MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognostic implications. This is partly due to a large proportion of PDACs carrying mutations in TP53, which impart gain-of-function characteristics that promote metastasis. There is evidence that microRNAs (miRNAs) may play a role in both gain-of-function TP53 mutations and metastasis, but this has not been fully explored in PDAC. Here we set out to identify miRNAs which are specifically dysregulated in metastatic PDAC. To achieve this, we utilised established mouse models of PDAC to profile miRNA expression in primary tumours expressing the metastasis-inducing mutant p53R172H and compared these to two control models carrying mutations, which promote tumour progression but do not induce metastasis. We show that a subset of miRNAs are dysregulated in mouse PDAC tumour tissues expressing mutant p53R172H, primary cell lines derived from mice with the same mutations and in TP53 null cells with ectopic expression of the orthologous human mutation, p53R175H. Specifically, miR-142-3p is downregulated in all of these experimental models. We found that DNA methyltransferase 1 (Dnmt1) is upregulated in tumour tissue and cell lines, which express p53R172H. Inhibition or depletion of Dnmt1 restores miR-142-3p expression. Overexpression of miR-142-3p attenuates the invasive capacity of p53R172H-expressing tumour cells. MiR-142-3p dysregulation is known to be associated with cancer progression, metastasis and the miRNA is downregulated in patients with PDAC. Here we link TP53 gain-of-function mutations to Dnmt1 expression and in turn miR-142-3p expression. Additionally, we show a correlation between expression of these genes and patient survival, suggesting that they may have potential to be therapeutic targets

The [alpha/Fe] Ratios in Dwarf Galaxies: Evidence for a Non-universal Stellar Initial Mass Function?

It is well established that the [alpha/Fe] ratios in elliptical galaxies increase with galaxy mass. This relation holds also for early-type dwarf galaxies, although it seems to steepen at low masses. The [alpha/Fe] vs. mass relation can be explained assuming that smaller galaxies form over longer timescales (downsizing), allowing a larger amount of Fe (mostly produced by long-living Type Ia Supernovae) to be released and incorporated into newly forming stars. Another way to obtain the same result is by using a flatter initial mass function (IMF) in large galaxies, increasing in this way the number of Type II Supernovae and therefore the production rate of alpha-elements. The integrated galactic initial mass function (IGIMF) theory predicts that the higher the star formation rate, the flatter the IMF. We have checked, by means of semi-analytical calculations, that the IGIMF theory, combined with the downsizing effect (i.e. the shorter duration of the star formation in larger galaxies), well reproduces the observed [alpha/Fe] vs. mass relation. In particular, we show a steepening of this relation in dwarf galaxies, in accordance with the available observations.Comment: 4 pages, 2 figures; to appear in the proceedings of the JENAM 2010 Symposium on Dwarf Galaxies (Lisbon, September 9-10, 2010

Evaluation Of Support Vector Machine Based Forecasting Tool In Electricity Price Forecasting For Australian National Electricity Market Participants

In this paper, we present an analysis of the results of a study into wholesale (spot) electricity price forecasting utilising Neural Networks (NNs) and Support Vector Machines (SVM). Frequent regulatory changes in electricity markets and the quickly evolving market participant pricing (bidding) strategies cause efficient retraining to be crucial in maintaining the accuracy of electricity price forecasting models. The efficiency of NN and SVM retraining for price forecasting was evaluated using Australian National Electricity Market (NEM), New South Wales regional data over the period from September 1998 to December 1998. The analysis of the results showed that SVMs with one unique solution, produce more consistent forecasting accuracies and so require less time to optimally train than NNs, which can result in a solution at any of a large number of local minima. The SVM and NN forecasting accuracies were found to be very similar

Support Vector Machine Based Electricity Price Forecasting For Electricity Markets utilising Projected Assessment of System Adequacy Data

In this paper we present an analysis of the results of a study into wholesale (spot) electricity price forecasting with Support Vector Machines (SVM) utilising past price and demand data and Projected Assessment of System Adequacy (PASA) data. The forecasting accuracy was evaluated using Australian National Electricity Market (NEM), New South Wales regional data over the year 2002. The inclusion of PASA data shows little improvement in forecasting accuracy

The MemProtMD database : a resource for membrane-embedded protein structures and their lipid interactions

