DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML

<b>Background</b>. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors (DNMTi), 5-azacytidine (AzaC) and 5-aza-2’-deoxycytidine (Decitabine), benefit some MDS/AML patients. However, the role of DNMTi-induced DNA hypomethylation in regulation of gene expression in AML is unclear.<p></p> <b>Results. </b> We compared the effects of AzaC on DNA methylation and gene expression using whole-genome single-nucleotide bisulfite-sequencing (WGBS) and RNA-sequencing in OCI-AML3 (AML3) cells. For data analysis, we used an approach recently developed for discovery of differential patterns of DNA methylation associated with changes in gene expression, that is tailored to single-nucleotide bisulfite-sequencing data (Washington University Interpolated Methylation Signatures (WIMSi)). By this approach, a subset of genes upregulated by AzaC was found to be characterized by AzaC-induced signature methylation loss flanking the transcription start site. These genes are enriched for genes increased in methylation and decreased in expression in AML3 cells compared to normal hematopoietic stem and progenitor cells. Moreover, these genes are preferentially upregulated by Decitabine in human primary AML blasts, and control cell proliferation, death and development. <p></p> <b>Conclusions.</b> Our WGBS and WIMSi data analysis approach has identified a set of genes whose is methylation and silencing in AML is reversed by DNMTi. These genes are good candidates for direct regulation by DNMTi, and their reactivation by DNMTi may contribute to therapeutic activity. This study also demonstrates the ability of WIMSi to reveal relationships between DNA methylation and gene expression, based on single-nucleotide bisulfite-sequencing and RNA-seq data.<p></p&gt

Aphasia Recovery: When, How and Who to Treat?

PURPOSE OF REVIEW: We now know that speech and language therapy (SALT) is effective in the rehabilitation of aphasia; however, there remains much individual variability in the response to interventions. So, what works for whom, when and how? RECENT FINDINGS: This review evaluates the current evidence for the efficacy of predominantly impairment-focused aphasia interventions with respect to optimal dose, intensity, timing and distribution or spacing of treatment. We conclude that sufficient dose of treatment is required to enable clinical gains and that e-therapies are a promising and practical way to achieve this goal. In addition, aphasia can be associated with other cognitive deficits and may lead to secondary effects such as low mood and social isolation. In order to personalise individual treatments to optimise recovery, we need to develop a greater understanding of the interactions between these factors

Soluble CD200 Correlates With Interleukin-6 Levels in Sera of COPD Patients: Potential Implication of the CD200/CD200R Axis in the Disease Course

BACKGROUND: COPD represents a multifactorial lung disorder with high morbidity and mortality. Despite intensive research concerning the underlying disease mechanisms, the involvement of the CD200/CD200R axis in supporting or preventing the onset of COPD has not yet been addressed. Since the CD200/CD200R axis is crucially implicated in the maintenance of pulmonary immune homeostasis, we hypothesized that it might be involved in controlling the onset of COPD. METHODS: To address this, we analyzed the serum samples from COPD patients and normal controls for soluble (s) CD200 and correlated the data to COPD-relevant clinical parameters. In addition, basic studies were conducted in CD200-deficient and wild-type mice in which COPD-like inflammation was induced with elastase/LPS followed by lung and serum component analysis. RESULTS: We observed a positive correlation between serum sCD200 and IL-6 levels as well as a trend toward a negative correlation of sCD200 with vitamin D3 in COPD patients. Further investigations in mice revealed that despite elevated serum concentration of MMP-9 in CD200KO mice, the early onset of COPD-like lung inflammation was similar in CD200-deficient and wild-type animals in terms of immune cell infiltration, emphysematous changes, and mucus overproduction. CONCLUSIONS: While our murine studies suggest that the co-inhibitory molecule CD200 does not appear to play a prominent role in the early onset of COPD-like features, correlation of sCD200 serum levels with COPD-related parameters in humans with established disease revealed that the CD200/CD200R axis may be mechanistically linked to the disease course in COPD patients

Analysis of model rotor blade pressures during parallel interaction with twin vortices

This paper presents and provides analysis of unsteady surface pressures measured on a model rotor blade as the blade experienced near parallel blade vortex interaction with a twin vortex system. To provide a basis for analysis, the vortex system was characterized by hot-wire measurements made in the interaction plane but in the absence of the rotor. The unsteady pressure response resulting from a single vortex interaction is then presented to provide a frame of reference for the twin vortex results. A series of twin vortex interaction cases are then presented and analyzed. It is shown that the unsteady blade pressures and forces are very sensitive to the inclination angle and separation distance of the vortex pair. When the vortex cores lie almost parallel to the blade chord, the interaction is characterized by a two-stage response associated with the sequential passage of the two cores. Conversely, when the cores lie on a plane that is almost perpendicular to the blade chord, the response is similar to that of a single vortex interaction. In all cases, the normal force response is consistent with the distribution of vertical velocity in the flow field of the vortex system. The pitching moment response, on the other hand, depends on the localized suction associated with the vortex cores as they traverse the blade chord

Single Eye mRNA-Seq Reveals Normalisation of the Retinal Microglial Transcriptome Following Acute Inflammation

Background: Whether retinal microglia can maintain or restore immune homeostasis during and after inflammation is unclear. We performed single-eye mRNA-sequencing on microglia at different timepoints following a single inflammatory stimulus to characterise their transcriptome during and after resolution of endotoxin-induced uveitis (EIU). / Experimental Approach: Cx3cr1CreER:R26-tdTomato (C57BL/6) male heterozygotes were administered tamoxifen via different regimes at 4–5 weeks of age. Four weeks post-tamoxifen, mice were injected intravitreally with 10 ng lipopolysaccharide (endotoxin induced uveitis, EIU). Six-hundred retinal microglia were obtained by FACS from individual naïve retinas and at 4 h, 18 h, and 2 weeks following EIU induction. Samples were sequenced to a depth of up to 16.7 million reads using the SMART-Seq v4 Ultra Low Input RNA kit. The data was analysed using Partek software and Ingenuity Pathway Analysis. Genes were considered differentially-expressed (DEG) if the FDR step-up p-value was ≤0.05 and the fold-change was ≥±2. / Results: Flow cytometric analysis indicates that the Cx3cr1CreER:R26-tdTomato strain is both sensitive (>95% tagging) and specific (>95% specificity) for microglia when tamoxifen is administered topically to the eye for 3 days. During “early” activation, 613 DEGs were identified. In contrast, 537 DEGs were observed during peak cellular infiltrate and none at 2 weeks, compared to baseline controls (1,069 total unique DEGs). Key marker changes were validated by qPCR, flow cytometry, and fluorescence microscopy. C5AR1 was identified and validated as a robust marker of differentiating microglial subsets during an LPS response. / Conclusion: Using EIU to provide a single defined inflammatory stimulus, mRNA-Seq identified acute transcriptional changes in retinal microglia which returned to their original transcriptome after 2 weeks. Yolk-sac derived microglia are capable of restoring their homeostatic state after acute inflammation

Native-English-Speaking Teachers:Disconnections Between Theory, Research, and Practice

Native-English-speaking teachers (NESTs) have long been in demand for perceived benefits of the skills they bring to the classroom. However, the notion that native speakers provide the best models of the target language and thus make the best teachers of the language has been criticised in the literature. This article reports on the disconnection between academic literature on NESTs and the realities they report. Drawing on data from an investigation into NEST schemes globally, the article suggests that lived classroom experiences of NESTs are complex, They are also often bilingual, experienced, and qualified, and regard local English teachers (LETs) they work with as experts and in control of how English is practised in the classroom. These characteristics contrast with much of the academic literature, which explores the concept of native speakerism, which tends to view NESTs negatively. The article proposes that one reason for the disconnection between theory and practice is the parallel lives of researchers and teachers, whether NESTs or LETs. Thus, each group’s realities and concerns are not always understood by the other. The article suggests that a substantial group of bilingual and bicultural NESTs consider the country where work home, so future theorisations of NESTs and native speakerism should take account of these teachers

