2,164 research outputs found
A critical role for ATF2 transcription factor in the regulation of E-selectin expression in response to non-endotoxin components of Neisseria meningitidis
Vascular injury is a serious complication of sepsis due to the gram-negative bacterium Neisseria meningitidis. One of the critical early steps in initiating this injury is via the interaction of leucocytes, particularly neutrophils, with adhesion molecules expressed on inflamed endothelium. We have previously demonstrated that both lipopolysaccharide (LPS) and non-LPS components of meningococci can induce very high levels of expression of the vascular endothelial cell adhesion molecule E-selectin, which is critical for early tethering and capture of neutrophils onto endothelium under flow. Using an LPS-deficient strain of meningococcus, we showed that very high levels of expression can be induced in primary endothelial cells, even in the context of weak activation of the major host signal transduction factor [nuclear factor-κB (NF-κB)]. In this study, we show that the particular propensity for N. meningitidis to induce high levels of expression is regulated at a transcriptional level, and demonstrate a significant role for phosphorylation of the ATF2 transcription factor, likely via mitogen-activated protein (MAP) kinases, on the activity of the E-selectin promoter. Furthermore, inhibition of E-selectin expression in response to the lpxA- strain by a p38 inhibitor indicates a significant role of a p38-dependent MAPK signalling pathway in ATF2 activation. Collectively, these data highlight the role that LPS and other bacterial components have in modulating endothelial function and their involvement in the pathogenesis of meningococcal sepsis. Better understanding of these multiple mechanisms induced by complex stimuli such as bacteria, and the specific inflammatory pathways they activate, may lead to improved, focused interventions in both meningococcal and potentially bacterial sepsis more generally
BKM Lie superalgebra for the Z_5 orbifolded CHL string
We study the Z_5-orbifolding of the CHL string theory by explicitly
constructing the modular form tilde{Phi}_2 generating the degeneracies of the
1/4-BPS states in the theory. Since the additive seed for the sum form is a
weak Jacobi form in this case, a mismatch is found between the modular forms
generated from the additive lift and the product form derived from threshold
corrections. We also construct the BKM Lie superalgebra, tilde{G}_5,
corresponding to the modular form tilde{Delta}_1 (Z) = tilde{Phi}_2 (Z)^{1/2}
which happens to be a hyperbolic algebra. This is the first occurrence of a
hyperbolic BKM Lie superalgebra. We also study the walls of marginal stability
of this theory in detail, and extend the arithmetic structure found by Cheng
and Dabholkar for the N=1,2,3 orbifoldings to the N=4,5 and 6 models, all of
which have an infinite number of walls in the fundamental domain. We find that
analogous to the Stern-Brocot tree, which generated the intercepts of the walls
on the real line, the intercepts for the N >3 cases are generated by linear
recurrence relations. Using the correspondence between the walls of marginal
stability and the walls of the Weyl chamber of the corresponding BKM Lie
superalgebra, we propose the Cartan matrices for the BKM Lie superalgebras
corresponding to the N=5 and 6 models.Comment: 30 pages, 2 figure
Observing Brownian motion in vibration-fluidized granular matter
At the beginning of last century, Gerlach and Lehrer observed the rotational
Brownian motion of a very fine wire immersed in an equilibrium environment, a
gas. This simple experiment eventually permitted the full development of one of
the most important ideas of equilibrium statistical mechanics: the very
complicated many-particle problem of a large number of molecules colliding with
the wire, can be represented by two macroscopic parameters only, namely
viscosity and the temperature. Can this idea, mathematically developed in the
so-called Langevin model and the fluctuation-dissipation theorem be used to
describe systems that are far from equilibrium? Here we address the question
and reproduce the Gerlach and Lehrer experiment in an archetype non-equilibrium
system, by immersing a sensitive torsion oscillator in a granular system of
millimetre-size grains, fluidized by strong external vibrations. The
vibro-fluidized granular medium is a driven environment, with continuous
injection and dissipation of energy, and the immersed oscillator can be seen as
analogous to an elastically bound Brownian particle. We show, by measuring the
noise and the susceptibility, that the experiment can be treated, in first
approximation, with the same formalism as in the equilibrium case, giving
experimental access to a ''granular viscosity'' and an ''effective
temperature'', however anisotropic and inhomogeneous, and yielding the
surprising result that the vibro-fluidized granular matter behaves as a
''thermal'' bath satisfying a fluctuation-dissipation relation
Installing the "magic methyl" - C-H methylation in synthesis
The selective and efficient C-H methylation of sp2 and sp3 carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures
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Science and Technology Roadmapping to Support Project Planning
Disciplined science and technology roadmapping provides a framework to coordinate research and development activities with project objectives. This case-history paper describes initial project technology needs identification, assessment and R&D ranking activities supporting characterization of 781 waste tanks requiring a 'hazardous waste determination' or 'verification of empty' decision to meet an Idaho state Voluntary Consent Order
Exoplanets and SETI
The discovery of exoplanets has both focused and expanded the search for
extraterrestrial intelligence. The consideration of Earth as an exoplanet, the
knowledge of the orbital parameters of individual exoplanets, and our new
understanding of the prevalence of exoplanets throughout the galaxy have all
altered the search strategies of communication SETI efforts, by inspiring new
"Schelling points" (i.e. optimal search strategies for beacons). Future efforts
to characterize individual planets photometrically and spectroscopically, with
imaging and via transit, will also allow for searches for a variety of
technosignatures on their surfaces, in their atmospheres, and in orbit around
them. In the near-term, searches for new planetary systems might even turn up
free-floating megastructures.Comment: 9 page invited review. v2 adds some references and v3 has other minor
additions and modification
Biochemical autoregulatory gene therapy for focal epilepsy.
Despite the introduction of more than one dozen new antiepileptic drugs in the past 20 years, approximately one-third of people who develop epilepsy continue to have seizures on mono- or polytherapy1. Viral-vector-mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci2. Several such strategies have shown encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory or motor function. Here, we describe an autoregulatory antiepileptic gene therapy, which relies on neuronal inhibition in response to elevations in extracellular glutamate. It is effective in a rodent model of focal epilepsy and is well tolerated, thus lowering the barrier to clinical translation
Non-L\'evy mobility patterns of Mexican Me'Phaa peasants searching for fuelwood
We measured mobility patterns that describe walking trajectories of
individual Me'Phaa peasants searching and collecting fuelwood in the forests of
"La Monta\~na de Guerrero" in Mexico. These one-day excursions typically follow
a mixed pattern of nearly-constant steps when individuals displace from their
homes towards potential collecting sites and a mixed pattern of steps of
different lengths when actually searching for fallen wood in the forest.
Displacements in the searching phase seem not to be compatible with L\'evy
flights described by power-laws with optimal scaling exponents. These findings
however can be interpreted in the light of deterministic searching on heavily
degraded landscapes where the interaction of the individuals with their scarce
environment produces alternative searching strategies than the expected L\'evy
flights. These results have important implications for future management and
restoration of degraded forests and the improvement of the ecological services
they may provide to their inhabitants.Comment: 15 pages, 4 figures. First version submitted to Human Ecology. The
final publication will be available at http://www.springerlink.co
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