ResearchPad - brief-definitive-report https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis]]> https://www.researchpad.co/article/elastic_article_15300 Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in SFTPA1 promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.

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<![CDATA[Interstitial-resident memory CD8<sup>+</sup> T cells sustain frontline epithelial memory in the lung]]> https://www.researchpad.co/article/elastic_article_15299

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<![CDATA[Selective inhibition of low-affinity memory CD8<sup>+</sup> T cells by corticosteroids]]> https://www.researchpad.co/article/elastic_article_15298

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<![CDATA[Modulation of the fungal mycobiome is regulated by the chitin-binding receptor FIBCD1]]> https://www.researchpad.co/article/elastic_article_15294 Host–microbiota interactions are critical in regulating mammalian health and disease. In addition to bacteria, parasites, and viruses, beneficial communities of fungi (the mycobiome) are important modulators of immune- and tissue-homeostasis. Chitin is a major component of the fungal cell wall, and fibrinogen C containing domain 1 (FIBCD1) is a chitin-binding protein; however, the role of this molecule in influencing host–mycobiome interactions in vivo has never been examined. Here, we identify direct binding of FIBCD1 to intestinal-derived fungi and demonstrate that epithelial-specific expression of FIBCD1 results in significantly reduced fungal colonization and amelioration of fungal-driven intestinal inflammation. Collectively, these results identify FIBCD1 as a previously unrecognized microbial pattern recognition receptor through which intestinal epithelial cells can recognize and control fungal colonization, limit fungal dysbiosis, and dampen intestinal inflammation.

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<![CDATA[CXCR4 regulates Plasmodium development in mouse and human hepatocytes]]> https://www.researchpad.co/article/Ncc76c91f-2728-4c8b-91aa-a4526850f910

In the livers of Plasmodium-infected mammalian hosts, the rod-shaped mosquito-stage parasites develop into spherical exoerythrocytic forms, subsequently forming the erythrocyte-stage parasites and eventually causing malaria. Here, Bando et al. identify CXCR4 as a host factor for Plasmodium liver-stage development.

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<![CDATA[Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation]]> https://www.researchpad.co/article/5c91078dd5eed0c4841a44d1

Lee et al. generate knock-in mice with critical residues mutated in caspase-11 and GSDMD. This is the first compelling genetic evidence to demonstrate the critical roles of caspase-11 catalytic and auto-proteolytic activities, as well as GSDMD cleavage in a physiological response to LPS.

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<![CDATA[TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease]]> https://www.researchpad.co/article/5c910791d5eed0c4841a454a

Chakrabarty et al. show that human TLR5 ectodomain reduces amyloid β (Aβ) plaques by direct interaction with Aβ, demonstrating the feasibility of such immune decoy receptor strategies as potential biotherapies in Alzheimer’s disease.

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<![CDATA[Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau]]> https://www.researchpad.co/article/5c9107a0d5eed0c4841a4670

Microglia are central players in homeostasis and disease. Kang et al. reveal a novel ApoE-driven microglial pathway shared between aging, amyloidosis, and tauopathy that is exacerbated in females, suggesting a convergent mechanism for altering microglial reactivity during Alzheimer’s disease.

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<![CDATA[Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells]]> https://www.researchpad.co/article/5c910798d5eed0c4841a45bb

Transcriptional control of dendritic cell (DC) functions is poorly understood. Lau, Tiniakou, et al. report that transcription factor ETV6 optimizes gene expression in DCs and facilitates their ability to cross-prime T cells and initiate tumor-specific immune responses.

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<![CDATA[Effector CD4 T cells with progenitor potential mediate chronic intestinal inflammation]]> https://www.researchpad.co/article/5c368393d5eed0c4841f42b9

Effector CD4 T cells with progenitor properties are present during chronic intestinal inflammation, and these cells support the maintenance of disease. The expression of the glycosyltransferase ST6Gal-I by these cells promotes cell survival and TCF1 levels.

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<![CDATA[Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury]]> https://www.researchpad.co/article/5c368391d5eed0c4841f4257

Norris et al. show that microglia are the key phagocytes in removal of synaptic debris in the dorsal lateral geniculate nucleus after optic nerve injury. This microglial function is dependent on recognition of neurodegeneration and is mediated by the complement system.

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<![CDATA[The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination]]> https://www.researchpad.co/article/5c368388d5eed0c4841f40ba

The balance between inflammatory IFN-γ and antiinflammatory IL-10 plays a critical role in modulating type 1 immune responses. Yu et al. show that the transcription factor Bhlhe40 serves as a molecular switch between inflammatory and antiinflammatory Th1 cells.

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<![CDATA[Human stem cell–derived astrocytes replicate human prions in a PRNP genotype–dependent manner]]> https://www.researchpad.co/article/5c01f8c3d5eed0c4842beac0

Krejciova et al. present the first study demonstrating that CJD prions infect human stem cell–derived astrocytes in vitro. This provides a physiologically relevant model for discovery of key molecular pathogenic events of CJD and facilitates the development of future therapies.

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<![CDATA[R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease]]> https://www.researchpad.co/article/5c01f8d2d5eed0c4842bedad

Hayase et al. show that R-Spondin1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spondin1 or recombinant α-defensin prevents dysbiosis mediated by graft-versus-host disease, representing a novel approach to restore intestinal ecosystems and homeostasis.

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<![CDATA[USP1–UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses]]> https://www.researchpad.co/article/5c01f8cdd5eed0c4842becb0

TBK1 is a critical kinase required for the induction of type I IFNs and subsequent cellular antiviral responses. Yu et al. show that USP1–UAF1 deubiquitinase complex removes K48-linked polyubiquitination of TBK1, stabilizes its expression, and thus enhances antiviral responses.

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<![CDATA[A nonimmune function of T cells in promoting lung tumor progression]]> https://www.researchpad.co/article/5c01f8cfd5eed0c4842bed02

Green et al. find that T cell–derived amphiregulin facilitates lung tumor progression seemingly independently of the immune response, suggesting that T cells can promote tumor growth through the production of factors normally associated with tissue repair.

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<![CDATA[Identification and characterization of T reg–like cells in zebrafish]]> https://www.researchpad.co/article/5c01f8c7d5eed0c4842beb82

Kasheta et al. report the identification of T reg–like cells in zebrafish, a means to track and live-image these cells, and foxp3a-deficient mutants that display lymphoproliferation, severe inflammation, and other hallmarks of T reg deficiency syndromes.

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<![CDATA[Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene]]> https://www.researchpad.co/article/5c01f8d6d5eed0c4842bee95

The molecular mechanisms that regulate AID mutator activity at off-target genes are not well characterized. Mu et al. show AID phosphorylation dynamically controls activity at Myc and other sites. Pharmacological induction of AID phosphorylation leads to increased mutations, double strand breakss and translocations.

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<![CDATA[A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome]]> https://www.researchpad.co/article/5c01f8c9d5eed0c4842bebeb

Pierce et al. describe a pediatric patient with a fatal systemic capillary leak syndrome (Clarkson’s disease). They identify a point mutation in p190BRhoGAP and show that patient-derived microvascular endothelial cells show prolonged activation RhoB that correlates with impaired barrier recovery after treatment with TNF compared with control cultures.

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