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Extensive diversification of IgH subclass-encoding genes and IgM subclass switching in crocodilians
Different mechanisms for generating antibody diversity have evolved since the emergence of immunoglobulin genes in jawed vertebrates. By sequencing the crocodilian immunoglobulin heavy-chain locus, Chenget al. uncover new insights into the evolutionary origins of adaptive immunity.
- Gang Cheng
- , Yang Gao
- & Yaofeng Zhao
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| Open AccessExtracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors
Levels of extracellular calcium can increase at sites of infection and inflammation; however, the physiological significance of this has been unclear. This work shows that extracellular calcium acts as a danger signal, triggering the NLRP3 inflammasome via two G protein-coupled receptors.
- Manuela Rossol
- , Matthias Pierer
- & Ulf Wagner
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In vivo imaging of virological synapses
In vitro, retroviruses spread between cells via structures resembling synapses. Sewaldet al. now demonstrate that virological synapses can also be observed in living mice by intravital microscopy, validating this concept in vivo.
- Xaver Sewald
- , David G. Gonzalez
- & Walther Mothes
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| Open AccessVirus-like glycodendrinanoparticles displaying quasi-equivalent nested polyvalency upon glycoprotein platforms potently block viral infection
Host–pathogen relationships can be mediated by polyvalent glycan ligand–protein interactions. Here well-defined highly valent glycodendrimeric constructs are synthesized that can mimic pathogens, and can inhibit a model of infection by the Ebola virus.
- Renato Ribeiro-Viana
- , Macarena Sánchez-Navarro
- & Benjamin G. Davis
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PPARγ is an E3 ligase that induces the degradation of NFκB/p65
NFκB/p65 and PPARγ are both transcription factors that perform distinct but overlapping roles in cellular regulation. Hou et al. report that PPARγ acts as an E3 ubiquitin ligase and promotes Lys48-linked ubiquitination and degradation of p65, terminating NFκB-mediated inflammation and tumorigenesis.
- Yongzhong Hou
- , France Moreau
- & Kris Chadee
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Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers
The proteome of the malarial parasite Plasmodium falciparum has an overabundance of aggregation-prone asparagine repeat-containing proteins. Muralidharan et al. show that PlasmodiumHsp110 protein potently prevents aggregation of asparagine-rich proteins, thereby allowing the parasite to survive febrile episodes.
- Vasant Muralidharan
- , Anna Oksman
- & Daniel E. Goldberg
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Spread of white-nose syndrome on a network regulated by geography and climate
Knowledge of how a disease spreads can lead to useful predictions to help manage and contain it. Here, Maher et al.model white-nose syndrome spreading in North American bats, and show that concentrated habitat distribution and longer winters can mediate pathogen dispersal, matching the ecological traits of bats.
- Sean P. Maher
- , Andrew M. Kramer
- & John M. Drake
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| Open AccessT-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements
T-bet and GATA3 regulate differentiation of T cells into Th1 or Th2 cell fates, but little is known about their functional interaction outside of the IFNγ and Il4 /Il5/Il13 loci. Kanhere et al. map these factors across the genome in human T cells, revealing unappreciated breadth of function and interplay between them.
- Aditi Kanhere
- , Arnulf Hertweck
- & Richard G. Jenner
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Identification and characterization of polyclonal αβ-T cells with dendritic cell properties
The division of the immune system into innate and adaptive arms has become blurred in recent years. Kuka et al.identify a novel population of αβ-T-cell receptor-expressing cells in mice and humans that both presents and responds to antigen and produces interleukin-12, thus exhibiting core properties of both dendritic cells and T cells.
- Mirela Kuka
- , Ivana Munitic
- & Jonathan D. Ashwell
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| Open AccessFibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation
Multiple sclerosis is characterized by the activation of microglia cells. Davalos et al. investigate the early stages of neuroinflammation in mice and reveal that the plasma protein fibrinogen induces microglial clustering around the brain vasculature, which facilitates lesion formation and focal axonal damage.
