Hot new directions for quasi-Monte Carlo research in step with applications

This article provides an overview of some interfaces between the theory of quasi-Monte Carlo (QMC) methods and applications. We summarize three QMC theoretical settings: first order QMC methods in the unit cube $[0,1]^s$ and in $\mathbb{R}^s$, and higher order QMC methods in the unit cube. One important feature is that their error bounds can be independent of the dimension $s$ under appropriate conditions on the function spaces. Another important feature is that good parameters for these QMC methods can be obtained by fast efficient algorithms even when $s$ is large. We outline three different applications and explain how they can tap into the different QMC theory. We also discuss three cost saving strategies that can be combined with QMC in these applications. Many of these recent QMC theory and methods are developed not in isolation, but in close connection with applications

DeLLITE Depression in late life: an intervention trial of exercise. Design and recruitment of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Physical activity shows potential in combating the poor outcomes associated with depression in older people. Meta-analyses show gaps in the research with poor trial design compromising certainty in conclusions and few programmes showing sustained effects.</p> <p>Methods/design</p> <p>The Depression in Late Life: an Intervention Trial of Exercise (DeLLITE) is a 12 month randomised controlled trial of a physical activity intervention to increase functional status in people aged 75 years and older with depressive symptoms. The intervention involves an individualised activity programme based on goal setting and progression of difficulty of activities delivered by a trained nurse during 8 home visits over 6 months. The control group received time matched home visits to discuss social contacts and networks. Baseline, 6 and 12 months measures were assessed in face to face visits with the primary outcome being functional status (SPPB, NEADL). Secondary outcomes include depressive symptoms (Geriatric Depression Scale), quality of life (SF-36), physical activity (AHS Physical Activity Questionnaire) and falls (self report).</p> <p>Discussion</p> <p>Due to report in 2008 the DeLLITE study has recruited 70% of those eligible and tests the efficacy of a home based, goal setting physical activity programme in improving function, mood and quality of life in older people with depressive symptomatology. If successful in improving function and mood this trial could prove for the first time that there are long term health benefit of physical activity, independent of social activity, in this high risk group who consume excess health related costs.</p> <p>Trial registration</p> <p>Australian and New Zealand Clinical Trials Register ACTRN12605000475640</p

EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans

Oral epithelial cells discriminate between pathogenic and non-pathogenic stimuli, and only induce an inflammatory response when they are exposed to high levels of a potentially harmful microorganism. The pattern recognition receptors (PRRs) in epithelial cells that mediate this differential response are poorly understood. Here, we demonstrate that the ephrin type-A receptor 2 (EphA2) is an oral epithelial cell PRR that binds to exposed β-glucans on the surface of the fungal pathogen Candida albicans. Binding of C. albicans to EphA2 on oral epithelial cells activates signal transducer and activator of transcription 3 and mitogen-activated protein kinase signalling in an inoculum-dependent manner, and is required for induction of a proinflammatory and antifungal response. EphA2 -/- mice have impaired inflammatory responses and reduced interleukin-17 signalling during oropharyngeal candidiasis, resulting in more severe disease. Our study reveals that EphA2 functions as a PRR for β-glucans that senses epithelial cell fungal burden and is required for the maximal mucosal inflammatory response to C. albicans

Myeloid C-type lectins in innate immunity

C-type lectins expressed on myeloid cells comprise a family of proteins that share a common structural motif, and some act as receptors in pathogen recognition. But just as the presence of leucine-rich repeats alone is not sufficient to define a Toll-like receptor, the characterization of C-type lectin receptors in innate immunity requires the identification of accompanying signaling motifs. Here we focus on the known signaling pathways of myeloid C-type lectins and on their possible functions as autonomous activating or inhibitory receptors involved in innate responses to pathogens or self

Reviewing microbial behaviors in ecosystems leading to a natural quorum quenching occurrence

Quorum sensing is considered one of the most important discoveries in cell-to-cell communication. Although revealed in Bacteria, it has been identified as well as a mechanism present in the other two domains, Eukaryota and Archaea. This phenomenon consists mainly of an exchange and sensing of "words" produced by each cell: chemical signals known as autoinducers. The process takes places at high cell densities and confined environments, triggering the expression of specific genes that manifest in a determined phenotype. Quorum sensing has a fundamental importance in the organisms' fitness in natural ecosystems since it activates many of the traits needed by cells to survive under specific conditions, and thus a wide variety of chemical signals, which are detailed throughout the review, have evolved in response to the needs of an organism in the ecosystem it inhabits. As a counterpart, derived from the natural occurrence of quorum sensing, comes it's antagonistic process named quorum quenching. Acting in the exact opposite way, quorum quenching interferes or degrades the autoinducers confusing and stopping communication, hence affecting transcriptional regulation and expression of a specific phenotype. The main reasons for stopping this mechanism go from fading their own signals when perceiving scarce nutrients conditions, to degrading competitors' signals to take advantage in the ecosystem. Some of the most studied purposes and means known up to date to be used by cells for making quorum quenching in their ecosystems is what will be discussed along this review, offering information for future works on quorum quencher molecules bioprospection

Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages

Creative Commons Attribution Non-Commerical Share Alike 3.0 License.-- et al.Cot/tpl2 is the only MAP3K that activates MKK1/2-Erk1/2 in Toll-like receptor-activated macrophages. Here we show that Cot/tpl2 regulates RSK, S6 ribosomal protein, and 4E-BP phosphorylation after stimulation of bone marrow-derived macrophages with lipopolysaccharide (LPS), poly I:C, or zymosan. The dissociation of the 4E-BP-eIF4E complex, a key event in the cap-dependent mRNA translation initiation, is dramatically reduced in LPS-stimulated Cot/tpl2-knockout (KO) macrophages versus LPS-stimulated wild-type (Wt) macrophages. Accordingly, after LPS activation, increased cap-dependent translation is observed in Wt macrophages but not in Cot/tpl2 KO macrophages. In agreement with these data, Cot/tpl2 increases the polysomal recruitment of the 5´ TOP eEF1α and eEF2 mRNAs, as well as of inflammatory mediator gene-encoding mRNAs, such as tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and KC in LPS-stimulated macrophages. In addition, Cot/tpl2 deficiency also reduces total TNFα, IL-6, and KC mRNA expression in LPS-stimulated macrophages, which is concomitant with a decrease in their mRNA half-lives. Macrophages require rapid fine control of translation to provide an accurate and not self-damaging response to host infection, and our data show that Cot/tpl2 controls inflammatory mediator gene-encoding mRNA translation in Toll-like receptor-activated macrophages.This work was supported by SAF 2011-24481 and Mutua Madrileña grants to S.A. and by FIS 2009-80145 and Universidad Autónoma de Madrid CM-CCG10-4911 grants to G.S. PD 0325901 was a gift from Philip Cohen, rapamycin was from Victor Calvo, and the biscitronic pcDNA3rLuc-polIRESfLuc plasmid was generously provided by Alexey Benyumov. M.L.P. is a recipient of an FPU Fellowship from the Universidad Autónoma de Madrid. S.G. holds a research contract from the Ramón y Cajal Program of Spain.Peer reviewe