ResearchPad - 311 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma]]> https://www.researchpad.co/article/N6caa7ca8-11eb-46b1-8fa5-5c06a6cb1ad6 Summary: Inflammation and Caspase-a activation occur early in a new zebrafish model for fibrolamellar carcinoma (FLC). Pharmacological inhibition of TNFα secretion and caspase-1 might be useful approaches to treat FLC patients.

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<![CDATA[Genetic background modifies phenotypic severity and longevity in a mouse model of Niemann-Pick disease type C1]]> https://www.researchpad.co/article/N7750ad3e-39e7-4c02-947f-3e6b164680f9

ABSTRACT

Niemann-Pick disease type C1 (NPC1) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. NPC1 is extremely heterogeneous in the timing of clinical presentation and is associated with a wide spectrum of causative NPC1 mutations. To study the genetic architecture of NPC1, we have generated a new NPC1 mouse model, Npc1em1Pav. Npc1em1Pav/em1Pav mutants showed notably reduced NPC1 protein compared to controls and displayed the pathological and biochemical hallmarks of NPC1. Interestingly, Npc1em1Pav/em1Pav mutants on a C57BL/6J genetic background showed more severe visceral pathology and a significantly shorter lifespan compared to Npc1em1Pav/em1Pav mutants on a BALB/cJ background, suggesting that strain-specific modifiers contribute to disease severity and survival. QTL analysis for lifespan of 202 backcross N2 mutants on a mixed C57BL/6J and BALB/cJ background detected significant linkage to markers on chromosomes 1 and 7. The discovery of these modifier regions demonstrates that mouse models are powerful tools for analyzing the genetics underlying rare human diseases, which can be used to improve understanding of the variability in NPC1 phenotypes and advance options for patient diagnosis and therapy.

This article has an associated First Person interview with the first author of the paper.

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<![CDATA[Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2]]> https://www.researchpad.co/article/N47ae0984-aed2-400d-b024-8d4692148a59

Cytokines and lipid mediators are key regulators of inflammation; but how they are mechanistically linked is poorly understood. Here, Mukhopadhyay et al. show a novel regulation between cytokine IL-10 and lipid mediator PGE2 that functionally connects them to intestinal inflammation.

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<![CDATA[Cartilage-binding antibodies induce pain through immune complex–mediated activation of neurons]]> https://www.researchpad.co/article/Na7860b3f-5167-4c8c-8256-a5dd2ac68b04

This work elucidates a novel pain mechanism generated by rheumatoid arthritis–associated autoantibodies, uncoupled from inflammation, that is dependent on immune complex formation and activation of neuronal FcγRI.

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<![CDATA[Inherited IL-18BP deficiency in human fulminant viral hepatitis]]> https://www.researchpad.co/article/Ne7f3a1f6-1e5b-4764-8b97-962cbded256d

We report autosomal recessive IL-18BP deficiency in a child who died of fulminant hepatitis upon infection with hepatitis A virus. Deficiency of IL-18BP leads to excessive IL-18 activity and uncontrolled IL-18–mediated hepatotoxicity in the infected liver.

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<![CDATA[C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa]]> https://www.researchpad.co/article/N37fbb268-48e3-483d-9cdd-12ba39f6fa75

Silverman et al. demonstrate that complement activation features prominently in retinitis pigmentosa in close association with activated microglia. This response mediates adaptive neuroprotection for photoreceptors by facilitating a C3-CR3–dependent clearance of apoptotic photoreceptors by microglial phagocytosis.

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<![CDATA[The complex of MCMV proteins and MHC class I evades NK cell control and drives the evolution of virus-specific activating Ly49 receptors]]> https://www.researchpad.co/article/N989f348c-e147-4453-b328-a46bf1b383d8

Železnjak et al. demonstrate that two MCMV-encoded proteins interact with MHC I molecules, forming an altered-self complex that prevents missing self recognition by increasing specificity for inhibitory Ly49 receptors. This led to the evolution of CMV-specific activating Ly49s.

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<![CDATA[Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata]]> https://www.researchpad.co/article/N98398ef1-8133-4435-8d86-ad6f1eeed180

ABSTRACT

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13C6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted.

This article has an associated First Person interview with the joint first authors of the paper.

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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[ARID5B regulates metabolic programming in human adaptive NK cells]]> https://www.researchpad.co/article/5c910796d5eed0c4841a459f

“Adaptive” NK cells expressing the activating receptor NKG2C expand and persist in HCMV-seropositive individuals. Cichocki et al. demonstrate enhanced oxidative and glycolytic metabolism for adaptive NK cells and implicate ARID5B as an important regulator of mitochondrial metabolism, IFN-γ production, and survival.

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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[NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation]]> https://www.researchpad.co/article/5c69eca8d5eed0c48414e0ca

Kimura et al. demonstrate that NQO1 plays a crucial role in degrading IκB-ζ protein through forming the complex together with PDLIM2 and selectively suppresses IL-6 and IL-12 production induced by TLR ligands.

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<![CDATA[ICAM-1 controls development and function of ILC2]]> https://www.researchpad.co/article/5c69ecaad5eed0c48414e0f3

ILC2s are key players in allergic airway inflammation. Lei et al. show that ICAM-1 controls ILC2 development and function through regulating ERK signaling pathway, suggesting targeting ICAM-1 as a potential strategy for ILC2-induced asthma.

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<![CDATA[CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis]]> https://www.researchpad.co/article/5c69ecb8d5eed0c48414e26b

Deregulated NF-κB activation is linked to immunological disorders. Huang et al. revealed CRL4DCAF2 as a negative regulator in controlling NIK stability in DCs. Lower level of DCAF2 is associated with noncanonical NF-κB activation and hyperproduction of IL-23 in psoriasis patients.

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<![CDATA[Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection]]> https://www.researchpad.co/article/5c36838cd5eed0c4841f417d

This study demonstrates that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is essential during Mycobacterium tuberculosis infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection.

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<![CDATA[A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival]]> https://www.researchpad.co/article/5c36838ad5eed0c4841f4116

A20 (TNFAIP3) and ABIN-1 (TNIP1), two candidate inflammatory bowel disease (IBD) susceptibility genes, preserve intestinal homeostasis by cooperatively restricting intestinal epithelial cell death. A20 and ABIN-1 synergistically restrict both TNF-dependent and TNF-independent cell death.

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<![CDATA[MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation]]> https://www.researchpad.co/article/5c01f8dad5eed0c4842bef61

Singh et al. examined microRNA expression and physiological requirements in type 2 innate lymphoid cells (ILC2s). The miR-17∼92 cluster promotes ILC2 growth, cytokine expression, and function in allergic inflammation.

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<![CDATA[Mast cells acquire MHCII from dendritic cells during skin inflammation]]> https://www.researchpad.co/article/5c01f8c2d5eed0c4842bea6c

Dudeck et al. demonstrate that inflammatory conditions induce dynamic interactions between mast cells (MCs) and dendritic cells (DCs) culminating in protein exchange. Resident MCs are equipped with DC MHCII and empowered to initiate T cell–driven inflammation during migration-based DC absence.

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