- Dimitrios Davalos
- , Jae Kyu Ryu
- & Katerina Akassoglou
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MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice
Mice lacking the anti-inflammatory cytokine IL-10 can develop colitis, which depends on inappropriate responses to commensal bacteria. Hoshiet al. now show that these responses are driven by colonic mononuclear phagocytes, providing insight to the initiating events, which may underlie inflammatory bowel disease.
- Namiko Hoshi
- , Dominik Schenten
- & Ruslan Medzhitov
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Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia
One of the five IL-17 receptors, IL-17RD lacks a motif thought to be required for downstream signalling. Melletet al. show that IL-17RD tunes IL-17A-dependent signalling; in its absence, MAPK signalling and neutrophil recruitment are impaired, but NF-κB activation is enhanced.
- Mark Mellett
- , Paola Atzei
- & Paul N. Moynagh
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Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus
Autoreactive T cells are eliminated as they encounter self-antigens during transit through the thymus. Uedaet al. reveal that mice lacking the Hippo homologue Mst1 develop autoimmunity as a result of impaired integrin-dependent T cell migration through this negatively selective niche.
- Yoshihiro Ueda
- , Koko Katagiri
- & Tatsuo Kinashi
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| Open AccessExtracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors
Mast cells are mediators of type I allergic disease and inflammation. Here, Kurashimaet al. show that mast cells are increased in the colons of mice with colitis, and that activation of the cells and subsequent inflammation can be blocked by inhibition of the purinoceptor, P2X7.
- Yosuke Kurashima
- , Takeaki Amiya
- & Hiroshi Kiyono
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Macrophage VLDL receptor promotes PAFAH secretion in mother's milk and suppresses systemic inflammation in nursing neonates
Mother's milk contains a number of protective factors, such as the anti-inflammatory enzyme PAFAH. Here, Duet al. show that the VLDL receptor protects nursing newborns from systemic inflammation by maintaining secretion of PAFAH from maternal macrophages into mother's milk.
- Yang Du
- , Marie Yang
- & Yihong Wan
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| Open AccessFoxP3+ regulatory CD4 T cells control the generation of functional CD8 memory
The role of CD4+ T cells in the generation of memory CD8+ T cells is not fully understood. In this study, the exposure of CD8 memory precursors to interleukin-2 during early antigen priming is shown to be controlled by FoxP3+ regulatory CD4+T cells, resulting in the production of functional memory cells.
- M.G. de Goër de Herve
- , S. Jaafoura
- & Y. Taoufik
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| Open AccessEpidermal phospholipase Cδ1 regulates granulocyte counts and systemic interleukin-17 levels in mice
Phospholipase C is a signalling molecule with many cellular functions, but its physiological role at the organismal level is largely unknown. Kanemaruet al.show that phospholipase Cδ1 in the mouse epidermis influences interleukin and leukocyte concentrations in the blood.
- Kaori Kanemaru
- , Yoshikazu Nakamura
- & Kiyoko Fukami
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The CD4+ T-cell help signal is transmitted from APC to CD8+ T-cells via CD27–CD70 interactions
CD8+ memory cytotoxic T lymphocytes need help from CD4+ T cells to undergo secondary expansion but the mechanisms of help are not fully understood. Here, it is shown that, after activation by CD4+ T cells, antigen-presenting cells activate CD8+T cells via the CD70/CD27 co-stimulatory pathway.
- Sonia Feau
- , Zacarias Garcia
- & Stephen P. Schoenberger
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| Open AccessMolecular memory of prior infections activates the CRISPR/Cas adaptive bacterial immunity system
The clustered regularly interspaced short palindromic repeats (CRISPR) system protects prokaryotes from foreign DNA. Here, bacteriophage DNA containing mutations that can circumvent this response are shown to be incorporated into the CRISPR locus, allowing bacteria to remember previous infections in an adaptive manner.
