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

Cannibalism and infectious disease: Friends or foes?

© 2017 by The University of Chicago. Cannibalism occurs in a majority of both carnivorous and noncarnivorous animal taxa from invertebrates to mammals. Similarly, infectious parasites are ubiquitous in nature. Thus, interactions between cannibalism and disease occur regularly. While some adaptive benefits of cannibalism are clear, the prevailing view is that the risk of parasite transmission due to cannibalism would increase disease spread and, thus, limit the evolutionary extent of cannibalism throughout the animal kingdom. In contrast, surprisingly little attention has been paid to the other half of the interaction between cannibalism and disease, that is, how cannibalism affects parasites. Here we examine the interaction between cannibalism and parasites and show howadvances across independent lines of research suggest that cannibalism can also reduce the prevalence of parasites and, thus, infection risk for cannibals. Cannibalism does this by both directly killing parasites in infected victims and by reducing the number of susceptible hosts, often enhanced by the stage-structured nature of cannibalism and infection. While the well-established view that disease should limit cannibalism has held sway, we present theory and examples from a synthesis of the literature showing how cannibalism may also limit disease and highlight key areas where conceptual and empirical work is needed to resolve this debate

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

Proposal for the integration of the semantic structure of Wikipedia categories into Wikidata using SKOS

DBpedia is the most prominent dataset in Linked Open Data ecosystem. Wikidata is a Wikimedia movement initiative to represent knowledge as data, structured, defined and maintained collaboratively. Both are cross-domain Open Knowledge Graphs. WikiData is intended to change the way in which data is used by the Wikimedia editors, and it will probably have influence in how DBpedia data is collected. So, improving the semantic of Wikipedia Categories in Wikidata will have a deep impact in Knowledge Organization. In this work we propose a methodology for the SKOS integration into de WikiData data model of the Wikipedia Category semantic structure. An analytic comparative report of how Wikipedia categories are treated in DBpedia and WikiData is conducted, including not only the terms itself, but also their relationships and correspondences. Equivalence patterns between the objects or entities of the three sources - Wikipedia, DBpedia and Wikidata - are identified. Other content elements, such as articles, participation records or external links are also take in consideration. Then, keeping in mind the autodescriptive nature of WikiData infrastructure a set of entities and properties that allow the use of SKOS to represent semantic relationships are suggested. Last, we have designed and tested a methodology for the automatic design of an automatic process of reuse of semantic representation of semantic relations in Dbpedia. The proposal details the SKOS properties and classes that should be included as WikiData entities, in order to represent categories semantic relationships and its mappings and cross-references with other SKOS datasets. Technical advice of how obtain and adapt DBpedia categories RDF statements in order to be incorporated in WikiData is exposed. This methodology, whose results are a kind of alignment between DBpedia and WikiData categories, is built upon the matching between their different representations. A bunch of tasks, procedures and tools are developed, that allow manage not only concepts, but also SKOS labels and semantic relationships existing in Dbpedia. Adding semantic relationships of Wikipedia categories in Wikidata is viable, and DBpedia is a worthy tool for do this. Including semantic relationships in Wikidata improve its quality as a Knowledge Organization resource. Wikidata categories, whose source is Wikipedia, may be used as an element to align thesauri, subject headings, taxonomies, etc. Due this reason, apply SKOS in category representation could be the first step for Wikidata not only to be a factual database, but also a knowledge organization platform

Lead-related quantum emitters in diamond

We report on quantum emission from Pb-related color centers in diamond following ion implantation and high-temperature vacuum annealing. First-principles calculations predict a negatively charged Pb-vacancy (PbV) center in a split-vacancy configuration, with a zero-phonon transition around 2.4 eV. Cryogenic photoluminescence measurements performed on emitters in nanofabricated pillars reveal several transitions, including a prominent doublet near 520 nm. The splitting of this doublet, 5.7 THz, exceeds that reported for other group-IV centers. These observations are consistent with the PbV center, which is expected to have a combination of narrow optical transitions and stable spin states, making it a promising system for quantum network nodes.U.S. Army Research Laboratory. Center for Distributed Quantum InformationNational Science Foundation (U.S.). Graduate Research Fellowship ProgramNational Science Foundation (U.S.) (Grant DMR-1231319)United States. National Aeronautics and Space Administration (Space Technology Research Fellowship)MIT-Harvard Center for Ultracold Atoms MIT International Science and Technology Initiativ

