The turnover and clearance of cells is an essential process that is part of many physiological and pathological processes. Improper or deficient clearance of apoptotic cells can lead to excessive ...inflammation and autoimmune disease. The steps involved in cell clearance include: migration of the phagocyte toward the proximity of the dying cells, specific recognition and internalization of the dying cell, and degradation of the corpse. The ability of phagocytes to recognize and react to dying cells to perform efficient and immunologically silent engulfment has been well-characterized in vitro and in vivo. However, how apoptotic cells themselves initiate the corpse removal and also influence the cells within the neighboring environment during clearance was less understood. Recent exciting observations suggest that apoptotic cells can attract phagocytes through the regulated release of 'find-me' signals. More recent studies also suggest that these find-me signals can have additional roles outside of phagocyte attraction to help orchestrate engulfment. This review will discuss our current understanding of the different find-me signals released by apoptotic cells, how they may be relevant in vivo, and their additional roles in facilitating engulfment.
The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a ...pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.
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•Two trivalent adenoviral-vectored COVID-19 vaccines were developed and evaluated•Intranasal, but not intramuscular, immunization induces tripartite mucosal immunity•Intranasal immunization protects against ancestral and variant strains of SARS-CoV-2•Optimal protection requires B and T cell immunity and trained innate immunity
Respiratory mucosal immunization with a next-generation adenoviral-vectored trivalent COVID-19 vaccine expressing spike, nucleocapsid, and RdRp antigens, induces all-around protective mucosal immunity against SARS-CoV-2 via induction of systemic and local antibodies, lung-tissue-resident memory T cells, and trained alveolar macrophages.
A large body of evidence has shown that treatments that interfere with memory consolidation become ineffective when animals are subjected to an intense learning experience; this effect has been ...observed after systemic and local administration of amnestic drugs into several brain areas, including the striatum. However, the effects of amnestic treatments on the process of extinction after intense training have not been studied. Previous research demonstrated increased spinogenesis in the dorsomedial striatum, but not in the dorsolateral striatum after intense training, indicating that the dorsomedial striatum is involved in the protective effect of intense training. To investigate this issue, male Wistar rats, previously trained with low, moderate, or high levels of foot shock, were used to study the effect of tetrodotoxin inactivation of dorsomedial striatum on memory consolidation and subsequent extinction of inhibitory avoidance. Performance of the task was evaluated during seven extinction sessions. Tetrodotoxin produced a marked deficit of memory consolidation of inhibitory avoidance trained with low and moderate intensities of foot shock, but normal consolidation occurred when a relatively high foot shock was used. The protective effect of intense training was long-lasting, as evidenced by the high resistance to extinction exhibited throughout the extinction sessions. We discuss the possibility that increased dendritic spinogenesis in dorsomedial striatum may underly this protective effect, and how this mechanism may be related to the resilient memory typical of post-traumatic stress disorder (PTSD).
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•The granite sludge has been used as SCM in the design of the new blended cements.•Granite quarry dust exhibits no alkali-silica reactivity.•Binder bearing 20% granite quarry dust are low heat ...cements.•The new cements are apt for aesthetically sensitive applications.•The new blended cements have good durable behaviour.
Cements prepared to new designs in which different types of waste are used as additions must be tested for mechanical strength and durability to ensure their performance will be satisfactory throughout their service life. This study explored the effect of adding 10% or 20% granite quarry dust to cement on properties such as transport (total and capillary water absorption and electrical resistivity), dimensional stability (drying shrinkage and expansion), the alkali-silica reaction, heat of hydration and colour. No alkali-silica reaction was observed in the new materials and expansion and contraction were less intense than in conventional cement. The water absorption and capillary absorption coefficients rose less in the additioned cements than the replacement ratio, whilst their higher resistivity values afforded greater corrosion protection than found in the reference. The inclusion of this waste also prompted a rise in lightness and a decline in peak heat of hydration. The multivariate analysis of variance (MANOVA) conducted showed that the factors time and replacement ratio affected the properties significantly, whereas the combined effect of the two was statistically significant or otherwise depending on the property analysed. The findings showed that the partial replacement of cement with quarry dust is not detrimental to product durability and the recycled material qualifies as a strength class 42.5, type II/A binder. The materials bearing 20% granite quarry dust, in turn, were found to meet the requirements to qualify as low heat cements (CEM II/A LH).
Thrombosis is a common, life-threatening consequence of systemic infection; however, the underlying mechanisms that drive the formation of infection-associated thrombi are poorly understood. Here, ...using a mouse model of systemic Salmonella Typhimurium infection, we determined that inflammation in tissues triggers thrombosis within vessels via ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin exposed to the vasculature following breaching of the vessel wall. During infection, mice developed thrombi that persisted for weeks within the liver. Bacteria triggered but did not maintain this process, as thrombosis peaked at times when bacteremia was absent and bacteria in tissues were reduced by more than 90% from their peak levels. Thrombus development was triggered by an innate, TLR4-dependent inflammatory cascade that was independent of classical glycoprotein VI-mediated (GPVI-mediated) platelet activation. After infection, IFN-γ release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-γ, or depletion of monocytic-lineage cells or CLEC-2 on platelets markedly inhibited the process. Together, our data indicate that infection-driven thrombosis follows local inflammation and upregulation of podoplanin and platelet activation. The identification of this pathway offers potential therapeutic opportunities to control the devastating consequences of infection-driven thrombosis without increasing the risk of bleeding.
