Detecting microRNA binding and siRNA off-target effects from expression data.

Sylamer is a method for detecting microRNA target and small interfering RNA off-target signals in 3' untranslated regions from a ranked gene list, sorted from upregulated to downregulated, after a microRNA perturbation or RNA interference experiment. The output is a landscape plot that tracks occurrence biases using hypergeometric P-values for all words across the gene ranking. We demonstrated the utility, speed and accuracy of this approach on several datasets

ATLASGAL - star forming efficiencies and the Galactic star formation rate

The ATLASGAL survey has characterized the properties of approximately 1000 embedded H ii regions and found an empirical relationship between the clump mass and bolometric luminosity that covers 3-4 orders of magnitude. Comparing this relation with simulated clusters drawn from an initial mass function and using different star formation efficiencies we find that a single value is unable to fit the observed luminosity to mass (L/M) relation. We have used a Monte Carlo simulation to generate 200 000 clusters using the L/M-ratio as a constraint to investigate how the star formation efficiency changes as a function of clump mass. This has revealed that the star formation efficiency decreases with increasing clump mass with a value of 0.2 for clumps with masses of a few hundred solar masses and dropping to 0.08 for clumps with masses of a few thousand solar masses. We find good agreement between our results and star formation efficiencies determined from counts of embedded objects in nearby molecular clouds. Using the star formation efficiency relationship and the infrared excess time for embedded star formation of 2 ± 1 Myr we estimate the Galactic star formation rate to be approximately 0.9 ± 0.45 M· yr-1, which is in good agreement with previously reported values. This model has the advantage of providing a direct means of determining the star formation rate and avoids the difficulties encountered in converting infrared luminosities to stellar mass that affect previous galactic and extragalactic studies

CHIMPS: Physical properties of molecular clumps across the inner Galaxy

The latest generation of high-angular-resolution unbiased Galactic plane surveys in molecular-gas tracers are enabling the interiors of molecular clouds to be studied across a range of environments. The CO Heterodyne Inner MilkyWay Plane Survey (CHIMPS) simultaneously mapped a sector of the inner Galactic plane, within 27:8 . 46:2 and jbj 0: 5, in 13CO (3-2) and C18O (3-2) at an angular resolution of 15 arcsec. The combination of the CHIMPS data with 12CO (3-2) data from the CO High Resolution Survey (COHRS) has enabled us to perform a voxel-by-voxel local-thermodynamic-equilibrium (LTE) analysis, determining the excitation temperature, optical depth, and column density of 13CO at each; b; v position. Distances to discrete sources identified by FELLWALKER in the 13CO (3-2) emission maps were determined, allowing the calculation of numerous physical properties of the sources, and we present the first source catalogues in this paper.We find that, in terms of size and density, the CHIMPS sources represent an intermediate population between large-scale molecular clouds identified by CO and dense clumps seen in thermal dust continuum emission, and therefore represent the bulk transition from the diffuse to the dense phase of molecular gas.We do not find any significant systematic variations in the masses, column densities, virial parameters, mean excitation temperature, or the turbulent pressure over the range of Galactocentric distance probed, but we do find a shallow increase in the mean volume density with increasing Galactocentric distance. We find that inter-arm clumps have significantly narrower linewidths, and lower virial parameters and excitation temperatures than clumps located in spiral arms. When considering the most reliable distance-limited subsamples, the largest variations occur on the clump-to-clump scale, echoing similar recent studies that suggest that the star-forming process is largely insensitive to the Galactic-scale environment, at least within the inner disc

