MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells

Triazole derivatives of melampomagnolide B (MMB) have been synthesized via click chemistry methodologies and screened against a panel of 60 human cancer cell lines. Several derivatives showed promising anti-cancer activity, affording growth inhibition (GI50) values in the nanomolar range (GI50 = 0.02–0.99 μM). Lead compound 7h exhibited EC50 values of 400 nM and 700 nM, respectively, against two AML clinical specimens. Compound 7h was significantly more potent than parthenolide as an inhibitor of p65 phosphorylation in both hematological and solid tumor cell lines, indicating its ability to inhibit the NF-κB pathway. In TMD-231 breast cancer cells, treatment with 7h reduced DNA binding activity of NF-κB through inhibition of IKK-β mediated p65 phosphorylation and caused elevation of basal IκBα levels through inhibition of constitutive IκBα turnover and NF-κB activation. Molecular docking and dynamic modeling studies indicated that 7h interacts with the kinase domain of the monomeric IKKβ subunit, leading to inhibition of IKKβ activation, and compromising phosphorylation of downstream targets of the NF-κB pathway; dynamic modeling studies show that this interaction also causes unwinding of the α-helix of the NEMO binding site on IKKβ. Molecular docking studies with 10, a water-soluble analog of 7h, demonstrate that this analog interacts with the dimerization/oligomerization domain of monomeric IKKβ and may inhibit oligomer formation and subsequent autophosphorylation. Sesquiterpene lactones 7h and 10 are considered ideal candidates for potential clinical development

Dynamics of nearly inviscid Faraday waves in almost circular containers

Parametrically driven surface gravity-capillary waves in an elliptically distorted circular cylinder are studied. In the nearly inviscid regime, the waves couple to a streaming flow driven in oscillatory viscous boundary layers. In a cylindrical container, the streaming flow couples to the spatial phase of the waves, but in a distorted cylinder, it couples to their amplitudes as well. This coupling may destabilize pure standing oscillations, and lead to complex time-dependent dynamics at onset. Among the new dynamical behavior that results are relaxation oscillations involving abrupt transitions between standing and quasiperiodic oscillations, and exhibiting ‘canards’

Visual Search Strategies of Soccer Players Executing a Power vs. Placement Penalty Kick

Introduction: When taking a soccer penalty kick, there are two distinct kicking techniques that can be adopted; a ‘power’ penalty or a ‘placement’ penalty. The current study investigated how the type of penalty kick being taken affected the kicker’s visual search strategy and where the ball hit the goal (end ball location). Method: Wearing a portable eye tracker, 12 university footballers executed 2 power and placement penalty kicks, indoors, both with and without the presence of a goalkeeper. Video cameras were used to determine initial ball velocity and end ball location. Results: When taking the power penalty, the football was kicked significantly harder and more centrally in the goal compared to the placement penalty. During the power penalty, players fixated on the football for longer and more often at the goalkeeper (and by implication the middle of the goal), whereas in the placement penalty, fixated longer at the goal, specifically the edges. Findings remained consistent irrespective of goalkeeper presence. Discussion/conclusion: Findings indicate differences in visual search strategy and end ball location as a function of type of penalty kick. When taking the placement penalty, players fixated and kicked the football to the edges of the goal in an attempt to direct the ball to an area that the goalkeeper would have difficulty reaching and saving. Fixating significantly longer on the football when taking the power compared to placement penalty indicates a greater importance of obtaining visual information from the football. This can be attributed to ensuring accurate foot-to-ball contact and subsequent generation of ball velocity. Aligning gaze and kicking the football centrally in the goal when executing the power compared to placement penalty may have been a strategy to reduce the risk of kicking wide of the goal altogether

Quantitative Multicolor Compositional Imaging Resolves Molecular Domains in Cell-Matrix Adhesions

