticity. Such local “physiological insurance” may have a strong significance for the maintenance of bacterial abundance and production in the face of environmental perturbations
Species Richness and Trophic Diversity Increase Decomposition in a Co-Evolved Food Web
Ecological communities show great variation in species richness, composition and food web structure across similar and diverse ecosystems. Knowledge of how this biodiversity relates to ecosystem functioning is important for understanding the maintenance of diversity and the potential effects of species losses and gains on ecosystems. While research often focuses on how variation in species richness influences ecosystem processes, assessing species richness in a food web context can provide further insight into the relationship between diversity and ecosystem functioning and elucidate potential mechanisms underpinning this relationship. Here, we assessed how species richness and trophic diversity affect decomposition rates in a complete aquatic food web: the five trophic level web that occurs within water-filled leaves of the northern pitcher plant, Sarracenia purpurea. We identified a trophic cascade in which top-predators — larvae of the pitcher-plant mosquito — indirectly increased bacterial decomposition by preying on bactivorous protozoa. Our data also revealed a facultative relationship in which larvae of the pitcher-plant midge increased bacterial decomposition by shredding detritus. These important interactions occur only in food webs with high trophic diversity, which in turn only occur in food webs with high species richness. We show that species richness and trophic diversity underlie strong linkages between food web structure and dynamics that influence ecosystem functioning. The importance of trophic diversity and species interactions in determining how biodiversity relates to ecosystem functioning suggests that simply focusing on species richness does not give a complete picture as to how ecosystems may change with the loss or gain of species
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