- Kirill A. Datsenko
- , Ksenia Pougach
- & Ekaterina Semenova
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Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation
Inositol polyphosphate 4 phosphatase regulates phosphoinositide signalling and is associated with an increased risk of asthma. Aichet al. show that, in a mouse model of airway inflammation, calpains degrade inositol polyphosphate 4 phosphatase resulting in exacerbated phosphoinositide 3-kinase signalling.
- Jyotirmoi Aich
- , Ulaganathan Mabalirajan
- & Balaram Ghosh
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| Open AccessFasciola hepatica is associated with the failure to detect bovine tuberculosis in dairy cattle
The incidence of bovine tuberculosis in the UK is increasing despite efforts to eradicate the disease. The authors of this paper show that infection of cattle with the parasiteFasciola hepaticaimpedes the diagnosis of tuberculosis, which may in part explain why the current eradication campaign is failing.
- Jen Claridge
- , Peter Diggle
- & Diana J.L. Williams
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| Open AccessBCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway
Class switch recombination diversifies antibody effector functions and requires expression of activation-induced cytidine deaminase (AID). In this study, ligation of the B-cell receptor and Toll-like receptors synergize to induce non-canonical NF-κB activation, AID expression and class switching recombination.
- Egest J. Pone
- , Jinsong Zhang
- & Paolo Casali
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Annexin A2 binds to endosomes following organelle destabilization by particulate wear debris
Endosomes contain hydrolytic enzymes, and recent reports have suggested that the endosomal membrane can be damaged by wear particles, resulting in the release of their contents and an inflammatory response. In this study, a role for annexin II in the repair of the damaged endosome membrane is reported.
- Brian Scharf
- , Cristina C. Clement
- & Laura Santambrogio
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Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs
Human immunodeficiency virus patients who maintain low levels of virus or have undetectable levels of virus exist. In this study, the HIV found in two of these patients is shown to replicatein vitro, suggesting that host factors have a role in suppressing virus levels.
- Robert W. Buckheit III
- , Tracy G. Allen
- & Joel N. Blankson
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The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation
TLRs have a role in innate immunity and TLR4 recognizes lipopolysaccharide on the cell wall of Gram-negative bacteria. Now, Doyle and colleagues show that a transmembrane protein TMED7, similar to aDrosophilahomologue, can negatively control TLR4 signalling, suggesting a conserved role in innate immunity.
- Sarah L. Doyle
- , Harald Husebye
- & Anne F. McGettrick
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Mapping of H3N2 influenza antigenic evolution in China reveals a strategy for vaccine strain recommendation
Influenza vaccines are updated frequently to accommodate changing influenza antigenicity. Here, the authors develop a new computational method for predicting the antigenicity of H3N2 influenza strains based on the HA sequence.
- Xiangjun Du
- , Libo Dong
- & Taijiao Jiang
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| Open AccessEvidence for the stress-linked immunocompetence handicap hypothesis in humans
Testosterone-dependent traits are thought to give an honest signal of male immune function, however, the exact effects remain unclear. This study shows a positive relationship between testosterone, facial attractiveness and the immune response to a hepatitis B vaccine, which is moderated by naturally co-occurring cortisol.
- Markus J. Rantala
- , Fhionna R. Moore
- & Indrikis Krams
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Sensing of mammalian IL-17A regulates fungal adaptation and virulence
It is unclear whether pathogens can advantageously exploit the host's immune response. UsingCandida albicans, the authors show that host IL-17A binds to the fungi and induces nutrient starvation and autophagy, which eventually leads to enhanced biofilm formation and resistance to the hosts' defence.
- Teresa Zelante
- , Rossana G. Iannitti
- & Luigina Romani
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| Open AccessInterferon-γ-producing immature myeloid cells confer protection against severe invasive group A Streptococcus infections
Myeloid cells are important in the response to severe infection by invasiveStreptococcusGroup A. In this study, a distinct population of immature myeloid cells with ring shaped nuclei that produce interferon-γ are shown to be important for protection of mice against the early stages of invasive infection.
