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

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

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

On the Riemann Tensor in Double Field Theory

Double field theory provides T-duality covariant generalized tensors that are natural extensions of the scalar and Ricci curvatures of Riemannian geometry. We search for a similar extension of the Riemann curvature tensor by developing a geometry based on the generalized metric and the dilaton. We find a duality covariant Riemann tensor whose contractions give the Ricci and scalar curvatures, but that is not fully determined in terms of the physical fields. This suggests that \alpha' corrections to the effective action require \alpha' corrections to T-duality transformations and/or generalized diffeomorphisms. Further evidence to this effect is found by an additional computation that shows that there is no T-duality invariant four-derivative object built from the generalized metric and the dilaton that reduces to the square of the Riemann tensor.Comment: 36 pages, v2: minor changes, ref. added, v3: appendix on frame formalism added, version to appear in JHE

An fMRI investigation of the effects of attempted naming on word retrieval in aphasia

In healthy controls, picture naming performance can be facilitated by a single prior exposure to the same picture ("priming"). This priming phenomenon is utilized in the treatment of aphasia, which often includes repeated picture naming as part of a therapeutic task. The current study sought to determine whether single and/or multiple exposures facilitate subsequent naming in aphasia and whether such facilitatory effects act through normal priming mechanisms. A functional magnetic resonance imaging paradigm was employed to explore the beneficial effects of attempted naming in two individuals with aphasia and a control group. The timing and number of prior exposures was manipulated, with investigation of both short-term effects (single prior exposure over a period of minutes) and long-term effects (multiple presentations over a period of days). Following attempted naming, both short-term and long-term facilitated items showed improvement for controls, while only the long-term condition showed benefits at a behavioral level for the participants with aphasia. At a neural level, effects of long-term facilitation were noted in the left precuneus for one participant with aphasia, a result also identified for the equivalent contrast in controls. It appears that multiple attempts are required to improve naming performance in the presence of anomia and that for some individuals with aphasia the source of facilitation may be similar to unimpaired mechanisms engaged outside the language network

Therapeutic effect of an intensive, comprehensive aphasia program: Aphasia LIFT

The development of intensive, comprehensive aphasia programs (ICAPs) is increasing due to evidence in favour of greater treatment intensity (Cherney, Patterson, Raymer, Frymark, & Schooling, 2008), the adoption of a broad, holistic, biopsychosocial approach in aphasia rehabilitation (Byng & Duchan, 2005; Kagan et al., 2008; Martin, Thompson, & Worrall, 2008; Simmons-Mackie & Kagan, 2007), and the desire to meet the needs of people with aphasia and their family members in therapy (Howe et al., 2012; Worrall et al., 2012). ICAPs comprise a range of therapy approaches (individual therapy, group therapy, patient/family education, technology), delivered at high intensity (minimum of three hours per day over at least two weeks), to a defined group of participants within a specified amount of time (Cherney, Worrall, & Rose, 2012). Aphasia LIFT (Language Impairment and Functioning Therapy) is a research-based ICAP that uses evidence-based therapy approaches to target language and functioning across the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) domains (WHO, 2001). The aim of this study was to determine the therapeutic effect of Aphasia LIFT on language impairment, functional communication, and communication-related quality of life (QOL)

Companionate Lives and Consonant Voices in We Two Together: The 1950 Dual Autobiography of Irish and Indian Reformers Margaret and James Cousins

This thesis explores We Two Together, the unique dual autobiography of the reformers Margaret and James Cousins. It places this rich text in the context of the first half of the twentieth century and demonstrates its value as a source for Irish, Indian, gender, and global history. It investigates how the Cousinses represent their efforts to create and maintain a companionate marriage over a lifetime, depict their work as activists for women’s suffrage, Indian nationalism, educational reform, and other causes, and recount the impact of cross-cultural encounters on their cosmopolitan lives. We Two Together provides insight into the lives of two extraordinary individuals as they witnessed and participated in several key social and political movements in Ireland and India. In bringing attention to this book, I hope that other historians will make use of it and that librarians will preserve the rare copies in their possession

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