CHIMPS: the 13^{13}CO/C18^{18}O (J=3-2) Heterodyne Inner Milky Way Plane Survey

We present the $^{13}$CO/C$^{18}$O (J=3-2) Heterodyne Inner Milky Way Plane Survey (CHIMPS) which has been carried out using the Heterodyne Array Receiver Program on the 15 m James Clerk Maxwell Telescope (JCMT) in Hawaii. The high-resolution spectral survey currently covers |b| < 0.5 deg and 28 < l < 46 deg, with an angular resolution of 15 arcsec in 0.5 km/s velocity channels. The spectra have a median rms of $\sim$ 0.6 K at this resolution, and for optically thin gas at an excitation temperature of 10 K, this sensitivity corresponds to column densities of $N_{\mathrm{H}_{2}} \sim 3 \times 10^{20}\,$cm$^{-2}$ and $N_{\mathrm{H}_{2}} \sim 4 \times 10^{21}\,$cm$^{-2}$ for $^{13}$CO and C$^{18}$O, respectively. The molecular gas that CHIMPS traces is at higher column densities and is also more optically thin than in other publicly available CO surveys due to its rarer isotopologues, and thus more representative of the three-dimensional structure of the clouds. The critical density of the J=3-2 transition of CO is $\gtrsim 10^{4}$ cm$^{-3}$ at temperatures of $\leq 20$ K, and so the higher density gas associated with star formation is well traced. These data complement other existing Galactic plane surveys, especially the JCMT Galactic Plane Survey which has similar spatial resolution and column density sensitivity, and the Herschel infrared Galactic Plane Survey. In this paper, we discuss the observations, data reduction and characteristics of the survey, presenting integrated emission maps for the region covered. Position-velocity diagrams allow comparison with Galactic structure models of the Milky Way, and while we find good agreement with a particular four arm model, there are some significant deviations

An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON

Childhood leukaemia: long-term excess mortality and the proportion ‘cured'

Survival from childhood leukaemia has increased, but the proportion of children cured is unknown. The proportion ‘cured' is defined as the proportion of survivors for whom, as a group, there is no longer excess mortality compared to the general population. Average time to cure is defined as the time since diagnosis at which the excess mortality rate has declined to or below a predetermined small value. Data on children diagnosed with leukaemia during 1971–2000 in Great Britain were used to estimate trends in survival, the proportion cured and the average time to cure. Five-year survival for all types of leukaemia combined rose from 33 to 79% by 2000. The percentage cured rose from 25 to 68% by 1995; it is predicted to increase to 73% for those diagnosed more recently. Average time to cure increased from 12 years (95% confidence interval (CI): 11–14) to 19 years (95% CI: 14–26) for lymphoid leukaemia (average annual increase of 0.3 years; P<0.001), but remained at about 5 years for acute nonlymphoblastic leukaemia. The proportion of children cured of leukaemia has risen dramatically, but the period of excess mortality associated with lymphoid leukaemia has also increased, possibly because of late relapse, secondary malignancy and toxicity from treatment

Small Deletion Variants Have Stable Breakpoints Commonly Associated with Alu Elements

Copy number variants (CNVs) contribute significantly to human genomic variation, with over 5000 loci reported, covering more than 18% of the euchromatic human genome. Little is known, however, about the origin and stability of variants of different size and complexity. We investigated the breakpoints of 20 small, common deletions, representing a subset of those originally identified by array CGH, using Agilent microarrays, in 50 healthy French Caucasian subjects. By sequencing PCR products amplified using primers designed to span the deleted regions, we determined the exact size and genomic position of the deletions in all affected samples. For each deletion studied, all individuals carrying the deletion share identical upstream and downstream breakpoints at the sequence level, suggesting that the deletion event occurred just once and later became common in the population. This is supported by linkage disequilibrium (LD) analysis, which has revealed that most of the deletions studied are in moderate to strong LD with surrounding SNPs, and have conserved long-range haplotypes. Analysis of the sequences flanking the deletion breakpoints revealed an enrichment of microhomology at the breakpoint junctions. More significantly, we found an enrichment of Alu repeat elements, the overwhelming majority of which intersected deletion breakpoints at their poly-A tails. We found no enrichment of LINE elements or segmental duplications, in contrast to other reports. Sequence analysis revealed enrichment of a conserved motif in the sequences surrounding the deletion breakpoints, although whether this motif has any mechanistic role in the formation of some deletions has yet to be determined. Considered together with existing information on more complex inherited variant regions, and reports of de novo variants associated with autism, these data support the presence of different subgroups of CNV in the genome which may have originated through different mechanisms

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here