269 research outputs found
MMB triazole analogs are potent NF-ÎșB 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 (GI50âŻ=âŻ0.02â0.99âŻÎŒM). Lead compound 7h exhibited EC50 values of 400âŻnM and 700âŻnM, 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-ÎșB pathway. In TMD-231 breast cancer cells, treatment with 7h reduced DNA binding activity of NF-ÎșB through inhibition of IKK-ÎČ mediated p65 phosphorylation and caused elevation of basal IÎșBα levels through inhibition of constitutive IÎșBα turnover and NF-ÎșB activation. Molecular docking and dynamic modeling studies indicated that 7h interacts with the kinase domain of the monomeric IKKÎČ subunit, leading to inhibition of IKKÎČ activation, and compromising phosphorylation of downstream targets of the NF-ÎșB pathway; dynamic modeling studies show that this interaction also causes unwinding of the α-helix of the NEMO binding site on IKKÎČ. Molecular docking studies with 10, a water-soluble analog of 7h, demonstrate that this analog interacts with the dimerization/oligomerization domain of monomeric IKKÎČ and may inhibit oligomer formation and subsequent autophosphorylation. Sesquiterpene lactones 7h and 10 are considered ideal candidates for potential clinical development
Time Delay Effects on Coupled Limit Cycle Oscillators at Hopf Bifurcation
We present a detailed study of the effect of time delay on the collective
dynamics of coupled limit cycle oscillators at Hopf bifurcation. For a simple
model consisting of just two oscillators with a time delayed coupling, the
bifurcation diagram obtained by numerical and analytical solutions shows
significant changes in the stability boundaries of the amplitude death, phase
locked and incoherent regions. A novel result is the occurrence of amplitude
death even in the absence of a frequency mismatch between the two oscillators.
Similar results are obtained for an array of N oscillators with a delayed mean
field coupling and the regions of such amplitude death in the parameter space
of the coupling strength and time delay are quantified. Some general analytic
results for the N tending to infinity (thermodynamic) limit are also obtained
and the implications of the time delay effects for physical applications are
discussed.Comment: 20 aps formatted revtex pages (including 13 PS figures); Minor
changes over the previous version; To be published in Physica
Dynamics of a Limit Cycle Oscillator under Time Delayed Linear and Nonlinear Feedbacks
We study the effects of time delayed linear and nonlinear feedbacks on the
dynamics of a single Hopf bifurcation oscillator. Our numerical and analytic
investigations reveal a host of complex temporal phenomena such as phase slips,
frequency suppression, multiple periodic states and chaos. Such phenomena are
frequently observed in the collective behavior of a large number of coupled
limit cycle oscillators. Our time delayed feedback model offers a simple
paradigm for obtaining and investigating these temporal states in a single
oscillator.We construct a detailed bifurcation diagram of the oscillator as a
function of the time delay parameter and the driving strengths of the feedback
terms. We find some new states in the presence of the quadratic nonlinear
feedback term with interesting characteristics like birhythmicity, phase
reversals, radial trapping, phase jumps and spiraling patterns in the amplitude
space. Our results may find useful applications in physical, chemical or
biological systems.Comment: VERSION 4: Fig. 10(d) added, an uncited reference removed; (To appear
in Physica D) (17 pages, 21 figures, two column, aps RevTeX); VERSION 3:
Revised. In Section 2, small tau approximation added; Section 3 is divided
into subsections; periodic solution discussed in detail; Figs. 7 and 11
discarded; Figs. 12 and 14 altered; three new figures (now Figs. 10, 11 and
21) added. VERSION 2: Figs. 1 and 2 replace
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 âpowerâ penalty or a âplacementâ penalty. The current study investigated how the type of penalty kick being taken affected the kickerâs 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
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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 (1981â2011). 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 â comprising cold peace (1981â91), a hybrid foreign policy of cold peace and strategic peace (1991â2003), and a pure strategic peace posture (2003â11). 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
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
Chemo-Radiotherapy of Oligometastases of Colorectal Cancer With Pegylated Liposomal Mitomycin-C Prodrug (Promitil): Mechanistic Basis and Preliminary Clinical Experience
Hypo-fractionated radiotherapy and stereotactic body radiotherapy are viable options for treatment of oligometastases. A prodrug of mitomycin-C is under clinical testing as a pegylated liposomal formulation (Promitil) with an improved safety profile over mitomycin-C. Promitil was offered to two patients with oligometastases from colorectal cancer as radiosensitizer. Each derived durable clinical benefit from Promitil administered immediately prior to and following irradiation. Transient toxicity to normal tissues of moderate to severe degree was observed. Promitil appears to have potential clinical value in this setting.HIGHLIGHTS- Delivery of radio-sensitizing drugs with pegylated (long-circulating) liposomes is a pharmacologically rational approach which remains largely clinically untested.- A mitomycin-c prodrug delivered by pegylated liposomes (Promitil) is activated by thiol groups, which are produced in excess by radiation-damaged cells, thus potentiating the radio-sensitizing effect of Promitil.- Two durable clinical responses in patient with colorectal oligometastases to Promitil and radiotherapy suggest that this approach may be of value in cancer chemo-radiotherapy
The Hot (Invisible?) Hand: Can Time Sequence Patterns of Success/Failure in Sports Be Modeled as Repeated Random Independent Trials?
The long lasting debate initiated by Gilovich, Vallone and Tversky in is revisited: does a âhot handâ phenomenon exist in sports? Hereby we come back to one of the cases analyzed by the original study, but with a much larger data set: all free throws taken during five regular seasons () of the National Basketball Association (NBA). Evidence supporting the existence of the âhot handâ phenomenon is provided. However, while statistical traces of this phenomenon are observed in the data, an open question still remains: are these non random patterns a result of âsuccess breeds successâ and âfailure breeds failureâ mechanisms or simply âbetterâ and âworseâ periods? Although free throws data is not adequate to answer this question in a definite way, we speculate based on it, that the latter is the dominant cause behind the appearance of the âhot handâ phenomenon in the data
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
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