Background: Cellular processes occur within dynamic and multi-molecular compartments whose characterization requires analysis at high spatio-temporal resolution. Notable examples for such complexes are cell-matrix adhesion sites, consisting of numerous cytoskeletal and signaling proteins. These adhesions are highly variable in their morphology, dynamics, and apparent function, yet their molecular diversity is poorly defined. Methodology/Principal Findings: We present here a compositional imaging approach for the analysis and display of multicomponent compositions. This methodology is based on microscopy-acquired multicolor data, multi-dimensional clustering of pixels according to their composition similarity and display of the cellular distribution of these composition clusters. We apply this approach for resolving the molecular complexes associated with focal-adhesions, and the time-dependent effects of Rho-kinase inhibition. We show here compositional variations between adhesion sites, as well as ordered variations along the axis of individual focal-adhesions. The multicolor clustering approach also reveals distinct sensitivities of different focaladhesion-associated complexes to Rho-kinase inhibition. Conclusions/Significance: Multicolor compositional imaging resolves ‘‘molecular signatures’ ’ characteristic to focaladhesions and related structures, as well as sub-domains within these adhesion sites. This analysis enhances the spatial information with additional ‘‘contents-resolved’ ’ dimensions. We propose that compositional imaging can serve as

Revisiting Egyptian Foreign Policy towards Israel under Mubarak: From Cold Peace to Strategic Peace

This article is the first academic study of Egyptian foreign policy towards Israel under Hosni Mubarak (1981–2011). It challenges a deeply entrenched conventional wisdom that Egypt pursued a cold-peace foreign policy towards Israel throughout this period. We demonstrate that Egyptian foreign policy towards Israel was dynamic – comprising cold peace (1981–91), a hybrid foreign policy of cold peace and strategic peace (1991–2003), and a pure strategic peace posture (2003–11). We also use the case of Egyptian foreign policy towards Israel as a heuristic to develop a conception of a new type of peace, strategic peace, as an intermediary analytical category between cold and stable peace

Emergent global oscillations in heterogeneous excitable media: The example of pancreatic beta cells

Using the standard van der Pol-FitzHugh-Nagumo excitable medium model I demonstrate a novel generic mechanism, diversity, that provokes the emergence of global oscillations from individually quiescent elements in heterogeneous excitable media. This mechanism may be operating in the mammalian pancreas, where excitable beta cells, quiescent when isolated, are found to oscillate when coupled despite the absence of a pacemaker region.Comment: See home page http://lec.ugr.es/~julya

UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma

Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade

Experimental observation of the amplitude death effect in two coupled nonlinear oscillators

The amplitude death phenomenon has been experimentally observed with a pair of thermo-optical oscillators linearly coupled by heat transfer. A parametric analysis has been done and compared with numerical simulations of a time delayed model. The role of the coupling strength is also discussed from experimental and numerical results

On distributions of functionals of anomalous diffusion paths

Functionals of Brownian motion have diverse applications in physics, mathematics, and other fields. The probability density function (PDF) of Brownian functionals satisfies the Feynman-Kac formula, which is a Schrodinger equation in imaginary time. In recent years there is a growing interest in particular functionals of non-Brownian motion, or anomalous diffusion, but no equation existed for their PDF. Here, we derive a fractional generalization of the Feynman-Kac equation for functionals of anomalous paths based on sub-diffusive continuous-time random walk. We also derive a backward equation and a generalization to Levy flights. Solutions are presented for a wide number of applications including the occupation time in half space and in an interval, the first passage time, the maximal displacement, and the hitting probability. We briefly discuss other fractional Schrodinger equations that recently appeared in the literature.Comment: 25 pages, 4 figure

“I Think I Became a Swimmer Rather than Just Someone with a Disability Swimming Up and Down”: Paralympic Athletes Perceptions of Self and Identity Development

This is an Accepted Manuscript of an article published by Taylor & Francis Group in Disability and Rehabilitation on 27 September 2016, available online at:DOI: https://doi.org/10.1080/09638288.2016.1217074.Purpose: The purpose of this study was to explore the role of swimming on Paralympic athletes’ perceptions of self and identity development. Method: A hermeneutic phenomenological approach was taken. During semi-structured interviews five Paralympic swimmers (aged 20-24 years) were asked questions about their swimming career, perceptions of self, integration, and impairment. Interviews were audio-recorded and transcribed verbatim. Results: An Interpretative Phenomenological Analysis1 yielded three superordinate themes: a) ‘One of the crowd’; none of the participants viewed themselves as disabled, nor as supercrips; these perceptions stemmed from family-, school-, and swimming- related experiences, b) ‘Becoming me’; participation in swimming facilitated self- and social-acceptance, and identity development, and c) ‘A badge of honour’; swimming presented opportunity to present and reinforce a positive identity. Conclusions: Swimming experiences enabled the participants to enhance personal and social identities, integrate through pro-social mechanisms, and to develop a career path following retirement from competition.through pro-social mechanisms, and to develop a career path following retirement from competition.Peer reviewe