1,168 research outputs found
Stapled Peptides as HIFâ1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency
Proteinâprotein interactions (PPIs) control virtually all cellular processes and have thus emerged as potential targets for development of molecular therapeutics. Peptideâbased inhibitors of PPIs are attractive given that they offer recognition potency and selectivity features that are ideal for function, yet, they do not predominantly populate the bioactive conformation, frequently suffer from poor cellular uptake and are easily degraded, for example, by proteases. The constraint of peptides in a bioactive conformation has emerged as a promising strategy to mitigate against these liabilities. In this work, using peptides derived from hypoxiaâinducible factor 1 (HIFâ1α) together with dibromomaleimide stapling, we identify constrained peptide inhibitors of the HIFâ1α/p300 interaction that are more potent than their unconstrained sequences. Contrary to expectation, the increased potency does not correlate with an increased population of an αâhelical conformation in the unbound state as demonstrated by experimental circular dichroism analysis. Rather, the ability of the peptide to adopt a bioactive αâhelical conformation in the p300 bound state is better supported in the constrained variant as demonstrated by molecular dynamics simulations and circular dichroism difference spectra
Response of a catalytic reaction to periodic variation of the CO pressure: Increased CO_2 production and dynamic phase transition
We present a kinetic Monte Carlo study of the dynamical response of a
Ziff-Gulari-Barshad model for CO oxidation with CO desorption to periodic
variation of the CO presure. We use a square-wave periodic pressure variation
with parameters that can be tuned to enhance the catalytic activity. We produce
evidence that, below a critical value of the desorption rate, the driven system
undergoes a dynamic phase transition between a CO_2 productive phase and a
nonproductive one at a critical value of the period of the pressure
oscillation. At the dynamic phase transition the period-averged CO_2 production
rate is significantly increased and can be used as a dynamic order parameter.
We perform a finite-size scaling analysis that indicates the existence of
power-law singularities for the order parameter and its fluctuations, yielding
estimated critical exponent ratios and . These exponent ratios, together with theoretical symmetry
arguments and numerical data for the fourth-order cumulant associated with the
transition, give reasonable support for the hypothesis that the observed
nonequilibrium dynamic phase transition is in the same universality class as
the two-dimensional equilibrium Ising model.Comment: 18 pages, 10 figures, accepted in Physical Review
Contour deformation trick in hybrid NLIE
The hybrid NLIE of AdS_5 x S^5 is applied to a wider class of states. We find
that the Konishi state of the orbifold AdS_5 x (S^5/Z_S) satisfies A_1 NLIE
with the source terms which are derived from contour deformation trick. For
general states, we construct a deformed contour with which the contour
deformation trick yields the correct source terms.Comment: 39 pages, 6 figures, v2: discussion on analyticity constraints
replaced by consistent deformed contou
Barriers to the development of palliative care in Western Europe
The Eurobarometer Survey of the <i>EAPC Task Force on the Development of Palliative Care in Europe</i> is part of a programme of work to produce comprehensive information on the provision of palliative care across Europe.
Aim: To identify barriers to the development of palliative care in Western Europe.
Method: A qualitative survey was undertaken amongst boards of national associations, eliciting opinions on opportunities for, and barriers to, palliative care development. By July 2006, 44/52 (85%) European countries had responded to the survey; we report here on the results from 22/25 (88%) countries in Western Europe.
Analysis: Data from the Eurobarometer survey were analysed thematically by geographical region and by the degree of development of palliative care in each country.
Results: From the data contained within the Eurobarometer, we identified six significant barriers to the development of palliative care in Western Europe: (i) Lack of palliative care education and training programmes (ii) Lack of awareness and recognition of palliative care (iii) Limited availability of/knowledge about opioid analgesics (iv) Limited funding (v) Lack of coordination amongst services (vi) Uneven palliative care coverage.
Conclusion: Findings from the EAPC Eurobarometer survey suggest that barriers to the development of palliative care in Western Europe may differ substantially from each other in both their scope and context and that some may be considered to be of greater significance than others. A number of common barriers to the development of the discipline do exist and much work still remains to be done in the identified areas. This paper provides a road map of which barriers need to be addressed
Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways
Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall.Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen activated protein kinase (MAPK) activation, though the molecular mechanisms of this process are poorly understood.
Here we report that tribbles-1, a recently described modulator of MAPK activation controls vascular smooth muscle cell proliferation and chemotaxis via the Jun Kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The
activity of this kinase is dependent on tribbles-1 levels, whilst the activation and the expression of MKK4/SEK1 is not. In addition, tribbles-1 expression is elevated in
human atherosclerotic arteries compared to non-atherosclerotic controls, suggesting that this protein may pay a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology
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