Integral membrane proteins fulfil important roles in many crucial biological processes, including cell signalling, molecular transport and bioenergetic processes. Advancements in experimental techniques are revealing high resolution structures for an increasing number of membrane proteins. Yet, these structures are rarely resolved in complex with membrane lipids. In 2015, the MemProtMD pipeline was developed to allow the automated lipid bilayer assembly around new membrane protein structures, released from the Protein Data Bank (PDB). To make these data available to the scientific community, a web database (http://memprotmd.bioch.ox.ac.uk) has been developed. Simulations and the results of subsequent analysis can be viewed using a web browser, including interactive 3D visualizations of the assembled bilayer and 2D visualizations of lipid contact data and membrane protein topology. In addition, ensemble analyses are performed to detail conserved lipid interaction information across proteins, families and for the entire database of 3506 PDB entries. Proteins may be searched using keywords, PDB or Uniprot identifier, or browsed using classification systems, such as Pfam, Gene Ontology annotation, mpstruc or the Transporter Classification Database. All files required to run further molecular simulations of proteins in the database are provided

Inherent-opening-controlled pattern formation in carbon nanotube arrays

We have introduced inherent openings into densely packed carbon nanotube arrays to study self-organized pattern formation when the arrays undergo a wetting–dewetting treatment from nanotube tips. These inherent openings, made of circular or elongated hollows in nanotube mats, serve as dewetting centres, from where liquid recedes from. As the dewetting centres initiate dry zones and the dry zones expand, surrounding nanotubes are pulled away from the dewetting centres by liquid surface tension. Among short nanotubes, the self-organized patterns are consistent with the shape of the inherent openings, i.e. slender openings lead to elongated trench-like structures, and circular holes result in relatively round nest-like arrangements. Nanotubes in a relatively high mat are more connected, like in an elastic body, than those in a short mat. Small cracks often initialize themselves in a relatively high mat, along two or more adjacent round openings; each of the cracks evolves into a trench as liquid dries up. Self-organized pattern control with inherent openings needs to initiate the dewetting process above the nanotube tips. If there is no liquid on top, inherent openings barely enlarge themselves after the wetting–dewetting treatment

X-ray observations of three young, early-type galaxies

Massive haloes of hot plasma exist around some, but not all elliptical galaxies. There is evidence that this is related to the age of the galaxy. In this paper, new X-ray observations are presented for three early-type galaxies that show evidence of youth, in order to investigate their X-ray components and properties. NGC 5363 and NGC 2865 were found to have X-ray emission dominated by purely discrete stellar sources. Limits are set on the mass distribution in one of the galaxies observed with XMM–Newton, NGC 4382, which contains significant hot gas. We detect the X-ray emission in NGC 4382 out to 4re. The mass-to-light ratio is consistent with a stellar origin in the inner regions but rises steadily to values indicative of some dark matter by 4re. These results are set in context with other data drawn from the literature, for galaxies with ages estimated from dynamical or spectroscopic indicators. Ages obtained from optical spectroscopy represent central luminosity-weighted stellar ages. We examine the X-ray evolution with age, normalized by B- and K-band luminosities. Low values of Log(LX/LB) and Log(LX/LK) are found for all galaxies with ages between 1 and 4 Gyr. Luminous X-ray emission only appears in older galaxies. This suggests that the interstellar medium is removed and then it takes several gigayears for hot gas haloes to build up, following a merger. A possible mechanism for gas expulsion might be associated with feedback from an active nucleus triggered during a merger

The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

The cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, levels of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts have been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis

Approximate Entropy Values Demonstrate Impaired Neuromotor Control of Spontaneous Leg Activity in Infants with Myelomeningocele

Purpose: One obstacle to providing early intervention to infants with myelomeningocele (MMC) is the challenge of quantifying impaired neuromotor control of movements early in life. Methods: We used the nonlinear analysis tool Approximate Entropy (ApEn) to analyze periodicity and complexity of supine spontaneous lower extremity movements of infants with MMC and typical development (TD) at 1, 3, 6, and 9 months of age. Results: Movements of infants with MMC were more regular and repeatable (lower ApEn values) than movements of infants with TD, indicating less adaptive and flexible movement patterns. For both groups ApEn values decreased with age, and the movements of infants with MMC were less complex than movements of infants with TD. Further, for infants with MMC, lesion level and age of walking onset correlated negatively with ApEn values. Conclusions: Our study begins to demonstrate the feasibility of ApEn to identify impaired neuromotor control in infants with MMC