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Search Results: 1 - 10 of 13715 matches for " Anna Huttenlocher "
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Neutrophil Reverse Migration Becomes Transparent with Zebrafish
Taylor W. Starnes,Anna Huttenlocher
Advances in Hematology , 2012, DOI: 10.1155/2012/398640
Abstract: The precise control of neutrophil-mediated inflammation is critical for both host defense and the prevention of immunopathology. In vivo imaging studies in zebrafish, and more recently in mice, have made the novel observation that neutrophils leave a site of inflammation through a process called neutrophil reverse migration. The application of advanced imaging techniques to the genetically tractable, optically transparent zebrafish larvae was critical for these advances. Still, the mechanisms underlying neutrophil reverse migration and its effects on the resolution or priming of immune responses remain unclear. Here, we review the current knowledge of neutrophil reverse migration, its potential roles in host immunity, and the live imaging tools that make zebrafish a valuable model for increasing our knowledge of neutrophil behavior in vivo. 1. Introduction “Certain of the lower animals, transparent enough to be observed alive, clearly show in their midst a host of small cells with moving extensions. In these animals the smallest lesion brings an accumulation of these elements at the point of damage. In small transparent larvae, it can easily be shown that the moving cells, reunited at the damage point do often close over foreign bodies [1].” Ilya Mechnikov, one of the fathers of immunology, spoke these words at his Nobel Prize lecture in 1908. More than one hundred years after his seminal studies using transparent starfish larvae to illuminate a role for phagocytosis in immunity, we are again exploiting the power of transparent larvae for research on the immune system. Studies of neutrophils in both humans and mammalian model systems have brought great advances in our knowledge of their functions; however, zebrafish, a small tropical fish with transparent larvae, have demonstrated that direct observation of neutrophils in live animals can provide important insights that would have otherwise faced significant technical challenges using mice. Neutrophils are the most abundant leukocytes in both humans and zebrafish, and they are critical for defending the host against microbial infection [2]. In response to wounding, infection, or other inflammatory stimuli, neutrophils are rapidly recruited to perform their well-known effector functions: degranulation, phagocytosis, production of reactive oxygen species (ROS), secretion of proinflammatory cytokines, and extrusion of neutrophil extracellular traps (NETs) [3, 4]. These responses are acknowledged to kill and sequester microorganisms at their site of entry and promote the activation of the adaptive immune
Heat Shock Modulates Neutrophil Motility in Zebrafish
Pui-ying Lam, Elizabeth A. Harvie, Anna Huttenlocher
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084436
Abstract: Heat shock is a routine method used for inducible gene expression in animal models including zebrafish. Environmental temperature plays an important role in the immune system and infection progression of ectotherms. In this study, we analyzed the impact of short-term heat shock on neutrophil function using zebrafish (Danio rerio) as an animal model. Short-term heat shock decreased neutrophil recruitment to localized Streptococcus iniae infection and tail fin wounding. Heat shock also increased random neutrophil motility transiently and increased the number of circulating neutrophils. With the use of the translating ribosome affinity purification (TRAP) method for RNA isolation from specific cell types such as neutrophils, macrophages and epithelial cells, we found that heat shock induced the immediate expression of heat shock protein 70 (hsp70) and a prolonged expression of heat shock protein 27 (hsp27). Heat shock also induced cell stress as detected by the splicing of X-box binding protein 1 (xbp1) mRNA, a marker for endoplasmic reticulum (ER) stress. Exogenous expression of Hsp70, Hsp27 and spliced Xbp1 in neutrophils or epithelial cells did not reproduce the heat shock induced effects on neutrophil recruitment. The effect of heat shock on neutrophils is likely due to a combination of complex changes, including, but not limited to changes in gene expression. Our results indicate that routine heat shock can alter neutrophil function in zebrafish. The findings suggest that caution should be taken when employing a heat shock-dependent inducible system to study the innate immune response.
