Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.

The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression

Tunnelling anisotropic magnetoresistance at La<inf>0.67</inf>Sr<inf>0.33</inf>MnO<inf>3</inf>-graphene interfaces

Using ferromagnetic La0.67Sr0.33MnO3 electrodes bridged by single-layer graphene, we observe magnetoresistive changes of ∼32–35 MΩ at 5 K. Magneto-optical Kerr effect microscopy at the same temperature reveals that the magnetoresistance arises from in-plane reorientations of electrode magnetization, evidencing tunnelling anisotropic magnetoresistance at the La0.67Sr0.33MnO3-graphene interfaces. Large resistance switching without spin transport through the non-magnetic channel could be attractive for graphene-based magnetic-sensing applications.This work was funded by grant F/09 154/E from the Leverhulme Trust, ERC Grant Hetero2D, EU Graphene Flagship (no. 604391), a Schlumberger Cambridge International Scholarship, a UK EPSRC DTA award, the Royal Society, and EPSRC Grants EP/K01711X/1, EP/K017144/1, EP/N010345/1, EP/M507799/1 and EP/L016087/1.This is the author accepted manuscript. The final version is available at http://scitation.aip.org/content/aip/journal/apl/108/11/10.1063/1.4942778

Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Do adults with high functioning autism or Asperger Syndrome differ in empathy and emotion recognition?

The present study examined whether adults with high functioning autism (HFA) showed greater difficulties in (i) their self-reported ability to empathise with others and/or (ii) their ability to read mental states in others’ eyes than adults with Asperger syndrome (AS). The Empathy Quotient (EQ) and ‘Reading the Mind in the Eyes’ Test (Eyes Test) were compared in 43 adults with AS and 43 adults with HFA. No significant difference was observed on EQ score between groups, while adults with AS performed significantly better on the Eyes Test than those with HFA. This suggests that adults with HFA may need more support, particularly in mentalizing and complex emotion recognition, and raises questions about the existence of subgroups within autism spectrum conditions

Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al

Long Spin Diffusion Length in Few-Layer Graphene Flakes.

We report a spin valve with a few-layer graphene flake bridging highly spin-polarized La_{0.67}Sr_{0.33}MnO_{3} electrodes, whose surfaces are kept clean during lithographic definition. Sharp magnetic switching is verified using photoemission electron microscopy with x-ray magnetic circular dichroism contrast. A naturally occurring high interfacial resistance ∼12  MΩ facilitates spin injection, and a large resistive switching (0.8  MΩ at 10 K) implies a 70-130  μm spin diffusion length that exceeds previous values obtained with sharp-switching electrodes.Leverhulme Trust (Grant ID: F/09 154/E), Schlumberger Cambridge (International Scholarship), Engineering and Physical Sciences Research Council (DTA award), Royal Society, EU Graphene Flagship (no. 604391), European Research Council (Grant Hetero2D), Engineering and Physical Sciences Research Council (Grant IDs: EP/K01711X/1, EP/K017144/1, EP/N010345/1, EP/M507799/1, EP/L016087/1), Wolfson College.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by the American Physical Society

Perfectionism and eating disorder symptoms in female university students: The central role of perfectionistic self-presentation

Purpose: Numerous studies have found perfectionism to show positive relations with eating disorder symptoms, but so far no study has examined whether perfectionistic self-presentation can explain these relations or whether the relations are the same for different eating disorder symptom groups. Methods: A sample of 393 female university students completed self-report measures of perfectionism (self-oriented perfectionism, socially prescribed perfectionism), perfectionistic self-presentation (perfectionistic self-promotion, nondisplay of imperfection, nondisclosure of imperfection), and three eating disorder symptom groups (dieting, bulimia, oral control). In addition, students reported their weight and height so their body mass index (BMI) could be computed. Results: Results of multiple regression analyses controlling for BMI indicated that socially prescribed perfectionism positively predicted all three symptom groups, whereas self-oriented perfectionism positively predicted dieting only. Moreover, perfectionistic self-presentation explained the positive relations that perfectionism showed with dieting and oral control, but not with bulimia. Further analyses indicated that all three aspects of perfectionistic self-presentation positively predicted dieting, whereas only nondisclosure of imperfection positively predicted bulimia and oral control. Overall, perfectionistic self-presentation explained 10.4-23.5% of variance in eating disorder symptoms, whereas perfectionism explained 7.9-12.1%. Conclusions: The findings suggest that perfectionistic self-presentation explains why perfectionistic women show higher levels of eating disorder symptoms, particularly dieting. Thus perfectionistic self-presentation appears to play a central role in the relations of perfectionism and disordered eating and may warrant closer attention in theory, research, and treatment of eating and weight disorders

A search for the decay modes B+/- to h+/- tau l

We present a search for the lepton flavor violating decay modes B+/- to h+/- tau l (h= K,pi; l= e,mu) using the BaBar data sample, which corresponds to 472 million BBbar pairs. The search uses events where one B meson is fully reconstructed in one of several hadronic final states. Using the momenta of the reconstructed B, h, and l candidates, we are able to fully determine the tau four-momentum. The resulting tau candidate mass is our main discriminant against combinatorial background. We see no evidence for B+/- to h+/- tau l decays and set a 90% confidence level upper limit on each branching fraction at the level of a few times 10^-5.Comment: 15 pages, 7 figures, submitted to Phys. Rev.

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications