Regulation of pancreatic cancer aggressiveness by stromal stiffening

No abstract available

The value of position-specific priors in motif discovery using MEME

<p>Abstract</p> <p>Background</p> <p>Position-specific priors have been shown to be a flexible and elegant way to extend the power of Gibbs sampler-based motif discovery algorithms. Information of many types–including sequence conservation, nucleosome positioning, and negative examples–can be converted into a prior over the location of motif sites, which then guides the sequence motif discovery algorithm. This approach has been shown to confer many of the benefits of conservation-based and discriminative motif discovery approaches on Gibbs sampler-based motif discovery methods, but has not previously been studied with methods based on expectation maximization (EM).</p> <p>Results</p> <p>We extend the popular EM-based MEME algorithm to utilize position-specific priors and demonstrate their effectiveness for discovering transcription factor (TF) motifs in yeast and mouse DNA sequences. Utilizing a discriminative, conservation-based prior dramatically improves MEME's ability to discover motifs in 156 yeast TF ChIP-chip datasets, more than doubling the number of datasets where it finds the correct motif. On these datasets, MEME using the prior has a higher success rate than eight other conservation-based motif discovery approaches. We also show that the same type of prior improves the accuracy of motifs discovered by MEME in mouse TF ChIP-seq data, and that the motifs tend to be of slightly higher quality those found by a Gibbs sampling algorithm using the same prior.</p> <p>Conclusions</p> <p>We conclude that using position-specific priors can substantially increase the power of EM-based motif discovery algorithms such as MEME algorithm.</p

The Borwein brothers, Pi and the AGM

We consider some of Jonathan and Peter Borweins' contributions to the high-precision computation of $\pi$ and the elementary functions, with particular reference to their book "Pi and the AGM" (Wiley, 1987). Here "AGM" is the arithmetic-geometric mean of Gauss and Legendre. Because the AGM converges quadratically, it can be combined with fast multiplication algorithms to give fast algorithms for the $n$-bit computation of $\pi$, and more generally the elementary functions. These algorithms run in almost linear time $O(M(n)\log n)$, where $M(n)$ is the time for $n$-bit multiplication. We outline some of the results and algorithms given in Pi and the AGM, and present some related (but new) results. In particular, we improve the published error bounds for some quadratically and quartically convergent algorithms for $\pi$, such as the Gauss-Legendre algorithm. We show that an iteration of the Borwein-Borwein quartic algorithm for $\pi$ is equivalent to two iterations of the Gauss-Legendre quadratic algorithm for $\pi$, in the sense that they produce exactly the same sequence of approximations to $\pi$ if performed using exact arithmetic.Comment: 24 pages, 6 tables. Changed style file and reformatted algorithms in v

Neuroaxial anesthesia in a patient with progressive systemic sclerosis : case presentation and review of the literature on systemic sclerosis

BACKGROUND: Systemic sclerosis (SSc), a progressive disease characterized by excessive accumulation of connective tissue components. Although most patients have long survival, some of them progress rapidly to death. Pulmonary system involvement and pulmonary hypertension are the most frequent cause of death. When the patient with SSc is to be operated, the anesthetic procedure could be a serious problem. In this article, we report a combined spinal – epidural technique in a patient with progressive SSc and the anesthetic considerations that could be recommended for these patients. CASE PRESENTATION: A 68-year-old woman who had a history of progressive systemic sclerosis, pulmonary fibrosis, kyphoscoliosis and decreased oral apertura underwent total hip arthroplasty. This operation was performed successfully under combined spinal epidural anesthesia. CONCLUSION: Systemic sclerosis is a complex disease that involves multiple organ systems. Every aspects of anesthetic care may be altered or hindered by the pathogenesis of disease. Although the choice of regional or general anesthesia is unclear, to choose combined spinal epidural anesthesia may be useful

RNAcontext: A New Method for Learning the Sequence and Structure Binding Preferences of RNA-Binding Proteins

Metazoan genomes encode hundreds of RNA-binding proteins (RBPs). These proteins regulate post-transcriptional gene expression and have critical roles in numerous cellular processes including mRNA splicing, export, stability and translation. Despite their ubiquity and importance, the binding preferences for most RBPs are not well characterized. In vitro and in vivo studies, using affinity selection-based approaches, have successfully identified RNA sequence associated with specific RBPs; however, it is difficult to infer RBP sequence and structural preferences without specifically designed motif finding methods. In this study, we introduce a new motif-finding method, RNAcontext, designed to elucidate RBP-specific sequence and structural preferences with greater accuracy than existing approaches. We evaluated RNAcontext on recently published in vitro and in vivo RNA affinity selected data and demonstrate that RNAcontext identifies known binding preferences for several control proteins including HuR, PTB, and Vts1p and predicts new RNA structure preferences for SF2/ASF, RBM4, FUSIP1 and SLM2. The predicted preferences for SF2/ASF are consistent with its recently reported in vivo binding sites. RNAcontext is an accurate and efficient motif finding method ideally suited for using large-scale RNA-binding affinity datasets to determine the relative binding preferences of RBPs for a wide range of RNA sequences and structures

