The lncRNA landscape of breast cancer reveals a role for DSCAM-AS1 in breast cancer progression.

Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer

Impact force identification with pseudo-inverse method on a lightweight structure for under-determined, even-determined and over-determined cases

Force identification using inverse technique is important especially when direct measurement through force transducer is not possible. Considering the effects of impact excitation force on the integrity of a lightweight structure, impact force identification has become the subject of several studies. A methodology utilising Operating Deflection Shape (ODS) analysis, Frequency Response Function (FRF) measurement and pseudo-inverse method to evaluate the dynamic force is presented. A rectangular plate with four ground supports was used as a test rig to simulate the motions of a simple vehicle body. By using the measured responses at remote points that are away from impact locations and measured FRFs of the test rig, unknown force locations and their time histories can be recovered by the proposed method. The performance of this approach in various cases such as under-determined, even-determined and over-determined cases was experimentally demonstrated. Good and bad combinations of response locations were selected based on the condition number of FRF matrix. This force identification method was examined under different response combinations and various numbers of response locations. It shows that in the over-determined case, good combination of response locations (i.e. low average of condition number of FRF matrix) and high number of response locations give the best accuracy of force identification result compared to under-determined and even-determined cases

Molecular Evolution of the Two-Component System BvgAS Involved in Virulence Regulation in Bordetella

The whooping cough agent Bordetella pertussis is closely related to Bordetella bronchiseptica, which is responsible for chronic respiratory infections in various mammals and is occasionally found in humans, and to Bordetella parapertussis, one lineage of which causes mild whooping cough in humans and the other ovine respiratory infections. All three species produce similar sets of virulence factors that are co-regulated by the two-component system BvgAS. We characterized the molecular diversity of BvgAS in Bordetella by sequencing the two genes from a large number of diverse isolates. The response regulator BvgA is virtually invariant, indicating strong functional constraints. In contrast, the multi-domain sensor kinase BvgS has evolved into two different types. The pertussis type is found in B. pertussis and in a lineage of essentially human-associated B. bronchiseptica, while the bronchiseptica type is associated with the majority of B. bronchiseptica and both ovine and human B. parapertussis. BvgS is monomorphic in B. pertussis, suggesting optimal adaptation or a recent population bottleneck. The degree of diversity of the bronchiseptica type BvgS is markedly different between domains, indicating distinct evolutionary pressures. Thus, absolute conservation of the putative solute-binding cavities of the two periplasmic Venus Fly Trap (VFT) domains suggests that common signals are perceived in all three species, while the external surfaces of these domains vary more extensively. Co-evolution of the surfaces of the two VFT domains in each type and domain swapping experiments indicate that signal transduction in the periplasmic region may be type-specific. The two distinct evolutionary solutions for BvgS confirm that B. pertussis has emerged from a specific B. bronchiseptica lineage. The invariant regions of BvgS point to essential parts for its molecular mechanism, while the variable regions may indicate adaptations to different lifestyles. The repertoire of BvgS sequences will pave the way for functional analyses of this prototypic system

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

Secure Iris Recognition Based on Local Intensity Variations

In this paper we propose a fast and efficient iris recognition algorithm which makes use of local intensity variations in iris textures. The presented system provides fully revocable biometric templates suppressing any loss of recognition performance

Unsuspected and extensive transmission of a drug-susceptible Mycobacterium tuberculosis strain

<p>Abstract</p> <p>Background</p> <p>A large and unsuspected tuberculosis outbreak involving 18.7% of the total of the tuberculosis cases studied, was detected in a population-based molecular epidemiological study performed in Zaragoza (Spain) from 2001 to 2004.</p> <p>Methods</p> <p>The <it>Mycobacterium tuberculosis </it>drug-susceptible strain, named <it>MTZ </it>strain, was genetically characterized by IS<it>6110</it>-RFLP, Spoligotyping and by MIRU-VNTR typing and the genetic patterns obtained were compared with those included in international databases. The characteristics of the affected patients, in an attempt to understand why the <it>MTZ </it>strain was so highly transmitted among the population were also analyzed.</p> <p>Results</p> <p>The genetic profile of the <it>MTZ </it>strain was rare and not widely distributed in our area or elsewhere. The patients affected did not show any notable risk factor for TB.</p> <p>Conclusion</p> <p>The <it>M. tuberculosis </it>strain <it>MTZ</it>, might have particular transmissibility or virulence properties, and we believe that greater focus should be placed on stopping its widespread dissemination.</p

One-shot genitalia are not an evolutionary dead end - Regained male polygamy in a sperm limited spider species

<p>Abstract</p> <p>Background</p> <p>Monogynous mating systems with extremely low male mating rates have several independent evolutionary origins and are associated with drastic adaptations involving self-sacrifice, one-shot genitalia, genital damage, and termination of spermatogenesis immediately after maturation. The combination of such extreme traits likely restricts evolutionary potential perhaps up to the point of making low male mating rates irreversible and hence may constitute an evolutionary dead end. Here, we explore the case of a reversion to multiple mating from monogynous ancestry in golden orb-web spiders, <it>Nephila senegalensis</it>.</p> <p>Results</p> <p>Male multiple mating is regained by the loss of genital damage and sexual cannibalism but spermatogenesis is terminated with maturation, restricting males to a single loading of their secondary mating organs and a fixed supply of sperm. However, males re-use their mating organs and by experimentally mating males to many females, we show that the sperm supply is divided between copulations without reloading the pedipalps.</p> <p>Conclusion</p> <p>By portioning their precious sperm supply, males achieve an average mating rate of four females which effectively doubles the maximal mating rate of their ancestors. A heritage of one-shot genitalia does not completely restrict the potential to increase mating rates in <it>Nephila </it>although an upper limit is defined by the available sperm load. Future studies should now investigate how males use this potential in the field and identify selection pressures responsible for a reversal from monogynous to polygynous mating strategies.</p

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited