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The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease.
Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation
Cellular Programming of Plant Gene Imprinting
Gene imprinting, the differential expression of maternal and paternal alleles, independently evolved in mammals and in flowering plants. A unique feature of flowering plants is a double-fertilization event in which the sperm fertilize not only the egg, which forms the embryo, but also the central cell, which develops into the endosperm (an embryo-supporting tissue). The distinctive mechanisms of gene imprinting in the endosperm, which involve DNA demethylation and histone methylation, begin in the central cell and sperm prior to fertilization. Flowering plants might have coevolved double fertilization and imprinting to prevent parthenogenetic development of the endosperm
Dark Matter in the Coming Decade: Complementary Paths to Discovery and Beyond
In this report we summarize the many dark matter searches currently being
pursued through four complementary approaches: direct detection, indirect
detection, collider experiments, and astrophysical probes. The essential
features of broad classes of experiments are described, each with their own
strengths and weaknesses. The complementarity of the different dark matter
searches is discussed qualitatively and illustrated quantitatively in two
simple theoretical frameworks. Our primary conclusion is that the diversity of
possible dark matter candidates requires a balanced program drawing from all
four approaches.Comment: Report prepared for the Community Summer Study (Snowmass) 2013, on
behalf of Cosmic Frontier Working Groups 1-4 (CF1: WIMP Dark Matter Direct
Detection, CF2: WIMP Dark Matter Indirect Detection, CF3: Non-WIMP Dark
Matter, and CF4: Dark Matter Complementarity); published versio
The fibrin-derived Ī³377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease
Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (Ī±MĪ²2, CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogenāMac-1 interaction in fibrinogen-Ī³390-396A knock-in mice or pharmacologically impeding fibrinogenāMac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (Ī³377-395) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogenāMac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the Ī³377-395 fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation
Resummation of heavy jet mass and comparison to LEP data
The heavy jet mass distribution in e+e- collisions is computed to
next-to-next-to-next-to leading logarithmic (NNNLL) and next-to-next-to leading
fixed order accuracy (NNLO). The singular terms predicted from the resummed
distribution are confirmed by the fixed order distributions allowing a precise
extraction of the unknown soft function coefficients. A number of quantitative
and qualitative comparisons of heavy jet mass and the related thrust
distribution are made. From fitting to ALEPH data, a value of alpha_s is
extracted, alpha_s(m_Z)=0.1220 +/- 0.0031, which is larger than, but not in
conflict with, the corresponding value for thrust. A weighted average of the
two produces alpha_s(m_Z) = 0.1193 +/- 0.0027, consistent with the world
average. A study of the non-perturbative corrections shows that the flat
direction observed for thrust between alpha_s and a simple non-perturbative
shape parameter is not lifted in combining with heavy jet mass. The Monte Carlo
treatment of hadronization gives qualitatively different results for thrust and
heavy jet mass, and we conclude that it cannot be trusted to add power
corrections to the event shape distributions at this accuracy. Whether a more
sophisticated effective field theory approach to power corrections can
reconcile the thrust and heavy jet mass distributions remains an open question.Comment: 33 pages, 14 figures. v2 added effect of lower numerical cutoff with
improved extraction of the soft function constants; power correction
discussion clarified. v3 small typos correcte
The Anthropocene is best understood as an ongoing, intensifying, diachronous event
Current debate on the status and character of the Anthropocene is focussed on whether this interval of geological time should be designated as a formal unit of epoch/series rank in the International Chronostratigraphic Chart/Geological Time Scale, or whether it is more appropriate for it to be considered as an informal āeventā comparable in significance with other major transformative events in deeper geological time. The case for formalizing the Anthropocene as a chronostratigraphical unit with a base at approximately 1950āCE is being developed by the Anthropocene Working Group of the Subcommission on Quaternary Stratigraphy. Here we outline the alternative position and explain why the time-transgressive nature of human impact on global environmental systems that is reflected in the recent stratigraphical record means that the Anthropocene is better seen not as a series/epoch with a fixed lower boundary, but rather as an unfolding, transforming and intensifying geological event
AN APPROACH FOR THE EFFECTIVE UTILIZATION OF GP-GPUS IN PARALLEL COMBINED SIMULATION
A major challenge in the field of Modeling & Simulation is providing efficient parallel computation for a variety of algorithms. Algorithms that are described easily and computed efficiently for continuous simulation, may be complex to describe and/or efficiently execute in a discrete event context, and vice-versa. Real-world models often employ multiple algorithms that are optimally defined in one approach or the other. Parallel combined simulation addresses this problem by allowing models to define algorithmic components across multiple paradigms. In this paper, we illustrate the performance of parallel combined simulation, where the continuous component is executed across multiple graphical processing units (GPU) and the discrete event component is executed across multiple central processing units (CPU).
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