Genome-wide identification of NBS-encoding resistance genes in Brassica rapa

Nucleotide-binding site (NBS)-encoding resistance genes are key plant disease-resistance genes and are abundant in plant genomes, comprising up to 2% of all genes. The availability of genome sequences from several plant models enables the identification and cloning of NBS-encoding genes from closely related species based on a comparative genomics approach. In this study, we used the genome sequence of Brassica rapa to identify NBS-encoding genes in the Brassica genome. We identified 92 non-redundant NBS-encoding genes [30 CC-NBS-LRR (CNL) and 62 TIR-NBS-LRR (TNL) genes] in approximately 100 Mbp of B. rapa euchromatic genome sequence. Despite the fact that B. rapa has a significantly larger genome than Arabidopsis thaliana due to a recent whole genome triplication event after speciation, B. rapa contains relatively small number of NBS-encoding genes compared to A. thaliana, presumably because of deletion of redundant genes related to genome diploidization. Phylogenetic and evolutionary analyses suggest that relatively higher relaxation of selective constraints on the TNL group after the old duplication event resulted in greater accumulation of TNLs than CNLs in both Arabidopsis and Brassica genomes. Recent tandem duplication and ectopic deletion are likely to have played a role in the generation of novel Brassica lineage-specific resistance genes

Agent-Based Model of Therapeutic Adipose-Derived Stromal Cell Trafficking during Ischemia Predicts Ability To Roll on P-Selectin

Intravenous delivery of human adipose-derived stromal cells (hASCs) is a promising option for the treatment of ischemia. After delivery, hASCs that reside and persist in the injured extravascular space have been shown to aid recovery of tissue perfusion and function, although low rates of incorporation currently limit the safety and efficacy of these therapies. We submit that a better understanding of the trafficking of therapeutic hASCs through the microcirculation is needed to address this and that selective control over their homing (organ- and injury-specific) may be possible by targeting bottlenecks in the homing process. This process, however, is incredibly complex, which merited the use of computational techniques to speed the rate of discovery. We developed a multicell agent-based model (ABM) of hASC trafficking during acute skeletal muscle ischemia, based on over 150 literature-based rules instituted in Netlogo and MatLab software programs. In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures. As verification, the model reasonably reproduced key aspects of ischemia and trafficking behavior including increases in wall shear stress, upregulation of key cellular adhesion molecules expressed on injured endothelium, increased secretion of inflammatory chemokines and cytokines, quantified levels of monocyte extravasation in selectin knockouts, and circulating monocyte rolling distances. Successful ABM verification prompted us to conduct a series of systematic knockouts in silico aimed at identifying the most critical parameters mediating hASC trafficking. Simulations predicted the necessity of an unknown selectin-binding molecule to achieve hASC extravasation, in addition to any rolling behavior mediated by hASC surface expression of CD15s, CD34, CD62e, CD62p, or CD65. In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 µm/s. Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications

Increasing boys' and girls' intention to avoid teenage pregnancy: a cluster randomised control feasibility trial of an interactive video drama based intervention in post-primary schools in Northern Ireland

Background: Adolescent men have a vital yet neglected role in reducing unintended teenage pregnancy (UTP). There is a need for gender-sensitive educational interventions. Objectives: To determine the value and feasibility of conducting an effectiveness trial of the If I Were Jack Relationship and Sexuality Education (RSE) intervention in a convenience quota sample of post-primary schools in Northern Ireland. Secondary objectives were to assess acceptability to schools, pupils (male/female, aged 14–15 years) and parents/guardians; to identify optimal delivery structures and systems; to establish participation rates and reach, including equality of engagement of different socioeconomic and religious types; to assess trial recruitment and retention rates; to assess variation in normal RSE practice; to refine survey instruments; to assess differences in outcomes for male and female pupils; to identify potential effect sizes that might be detected in an effectiveness trial and estimate appropriate sample size for that trial; and to identify costs of delivery and pilot methods for assessing cost-effectiveness. Design: Cluster randomised Phase II feasibility trial with an embedded process and economic evaluation. Intervention: A teacher-delivered classroom-based RSE resource – an interactive video drama (IVD) with classroom materials, teacher training and an information session for parents – to immerse young people in a hypothetical scenario of Jack, a teenager whose girlfriend is unintentionally pregnant. It addresses gender inequalities in RSE by focusing on young men and is designed to increase intentions to avoid UTP by encouraging young people to delay sexual intercourse and to use contraception consistently in sexual relationships. Main outcome measures: Abstinence from sexual intercourse (delaying initiation of sex or returning to abstinence) or avoidance of unprotected sexual intercourse (consistent correct use of contraception). Secondary outcomes included Knowledge, Attitudes, Skills and Intentions. Results: The intervention proved acceptable to schools, pupils and parents, as evidenced through positive process evaluation. One minor refinement to the parental component was required, namely the replacement of the teacher-led face-to-face information session for parents by online videos designed to deliver the intervention to parents/guardians into their home. School recruitment was successful (target 25%, achieved 38%). No school dropped out. Pupil retention was successful (target 85%, achieved 93%). The between-group difference in incidence of unprotected sex of 1.3% (95% confidence interval 0.55% to 2.2%) by 9 months demonstrated an effect size consistent with those reported to have had meaningful impact on UTP rates (resulting in an achievable sample size of 66 schools at Phase III). Survey instruments showed high acceptability and reliability of measures (Cronbach’s alpha: 0.5–0.7). Economic evaluation at Phase III is feasible because it was possible to (1) identify costs of delivering If I Were Jack (mean cost per pupil, including training of teachers, was calculated as £13.66); and (2) develop a framework for assessing cost-effectiveness. Conclusion: Trial methods were appropriate, and recruitment and retention of schools and pupils was satisfactory, successfully demonstrating all criteria for progression to a main trial. The perceived value of culture- and gender-sensitive public health interventions has been highlighted. Future work: Progression to a Phase III effectiveness trial. Trial registration: Current Controlled Trials ISRCTN99459996. Funding: This project was funded by the NIHR Public Health Research programme and will be published in full in Public Health Research; Vol. 5, No. 1. See the NIHR Journals Library website for further project information

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer