No abstract

We propose a new exact method for shortest-path distance queries on large-scale networks. Our method precomputes distance labels for vertices by performing a breadth-first search from every vertex. Seemingly too obvious and too inefficient at first glance, the key ingredient introduced here is pruning during breadth-first searches. While we can still answer the correct distance for any pair of vertices from the labels, it surprisingly reduces the search space and sizes of labels. Moreover, we show that we can perform 32 or 64 breadth-first searches simultaneously exploiting bitwise operations. We experimentally demonstrate that the combination of these two techniques is efficient and robust on various kinds of large-scale real-world networks. In particular, our method can handle social networks and web graphs with hundreds of millions of edges, which are two orders of magnitude larger than the limits of previous exact methods, with comparable query time to those of previous methods.

Experimental autoimmune encephalomyelitis (EAE) is a T lymphocyte-mediated autoimmune disease of the CNS. Significant roles for B cells and a rare IL-10-producing CD1dhiCD5+ regulatory B cell subset (B10 cells) have been identified during the initiation and progression of EAE. Whether and how the regulatory functions of B10 cells and regulatory FoxP3+ T cells (Treg) overlap or influence EAE immunopathogenesis independently has remained unanswered. The current studies demonstrate that the number of endogenous or adoptively transferred B10 cells directly influenced EAE pathogenesis through their production of IL-10. B10 cell numbers expanded quickly within the spleen but not CNS following myelin oligodendrocyte glycoprotein (MOG35-55) immunization, which paralleled B10 cell regulation of disease initiation. The adoptive transfer of MOG33-35-sensitized B10 cells into wild type mice reduced EAE initiation dramatically. However, B10 cells did not suppress ongoing EAE disease. Rather, Treg cell numbers expanded significantly within the CNS during disease progression, which paralleled their negative regulation of late-phase disease. Likewise, the preferential depletion of B10 cells in vivo during disease initiation enhanced EAE pathogenesis, while Treg cell depletion enhanced late-phase disease. B10 cells did not regulate T cell proliferation during in vitro assays, but significantly altered CD4+ T cell IFN-γ and TNF-α production. Furthermore, B10 cells down-regulated the ability of DCs to act as antigen-presenting cells and thereby indirectly modulated T cell proliferation. Thus, B10 cells predominantly control disease initiation, while Treg cells reciprocally inhibit late-phase disease, with overlapping B10 cell and Treg cell functions shaping the normal course of EAE immunopathogenesis.

No abstract

Mice subcutaneously injected with bleomycin, in an experimental model of human systemic sclerosis, develop cutaneous and lung fibrosis with autoantibody production. CD19 is a general "rheostat" that defines signaling thresholds critical for humoral immune responses, autoimmunity, and cytokine production. To determine the role of CD19 in the bleomycin-induced systemic sclerosis model, we investigated the development of fibrosis and autoimmunity in CD19-deficient mice. Bleomycin-treated wild-type mice exhibited dermal and lung fibrosis, hyper-gamma-globulinemia, autoantibody production, and enhanced serum and skin expression of various cytokines, including fibrogenic interleukin-4, interleukin-6, and transforming growth factor-beta1, all of which were inhibited by CD19 deficiency. Bleomycin treatment enhanced hyaluronan production in the skin, lung, and sera. Addition of hyaluronan, an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4, stimulated B cells to produce various cytokines, primarily through TLR4; CD19 deficiency suppressed this stimulation. These results suggest that bleomycin induces fibrosis by enhancing hyaluronan production, which activates B cells to produce fibrogenic cytokines mainly via TLR4 and induce autoantibody production, and that CD19 deficiency suppresses fibrosis and autoantibody production by inhibiting TLR4 signals.

No abstract

A recent trend in parameterized algorithms is the application of polytope tools (specifically, LPbranching) to FPT algorithms (e.g., Cygan et al., 2011;. Though the list of work in this direction is short, the results are already interesting, yielding significant speedups for a range of important problems. However, the existing approaches require the underlying polytope to have very restrictive properties, including half-integrality and Nemhauser-Trotter-style persistence properties. To date, these properties are essentially known to hold only for two classes of polytopes, covering the cases of Vertex Cover (Nemhauser and Trotter, 1975) and Node Multiway Cut (Garg et al., 1994).Taking a slightly different approach, we view half-integrality as a discrete relaxation of a problem, e.g., a relaxation of the search space from {0, 1}V to {0, 1 /2, 1} V such that the new problem admits a polynomial-time exact solution. Using tools from CSP (in particular Thapper andŽivný, 2012) to study the existence of such relaxations, we are able to provide a much broader class of half-integral polytopes with the required properties.Our results unify and significantly extend the previously known cases. In addition to the new insight into problems with half-integral relaxations, our results yield a range of new and improved FPT algorithms, including an O * (|Σ| 2k )-time algorithm for node-deletion Unique Label Cover with label set

No abstract