- Takayuki Matsumura
- , Manabu Ato
- & Kazuo Kobayashi
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| Open AccessModification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection
Epitopes presented by MHC-II molecules bind to T-cell receptors to activate CD4+ T cells. In this study, changes in the carboxy-terminal region of the influenza hemagglutinin epitope HA305-320alters the strength of binding to the T-cell receptor, thus modulating T-cell receptor usage and activation.
- David K. Cole
- , Kathleen Gallagher
- & Andrew Godkin
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| Open AccessRapid and adaptive evolution of MHC genes under parasite selection in experimental vertebrate populations
In vertebrates parasite-mediated selection is thought to maintain polymorphism in MHC genes where specific resistance MHC alleles increase under emerging selection. Here, experimental evidence is shown from six stickleback fish populations that varying parasite selection helps maintain MHC polymorphism.
- Christophe Eizaguirre
- , Tobias L. Lenz
- & Manfred Milinski
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| Open AccessStructure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor
Albumin transport proteins circulate in the blood and are protected from degradation by interaction with the neonatal Fc receptor. Andersenet al. investigate the albumin binding site of the neonatal Fc receptor and find pH sensitive ionic networks at the binding interface.
- Jan Terje Andersen
- , Bjørn Dalhus
- & Inger Sandlie
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A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer
The tumour microenvironment is often found to be immunosuppressive. Reppert and colleagues show that human and murine lung tumours harbour IL-17A-producing T cells, and that blocking IL-17A increases survival in mice, suggesting that anti-IL-17A therapy may be useful in treating lung cancer.
- S. Reppert
- , I. Boross
- & S. Finotto
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| Open AccessCompetition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential
The half-life of IgG is regulated by binding to the neonatal Fc receptor and, in the case of IgG3, is reduced compared to other IgG proteins. In this study, a mutation in IgG3 is shown to reduce binding to the neonatal Fc receptor, which can be competitively blocked by IgG1.
- Nigel M. Stapleton
- , Jan Terje Andersen
- & Gestur Vidarsson
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| Open AccessActivin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response
Activin is known to have a role in wound healing, but its role in skin cancer is unknown. Antsiferovaet al. show that activin is elevated in human skin tumours, and by modulating epidermal immune cells, exacerbates tumour progression in a mouse model of skin cancer.
- Maria Antsiferova
- , Marcel Huber
- & Sabine Werner
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gp96 expression in neutrophils is critical for the onset of Escherichia coli K1 (RS218) meningitis
E. coliK1 can elude the innate immune system and cause neonatal meningitis. This study shows thatE. coli K1 enters polymorphonuclear leukocytes (PMNs) using gp96 to reduce the oxidative burst, and that PMN-depleted mice are resistant to E. coliK1 infection, suggesting that PMNs permit bacterial survival in the host.
- Rahul Mittal
- & Nemani V. Prasadarao
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Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses
Parasites such as malaria elicit an immune response in their host, causing cytokine levels to increase. In this study, a parasite housekeeping gene, tyrosyl-tRNA synthetase, is shown to bind to host macrophages and, once inside the cells, enhance the levels of proinflammatory cytokines.
- Tarun Kumar Bhatt
- , Sameena Khan
- & Amit Sharma
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CD91-dependent programming of T-helper cell responses following heat shock protein immunization
Heat shock proteins bind to CD91 on antigen presenting cells, resulting in the presentation of chaperoned peptides to T cells. Here, heat shock protein binding is shown to induce phosphorylation of CD91 and stimulate the production of cytokines, thus priming various T-helper cell responses.
- Sudesh Pawaria
- & Robert J. Binder
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In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo
In response to antigens, B cells proliferate and form germinal centres before differentiating into memory B cells or long-lived plasma cells. Here, a culture method is used to expand B cells in vitro, with the ability to shift the fate of the cells between memory B cells and long-lived plasma cells.
- Takuya Nojima
- , Kei Haniuda
- & Daisuke Kitamura
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Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling
Transforming growth factor-β blocks the activation of pro-inflammatory cytokines, in part by the degradation of Myd88. This study shows that smad ubiquitin regulator proteins are shown to mediate the destruction of Myd8 and are therefore required for the anti-inflammatory effects of transforming growth factor-β.
- Youn Sook Lee
- , Jin Seok Park
- & Seok Hee Park
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Article
| Open AccessBacterial Pili exploit integrin machinery to promote immune activation and efficient blood-brain barrier penetration
Group BStreptococcuscauses meningitis in newborn infants but how the bacterium crosses the blood-brain barrier is unknown. Here, the bacterial pili adhesion molecule, PilA, is shown to bind to collagen and promote binding of the bacteria to integrins expressed on the blood-brain endothelium.
- Anirban Banerjee
- , Brandon J. Kim
- & Kelly S. Doran
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Chemotactic antiviral cytokines promote infectious apical entry of human adenovirus into polarized epithelial cells
Studying how pathogens enter polarized epithelial cells is important for understanding infection. Here, activation of chemokine receptors on the apical membrane of epithelial cells, is shown to engage Src family tyrosine signalling, resulting in relocation of the viral co-receptor αvβ3 to the apical membrane and adenovirus entry.
- Verena Lütschg
- , Karin Boucke
- & Urs F. Greber
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| Open AccessTranscription factor IRF8 directs a silencing programme for TH17 cell differentiation
The molecular mechanisms that regulate TH17 cell diversity are poorly understood. Ouyang et al. show that the transcription factor interferon regulatory factor-8 is required for TH17-cell differentiation and that its absence increases the severity of an experimental model of colitis.
- Xinshou Ouyang
- , Ruihua Zhang
- & Huabao Xiong
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| Open AccessUnidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells
Exosomes released from cells can transfer RNA to recipient cells. In this study, the authors demonstrate that microRNAs in exosomes from T cells can be transferred to antigen-presenting cells during immune synapsis, and that this can alter gene expression, suggesting a new form of cellular communication.
- María Mittelbrunn
- , Cristina Gutiérrez-Vázquez
- & Francisco Sánchez-Madrid
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| Open AccessThe nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells
Regulatory T cells are characterized by the expression of Foxp3, however, how the expression of this protein is controlled is unclear. Here, the authors show that the nuclear orphan receptor, Nr4a2, is a transcriptional activator of Foxp3, and suggest that it is required for the function of regulatory T cells.
- Takashi Sekiya
- , Ikkou Kashiwagi
- & Akihiko Yoshimura
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| Open AccessThe deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility
Deubiquitinating enzymes are involved in multiple cellular processes, including cell viability. The authors reveal a role for the deubiquitinating enzyme, USP17, in the migration of cells in response to chemokines and show that USP17 is required for the relocalization of GTPases involved in cell motility.
- Michelle de la Vega
- , Alyson A. Kelvin
- & James A. Johnston
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| Open AccessInflammation driven by tumour-specific Th1 cells protects against B-cell cancer
Inflammation can result in the formation of tumours, but the immune system is also involved in the elimination of cancer cells. Here, the authors show that inflammation driven by tumour-specific CD4+T cells results in tumour regression and identify a list of cytokines associated with cancer prevention.
- Ole Audun Werner Haabeth
- , Kristina Berg Lorvik
- & Alexandre Corthay
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| Open AccessProstaglandin E2 and SOCS1 have a role in intestinal immune tolerance
The gut is populated by a myriad of microorganisms and how the immune system tolerates their presence is of great interest. Here, by studying colon morphology in multiple knockout mice, the authors demonstrate a potential role for prostaglandin E2 and SOCS1 in mediating immune tolerance.
- Takatoshi Chinen
- , Kyoko Komai
- & Akihiko Yoshimura
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Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions
ThePlasmodium falciparum parasite that causes malaria has a complex life cycle in human erythrocytes. Using time-lapse three-dimensional imaging, the authors show the intraerythrocytic stages of the parasite and provide new insight into the export of P. falciparumproteins to Maurer's clefts.
- Christof Grüring
- , Arlett Heiber
- & Tobias Spielmann
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