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 γ377-395 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 (αMβ2, 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-γ390-396A knock-in mice or pharmacologically impeding fibrinogen–Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (γ377-395) 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 γ377-395 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 ‘event’ 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 1950 CE 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).