Determinants of phosphatidylinositol-4-phosphate 5-kinase type Iγ90 uropod location in T-lymphocytes and its role in uropod formation
Lucia Mathis,Sarah Wernimont,Sarah Affentranger,Anna Huttenlocher,Verena Niggli
PeerJ , 2015, DOI: 10.7717/peerj.131
Abstract: We have previously identified phosphatidylinositol-4-phosphate 5-kinase type I (PIPKI)γ90 as a T cell uropod component. However, the molecular determinants and functional consequences of its localization remain unknown. In this report, we seek to better understand the mechanisms involved in PIPKIγ90 uropod targeting and the role that PIPKIγ90 plays in T cell uropod formation. During T cell activation, PIPKIγ90 cocaps with the membrane microdomain-associated proteins flotillin-1 and -2 and accumulates in the uropod. We report that the C-terminal 26 amino acid extension of PIPKIγ90 is required for its localization to the uropod. We further use T cells from PIPKIγ90/ mice and human T cells expressing a kinase-dead PIPKIγ90 mutant to examine the role of PIPKIγ90 in a T cell uropod formation. We find that PIPKIγ90 deficient T cells have elongated uropods on ICAM-1. Moreover, in human T cells overexpression of PIPKIγ87, a naturally occurring isoform lacking the last 26 amino acids, suppresses uropod formation and impairs capping of uropod proteins such as flotillins. Transfection of human T cells with a dominant-negative mutant of flotillin-2 in turn attenuates capping of PIPKIγ90. Our data contribute to the understanding of the molecular mechanisms that regulate T cell uropod formation.
Modulation of Neutrophil Function by a Secreted Mucinase of Escherichia coli O157∶H7
Rose L. Szabady,Mary A. Lokuta,Kevin B. Walters,Anna Huttenlocher,Rodney A. Welch
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000320
Abstract: Escherichia coli O157:H7 is a human enteric pathogen that causes hemorrhagic colitis which can progress to hemolytic uremic syndrome, a severe kidney disease with immune involvement. During infection, E. coli O157:H7 secretes StcE, a metalloprotease that promotes the formation of attaching and effacing lesions and inhibits the complement cascade via cleavage of mucin-type glycoproteins. We found that StcE cleaved the mucin-like, immune cell-restricted glycoproteins CD43 and CD45 on the neutrophil surface and altered neutrophil function. Treatment of human neutrophils with StcE led to increased respiratory burst production and increased cell adhesion. StcE-treated neutrophils exhibited an elongated morphology with defective rear detachment and impaired migration, suggesting that removal of the anti-adhesive capability of CD43 by StcE impairs rear release. Use of zebrafish embryos to model neutrophil migration revealed that StcE induced neutrophil retention in the fin after tissue wounding, suggesting that StcE modulates neutrophil-mediated inflammation in vivo. Neutrophils are crucial innate effectors of the antibacterial immune response and can contribute to severe complications caused by infection with E. coli O157:H7. Our data suggest that the StcE mucinase can play an immunomodulatory role by directly altering neutrophil function during infection. StcE may contribute to inflammation and tissue destruction by mediating inappropriate neutrophil adhesion and activation.
Calpain 4 Is Not Necessary for LFA-1-Mediated Function in CD4+ T Cells
Sarah A. Wernimont,William T. N. Simonson,Peter A. Greer,Christine M. Seroogy,Anna Huttenlocher
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010513
Abstract: T cell activation and immune synapse formation require the appropriate activation and clustering of the integrin, LFA-1. Previous work has reported that the calpain family of calcium-dependent proteases are important regulators of integrin activation and modulate T cell adhesion and migration. However, these studies have been limited by the use of calpain inhibitors, which have known off-target effects.
Low-Volume Toolbox for the Discovery of Immunosuppressive Fungal Secondary Metabolites
Erwin Berthier equal contributor,Fang Yun Lim equal contributor,Qing Deng,Chun-Jun Guo,Dimitrios P. Kontoyiannis,Clay C. C. Wang,Julie Rindy,David J. Beebe,Anna Huttenlocher,Nancy P. Keller
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003289
Abstract: The secondary metabolome provides pathogenic fungi with a plethoric and versatile panel of molecules that can be deployed during host ingress. While powerful genetic and analytical chemistry methods have been developed to identify fungal secondary metabolites (SMs), discovering the biological activity of SMs remains an elusive yet critical task. Here, we describe a process for identifying the immunosuppressive properties of Aspergillus SMs developed by coupling a cost-effective microfluidic neutrophil chemotaxis assay with an in vivo zebrafish assay. The microfluidic platform allows the identification of metabolites inhibiting neutrophil recruitment with as little as several nano-grams of compound in microliters of fluid. The zebrafish assay demonstrates a simple and accessible approach for performing in vivo studies without requiring any manipulation of the fish. Using this methodology we identify the immunosuppressive properties of a fungal SM, endocrocin. We find that endocrocin is localized in Aspergillus fumigatus spores and its biosynthesis is temperature-dependent. Finally, using the Drosophila toll deficient model, we find that deletion of encA, encoding the polyketide synthase required for endocrocin production, yields a less pathogenic strain of A. fumigatus when spores are harvested from endocrocin permissive but not when harvested from endocrocin restrictive conditions. The tools developed here will open new “function-omic” avenues downstream of the metabolomics, identification, and purification phases.
Coordination and Efficiency in Decentralized Collaboration
Daniel M. Romero,Dan Huttenlocher,Jon Kleinberg
Computer Science , 2015,
Abstract: Environments for decentralized on-line collaboration are now widespread on the Web, underpinning open-source efforts, knowledge creation sites including Wikipedia, and other experiments in joint production. When a distributed group works together in such a setting, the mechanisms they use for coordination can play an important role in the effectiveness of the group's performance. Here we consider the trade-offs inherent in coordination in these on-line settings, balancing the benefits to collaboration with the cost in effort that could be spent in other ways. We consider two diverse domains that each contain a wide range of collaborations taking place simultaneously -- Wikipedia and GitHub -- allowing us to study how coordination varies across different projects. We analyze trade-offs in coordination along two main dimensions, finding similar effects in both our domains of study: first we show that, in aggregate, high-status projects on these sites manage the coordination trade-off at a different level than typical projects; and second, we show that projects use a different balance of coordination when they are "crowded," with relatively small size but many participants. We also develop a stylized theoretical model for the cost-benefit trade-off inherent in coordination and show that it qualitatively matches the trade-offs we observe between crowdedness and coordination.
Governance in Social Media: A case study of the Wikipedia promotion process
Jure Leskovec,Daniel Huttenlocher,Jon Kleinberg
Computer Science , 2010,
Abstract: Social media sites are often guided by a core group of committed users engaged in various forms of governance. A crucial aspect of this type of governance is deliberation, in which such a group reaches decisions on issues of importance to the site. Despite its crucial --- though subtle --- role in how a number of prominent social media sites function, there has been relatively little investigation of the deliberative aspects of social media governance. Here we explore this issue, investigating a particular deliberative process that is extensive, public, and recorded: the promotion of Wikipedia admins, which is determined by elections that engage committed members of the Wikipedia community. We find that the group decision-making at the heart of this process exhibits several fundamental forms of relative assessment. First we observe that the chance that a voter will support a candidate is strongly dependent on the relationship between characteristics of the voter and the candidate. Second we investigate how both individual voter decisions and overall election outcomes can be based on models that take into account the sequential, public nature of the voting.
Predicting Positive and Negative Links in Online Social Networks
Jure Leskovec,Daniel Huttenlocher,Jon Kleinberg
Computer Science , 2010,
Abstract: We study online social networks in which relationships can be either positive (indicating relations such as friendship) or negative (indicating relations such as opposition or antagonism). Such a mix of positive and negative links arise in a variety of online settings; we study datasets from Epinions, Slashdot and Wikipedia. We find that the signs of links in the underlying social networks can be predicted with high accuracy, using models that generalize across this diverse range of sites. These models provide insight into some of the fundamental principles that drive the formation of signed links in networks, shedding light on theories of balance and status from social psychology; they also suggest social computing applications by which the attitude of one user toward another can be estimated from evidence provided by their relationships with other members of the surrounding social network.
Signed Networks in Social Media
Jure Leskovec,Daniel Huttenlocher,Jon Kleinberg
Computer Science , 2010,
Abstract: Relations between users on social media sites often reflect a mixture of positive (friendly) and negative (antagonistic) interactions. In contrast to the bulk of research on social networks that has focused almost exclusively on positive interpretations of links between people, we study how the interplay between positive and negative relationships affects the structure of on-line social networks. We connect our analyses to theories of signed networks from social psychology. We find that the classical theory of structural balance tends to capture certain common patterns of interaction, but that it is also at odds with some of the fundamental phenomena we observe --- particularly related to the evolving, directed nature of these on-line networks. We then develop an alternate theory of status that better explains the observed edge signs and provides insights into the underlying social mechanisms. Our work provides one of the first large-scale evaluations of theories of signed networks using on-line datasets, as well as providing a perspective for reasoning about social media sites.
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