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•New method for insertion of large diameter pins in prepreg composite laminates.•Conical leading-edge pins exhibit low insertion force with better insertion quality.•Insertion forces ...increase exponentially with pin diameter.•Prepreg stack consolidation improves insertion quality by reducing tow distortions.
Existing Through-Thickness Reinforcement (TTR) methods for laminated composites using semi or fully rigid reinforcing elements, like tufting, stitching, and z-pinning, present limitations on reinforcing element geometry, strength, and stiffness. Where these application envelopes are exceeded, TTR element insertion results in unacceptable levels of damage to both the composite and/or TTR elements. Here, we demonstrate that low-speed insertion of rigid reinforcements into heated prepreg preforms is a feasible and robust reinforcement process capable of providing accurate TTR element placement with minimal tow disturbance compared with existing methods for similar pin sizes. The insertion process is characterised with respect to insertion forces, and mesoscale laminate deformation/damage for carbon-benzoxazine prepreg preforms. The research investigates the influence of pin leading edge on insertion for a range of pin diameters (1.2, 1.5, and 2.0 mm) and preform consolidation states, describing low insertion forces and good quality laminate preforms. Insertion forces increase with pin diameter, typically resulting from increased pin-tow contact area and friction. Large diameter sizes and low insertion forces expand the range and forms of materials that can be inserted compared to existing TTR methods and show that this method can potentially be transferred to benefit work on composite hole creation, joining, and repair.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Innate immune sensing of influenza A virus (IAV) induces activation of various immune effector mechanisms, including the nucleotide and oligomerization domain, leucine-rich repeat-containing protein ...family, pyrin domain containing 3 (NLRP3) inflammasome and programmed cell death pathways. Although type I IFNs are identified as key mediators of inflammatory and cell death responses during IAV infection, the involvement of various IFN-regulated effectors in facilitating these responses are less studied. In this study, we demonstrate the role of IFN regulatory factor (IRF)1 in promoting NLRP3 inflammasome activation and cell death during IAV infection. Both inflammasome-dependent responses and induction of apoptosis and necroptosis are reduced in cells lacking IRF1 infected with IAV. The observed reduction in inflammasome activation and cell death in IRF1-deficient cells during IAV infection correlates with reduced levels of Z-DNA binding protein 1 (ZBP1), a key molecule mediating IAV-induced inflammatory and cell death responses. We further demonstrate IRF1 as a transcriptional regulator of ZBP1. Overall, our study identified IRF1 as an upstream regulator of NLRP3 inflammasome and cell death during IAV infection and further highlights the complex and multilayered regulation of key molecules controlling inflammatory response and cell fate decisions during infections.
Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in proinflammatory cytokine production. Both ...microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3, resulting in caspase-1 activation and production of proinflammatory cytokines IL-1β and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1 were resistant to the development of high-fat diet-induced obesity, which correlated with protection from obesity-induced insulin resistance. Furthermore, hepatic triglyceride content, adipocyte size, and macrophage infiltration in adipose tissue were all reduced in mice deficient in inflammasome components. Monocyte chemoattractant protein (MCP)-1 is a key molecule that mediates macrophage infiltration. Indeed, defective inflammasome activation was associated with reduced MCP-1 production in adipose tissue. Furthermore, plasma leptin and resistin that affect energy use and insulin sensitivity were also changed by inflammasome-deficiency. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance, and suggest inhibition of the inflammasome as a potential therapeutic strategy.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain ...unclear. Here we found that the transcription factor IRF1 was required for activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for sensing by AIM2 depending on the pathogen encountered by the cell.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Human astroviruses (HAstV), positive sense single-stranded RNA viruses, are one of the leading causes of diarrhea worldwide. Despite their high prevalence, the cellular mechanisms of astrovirus ...pathogenesis remain ill-defined. Previous studies showed HAstV increased epithelial barrier permeability by causing a re-localization of the tight junction protein, occludin. In these studies, we demonstrate that HAstV replication induces epithelial-mesenchymal transition (EMT), by upregulating the transcription of EMT-related genes within 8 hours post-infection (hpi), followed by the loss of cell-cell contacts and disruption of polarity by 24 hpi. While multiple classical HAstV serotypes, including clinical isolates, induce EMT, the non-classical genotype HAstV-VA1 and two strains of reovirus are incapable of inducing EMT. Unlike the re-localization of tight junction proteins, HAstV-induced EMT requires productive replication and is dependent transforming growth factor-β (TGF-β) activity. Finally, inhibiting TGF-β signaling and EMT reduces viral replication, highlighting its importance in the viral life cycle. This finding puts classical strains of HAstV-1 in an exclusive group of non-oncogenic viruses triggering EMT.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fungi represent a significant proportion of the gut microbiota. Aberrant immune responses to fungi are frequently observed in inflammatory bowel diseases (IBD) and colorectal cancer (CRC), and ...mutations in the fungal-sensing pathways are associated with the pathogenesis of IBD. Fungal recognition receptors trigger downstream signaling via the common adaptor protein CARD9 and the kinase SYK. Here we found that commensal gut fungi promoted inflammasome activation during AOM-DSS-induced colitis. Myeloid cell-specific deletion of Card9 or Syk reduced inflammasome activation and interleukin (IL)-18 maturation and increased susceptibility to colitis and CRC. IL-18 promoted epithelial barrier restitution and interferon-γ production by intestinal CD8+ T cells. Supplementation of IL-18 or transfer of wild-type myeloid cells reduced tumor burden in AOM-DSS-treated Card9−/− and Sykfl/flLysMCre/+ mice, whereas treatment with anti-fungal agents exacerbated colitis and CRC. CARD9 deletion changes the gut microbial landscape, suggesting that SYK-CARD9 signaling maintains a microbial ecology that promotes inflammasome activation and thereby restrains colitis and colon tumorigenesis.