Thrombin promotes diet-induced obesity through fibrin-driven inflammation

Obesity promotes a chronic inflammatory and hypercoagulable state that drives cardiovascular disease, type 2 diabetes, fatty liver disease, and several cancers. Elevated thrombin activity underlies obesity-linked thromboembolic events, but the mechanistic links between the thrombin/fibrin(ogen) axis and obesity-associated pathologies are incompletely understood. In this work, immunohistochemical studies identified extravascular fibrin deposits within white adipose tissue and liver as distinct features of mice fed a high-fat diet (HFD) as well as obese patients. Fibγ390–396A mice carrying a mutant form of fibrinogen incapable of binding leukocyte αMβ2-integrin were protected from HFD-induced weight gain and elevated adiposity. Fibγ390–396A mice had markedly diminished systemic, adipose, and hepatic inflammation with reduced macrophage counts within white adipose tissue, as well as near-complete protection from development of fatty liver disease and glucose dysmetabolism. Homozygous thrombomodulin-mutant ThbdPro mice, which have elevated thrombin procoagulant function, gained more weight and developed exacerbated fatty liver disease when fed a HFD compared with WT mice. In contrast, treatment with dabigatran, a direct thrombin inhibitor, limited HFD-induced obesity development and suppressed progression of sequelae in mice with established obesity. Collectively, these data provide proof of concept that targeting thrombin or fibrin(ogen) may limit pathologies in obese patients

Factor XIII activity mediates red blood cell retention in venous thrombi

Venous thrombi, fibrin- and rbc-rich clots triggered by inflammation and blood stasis, underlie devastating, and sometimes fatal, occlusive events. During intravascular fibrin deposition, rbc are thought to become passively trapped in thrombi and therefore have not been considered a modifiable thrombus component. In the present study, we determined that activity of the transglutaminase factor XIII (FXIII) is critical for rbc retention within clots and directly affects thrombus size. Compared with WT mice, mice carrying a homozygous mutation in the fibrinogen γ chain (Fibγ390–396A) had a striking 50% reduction in thrombus weight due to reduced rbc content. Fibrinogen from mice harboring the Fibγ390–396A mutation exhibited reduced binding to FXIII, and plasma from these mice exhibited delayed FXIII activation and fibrin crosslinking, indicating these residues mediate FXIII binding and activation. FXIII-deficient mice phenocopied mice carrying Fibγ390–396A and produced smaller thrombi with fewer rbc than WT mice. Importantly, FXIII-deficient human clots also exhibited reduced rbc retention. The addition of FXIII to FXIII-deficient clots increased rbc retention, while inhibition of FXIII activity in normal blood reduced rbc retention and produced smaller clots. These findings establish the FXIII-fibrinogen axis as a central determinant in venous thrombogenesis and identify FXIII as a potential therapeutic target for limiting venous thrombosis

Cohesion as ‘common sense’: Everyday narratives of community and cohesion in New Labour’s Britain

The final, definitive version of this paper has been published in Politics, Vol. 36(3) July 2016, DOI: 10.1177/0263395715620811 published by SAGE Publishing. All rights reservedThis article engages with popular narratives of community and cohesion, explored through a series of focus groups in Bradford and Birmingham. This article argues that the participants interviewed used discourses propagated by government to make sense of these narratives in their neighbourhoods and communities. The use of these discourses constructs what Gramsci calls a ‘common sense’ position, which legitimises a specific and targeted notion of cohesion. However, participants can contaminate these discourses, which can lead to subtle changes or explicit challenges to dominant discourses on community and cohesion in the United Kingdom.Peer reviewe

Homing endonuclease I-TevIII: dimerization as a means to a double-strand break

Homing endonucleases are unusual enzymes, capable of recognizing lengthy DNA sequences and cleaving site-specifically within genomes. Many homing endonucleases are encoded within group I introns, and such enzymes promote the mobility reactions of these introns. Phage T4 has three group I introns, within the td, nrdB and nrdD genes. The td and nrdD introns are mobile, whereas the nrdB intron is not. Phage RB3 is a close relative of T4 and has a lengthier nrdB intron. Here, we describe I-TevIII, the H–N–H endonuclease encoded by the RB3 nrdB intron. In contrast to previous reports, we demonstrate that this intron is mobile, and that this mobility is dependent on I-TevIII, which generates 2-nt 3′ extensions. The enzyme has a distinct catalytic domain, which contains the H–N–H motif, and DNA-binding domain, which contains two zinc fingers required for interaction with the DNA substrate. Most importantly, I-TevIII, unlike the H–N–H endonucleases described so far, makes a double-strand break on the DNA homing site by acting as a dimer. Through deletion analysis, the dimerization interface was mapped to the DNA-binding domain. The unusual propensity of I-TevIII to dimerize to achieve cleavage of both DNA strands underscores the versatility of the H–N–H enzyme family