To determine the clinical profile of axial psoriatic arthritis (PsA) in a worldwide setting. Secondly, to identify factors associated with the development of axial involvement in patients with PsA.
...Data from 3684 patients with axial spondyloarthritis (axSpA) or PsA from the ASAS-perSpA study were analysed. The ASAS-perSpA is a cross-sectional study that recruited consecutive patients with SpA (as diagnosed by their rheumatologist) from 68 centers worldwide and collected patient and disease data. First, 2651 axSpA patients and 367 PsA patients with any history of axial involvement (axPsA) were compared using logistic regression to later identify predictive factors for rheumatologist diagnosis of axPsA. Secondly, 367 axPsA patients were compared with 666 PsA patients lacking axial involvement (peripheral PsA pPsA) and the characteristics associated with axial manifestations were explored by logistic regression analysis.
Patients with axPsA were older and less frequently males or HLA*B27 positive in comparison with axSpA patients. Additionally, while patients with axPsA had more peripheral manifestations and psoriasis, other extra-musculoskeletal manifestations (IBD and uveitis) were more frequent in those with axSpA. In the multivariable analysis, older age at diagnosis (OR = 1.04), peripheral arthritis (OR = 7.32) and dactylitis (OR = 2.82) were significantly associated with the diagnosis of axPsA. However, uveitis (OR = 0.22), IBD (OR = 0.12), HLA*B27 carriership (OR = 0.26) or sacroiliitis on imaging (OR = 0.5) were inversely associated with axPsA diagnosis as compared to axSpA. Axial involvement in patients with PsA was significantly associated with male gender (OR = 1.68), elevated CRP (OR = 2.87) and the absence of psoriasis (OR = 0.33).
In this worldwide setting axPsA was defined by rheumatologists as a unique phenotype, with disease features lying between axSpA and pure pPsA.
Tissue injury induces a long‐lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ‐opioid receptor (MOR) constitutive activity. To test the ...hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited 3 weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or β‐funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous opioid dependence, respectively. In naïve or sham controls, systemic naloxone (3 mg/kg) produced conditioned place aversion, and systemic naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In LS animals tested 3 weeks after plantar incision, systemic naltrexone reinstated mechanical hypersensitivity and produced an even greater increase in Fos than in sham controls, particularly in the capsular subdivision of the right CeA. One third of Fos+ profiles co‐expressed protein kinase C delta (PKCδ), and 35% of PKCδ neurons co‐expressed tdTomato+ in Oprm1Cre::tdTomato transgenic mice. CeA microinjection of naltrexone (1 µg) reinstated mechanical hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra‐CeA injection of the MOR‐selective inhibitor CTAP (300 ng) reinstated hypersensitivity in both male and female mice. We conclude that MORs in the capsular subdivision of the right CeA prevent the transition from acute to chronic postoperative pain.
Incision causes neuronal sensitization and acute postoperative pain. After injury resolves, endogenous µ‐opioid receptor (MOR) signaling in the central nucleus of the amygdala (CeA) suppresses latent pain sensitization. Inhibiting MOR signaling, either systemically or within the CeA, unmasks latent sensitization, leading to reinstatement of hypersensitivity.
► The ceramic waste analysed from the sanitary ware industry. ► This waste is used as a coarse aggregate in the manufacture of concretes. ► The mechanical behaviour of these concretes is better than ...convectional concretes. ► ITZ of the new aggregate/paste is more compact and stable than natural aggregate. ► The new aggregate does not interfere in the microstructure of recycled concretes.
Due to its physical, chemical and mechanical properties, the waste inevitably generated by the ceramic sanitary ware industry can be used in the production of concrete. This article reports the possibility of substituting 15%, 20% and 25% of natural coarse aggregate with recycled ceramic coarse aggregate, and presents an analysis of the resultant effects on the morphology and microstructure of recycled concretes, and consequently, on the mechanical behaviour of these ecoefficient concretes. The results demonstrate that ceramic waste does not interfere in either the hydration process or in the morphology of the hydrated products. The microstructure present in the interfacial transition zone (ITZ) of the recycled aggregate–paste is more compact and stable than that of the natural aggregate–paste. As regards mechanical behaviour, it was observed that as the percentage of substitution rose, the compressive strength of these concretes improved.
Lipopolysaccharide (LPS) O-antigen (O-Ag) is known to limit antibody binding to surface antigens, although the relationship between antibody, O-Ag and other outer-membrane antigens is poorly ...understood. Here we report, immunization with the trimeric porin OmpD from Salmonella Typhimurium (STmOmpD) protects against infection. Atomistic molecular dynamics simulations indicate this is because OmpD trimers generate footprints within the O-Ag layer sufficiently sized for a single IgG Fab to access. While STmOmpD differs from its orthologue in S. Enteritidis (SEn) by a single amino-acid residue, immunization with STmOmpD confers minimal protection to SEn. This is due to the OmpD-O-Ag interplay restricting IgG binding, with the pairing of OmpD with its native O-Ag being essential for optimal protection after immunization. Thus, both the chemical and physical structure of O-Ag are key for the presentation of specific epitopes within proteinaceous surface-antigens. This enhances combinatorial antigenic diversity in Gram-negative bacteria, while reducing associated fitness costs.
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