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•Commensal gut fungi contribute to inflammasome activation during experimental colitis•Microbial landscape is altered in Card9−/− mice•Defective inflammasome activation, IL-18 maturation in myeloid cells lacking CARD9 or SYK•Metronidazole treatment protects Card9−/− and SykLysM mice from colon tumorigenesis
Fungi represent a significant proportion of the gut microbiota, but how anti-fungal immunity contributes to tumor-promoting inflammatory responses is unclear. Malik et al. find that recognition of commensal gut fungi, sensed via the Card9-Syk signaling axis, is protective in the context of inflammation-associated cancer. IL-18 maturation downstream of inflammasome activation promotes epithelial barrier restitution and IFN-γ production by intestinal CD8+ T cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Regulatory T (T
reg
) cells derived from the thymus (tT
reg
) and periphery (pT
reg
) have central and distinct functions in immunosuppression, but mechanisms for the generation and ...activation of T
reg
subsets in vivo are unclear. Here, we show that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tT
reg
and pT
reg
cells. mTOR signaling is crucial for programming activated T
reg
-cell function to protect immune tolerance and tissue homeostasis. T
reg
-specific deletion of mTOR drives spontaneous effector T-cell activation and inflammation in barrier tissues and is associated with reduction in both thymic-derived effector T
reg
(eT
reg
) and pT
reg
cells. Mechanistically, mTOR functions downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, deletion of mitochondrial transcription factor A (Tfam) severely impairs T
reg
-cell suppressive function and eT
reg
-cell generation. Collectively, our results show that mTOR coordinates transcriptional and metabolic programs in activated T
reg
subsets to mediate tissue homeostasis.
Inflammasome activation is critical for host defenses against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) ...components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here, we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes. IRF8 governs the transcription of Naips to allow detection of flagellin or T3SS proteins to mediate NLRC4 inflammasome activation. Furthermore, we found that IRF8 confers protection against bacterial infection in vivo, owing to its role in inflammasome-dependent cytokine production and pyroptosis. Altogether, our findings suggest that IRF8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection.
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•IRF8 is required for the optimal activation of NLRC4 inflammasome•The expression of Naip1, Naip2, Naip5, and Naip6 is dependent on IRF8•IRF8 is dispensable for the activation of NLRP3, AIM2, and Pyrin inflammasomes•Irf8–/– mice are susceptible to S. Typhimurium and B. thailandensis infection
Optimal activation of NLRC4 inflammasome in response to pathogenic bacteria is dependent on IRF8.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the ...pro-inflammatory cytokines IL-1β and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria. IRGB10 directly targeted cytoplasmic bacteria through a mechanism requiring guanylate-binding proteins. Localization of IRGB10 to the bacterial cell membrane compromised bacterial structural integrity and mediated cytosolic release of ligands for recognition by inflammasome sensors. Overall, our results reveal IRGB10 as part of a conserved signaling hub at the interface between cell-autonomous immunity and innate immune sensing pathways.
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•IRGB10 is required for activation of multiple inflammasomes by bacteria•Recruitment of IRGB10 to the bacteria is dependent on GBPs•IRGB10 targeted bacterial cell membrane and mediated bacterial killing•IRGB10 liberated ligands and provided a conserved signaling hub for inflammasomes
Finding the route to the cytoplasm: an interferon-inducible protein localizes to the cell membrane of bacteria, compromising its structural integrity and mediating release of ligands, otherwise inaccessible, for sensing by inflammasomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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