Search Engine Advertising: Channel Substitution when Pricing Ads to Context

We explore substitution patterns across advertising platforms. Using data on the advertising prices paid by lawyers for 139 Google search terms in 195 locations, we exploit a natural experiment in “ambulance-chaser” regulations across states. When lawyers cannot contact clients by mail, advertising prices per click for search engine advertisements are 5%–7% higher. Therefore, online advertising substitutes for offline advertising. This substitution toward online advertising is strongest in markets with fewer customers, suggesting that the relationship between the online and offline media is mediated by the marketers' need to target their communications.NET Institut

Environmental conditioning in the control of macrophage thrombospondin-1 production

Thrombospondin-1 (TSP-1) is a multifunctional protein which is secreted into the extracellular matrix during inflammation, where it modulates numerous components of the immune infiltrate. Macrophages are a source of TSP-1, which they produce in response to TLR4 mediated signals. Their production of TSP-1 is regulated by environmental signals that establish a threshold for the level of protein secretion that can be induced by LPS stimulation. Th1 and Th2 cytokines raise this threshold which leads to less TSP-1 production, while signals that promote the generation of regulatory macrophages lower it. TSP-1 plays no direct role in the regulation of its own secretion. In vivo in uveitis, in the presence of TLR-4 ligands, TSP-1 is initially produced by recruited macrophages but this decreases in the presence of inflammatory cytokines. The adaptive immune system therefore plays a dominant role in regulating TSP-1 production in the target organ during acute inflammation

Ramond-Ramond Cohomology and O(D,D) T-duality

In the name of supersymmetric double field theory, superstring effective actions can be reformulated into simple forms. They feature a pair of vielbeins corresponding to the same spacetime metric, and hence enjoy double local Lorentz symmetries. In a manifestly covariant manner --with regard to O(D,D) T-duality, diffeomorphism, B-field gauge symmetry and the pair of local Lorentz symmetries-- we incorporate R-R potentials into double field theory. We take them as a single object which is in a bi-fundamental spinorial representation of the double Lorentz groups. We identify cohomological structure relevant to the field strength. A priori, the R-R sector as well as all the fermions are O(D,D) singlet. Yet, gauge fixing the two vielbeins equal to each other modifies the O(D,D) transformation rule to call for a compensating local Lorentz rotation, such that the R-R potential may turn into an O(D,D) spinor and T-duality can flip the chirality exchanging type IIA and IIB supergravities.Comment: 1+37 pages, no figure; Structure reorganized, References added, To appear in JHEP. cf. Gong Show of Strings 2012 (http://wwwth.mpp.mpg.de/members/strings/strings2012/strings_files/program/Talks/Thursday/Gongshow/Lee.pdf

Quantitative Assessment of Experimental Ocular Inflammatory Disease

Ocular inflammation imposes a high medical burden on patients and substantial costs on the health-care systems that mange these often chronic and debilitating diseases. Many clinical phenotypes are recognized and classifying the severity of inflammation in an eye with uveitis is an ongoing challenge. With the widespread application of optical coherence tomography in the clinic has come the impetus for more robust methods to compare disease between different patients and different treatment centers. Models can recapitulate many of the features seen in the clinic, but until recently the quality of imaging available has lagged that applied in humans. In the model experimental autoimmune uveitis (EAU), we highlight three linked clinical states that produce retinal vulnerability to inflammation, all different from healthy tissue, but distinct from each other. Deploying longitudinal, multimodal imaging approaches can be coupled to analysis in the tissue of changes in architecture, cell content and function. This can enrich our understanding of pathology, increase the sensitivity with which the impacts of therapeutic interventions are assessed and address questions of tissue regeneration and repair. Modern image processing, including the application of artificial intelligence, in the context of such models of disease can lay a foundation for new approaches to monitoring tissue health