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"Shepherd, Dawn"
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The Oxford handbook of the archaeology of childhood
Real understanding of past societies is not possible without including children, and yet they have been strangely invisible in the archaeological record. Compelling explanation about past societies cannot be achieved without including and investigating children and childhood.00However marginal the traces of children's bodies and bricolage may seem compared to adults, archaeological evidence of children and childhood can be found in the most astonishing places and spaces. The archaeology of childhood is one of the most exciting and challenging areas for new discovery about past societies. Children are part of every human society, but childhood is a cultural construct. Each society develops its own idea about what a childhood should be, what children can or should do, and how they are trained to take their place in the world. Children also play a part in creating the archaeological record itself.
Book
MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live
Salmonella enterica
serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.
Most MAIT cell response to infection studies are of mice. Here the authors characterize MAIT cell population responses to
Salmonella
Paratyphi A infection of 25 human volunteers using TCR clonotype analysis and mass cytometry of pre-infection matched to post-infection samples.
Journal Article
Essential role for autophagy during invariant NKT cell development
Significance Autophagy is an evolutionarily conserved catabolic process essential to maintaining cellular homeostasis through the breakdown and recycling of damaged organelles and long-lived proteins. We report that autophagy plays an essential cell-intrinsic role in maintaining the survival of a subset of innate-like cells known as invariant natural killer T (iNKT) cells. Autophagy deficiency prevents transition to a quiescent state after population expansion of thymic iNKT cells. Hence, autophagy-deficient iNKT cells accumulate mitochondria and oxygen radicals and subsequently die of apoptosis.
Autophagy is an evolutionarily conserved cellular homeostatic pathway essential for development, immunity, and cell death. Although autophagy modulates MHC antigen presentation, it remains unclear whether autophagy defects impact on CD1d lipid loading and presentation to invariant natural killer T (iNKT) cells and on iNKT cell differentiation in the thymus. Furthermore, it remains unclear whether iNKT and conventional T cells have similar autophagy requirements for differentiation, survival, and/or activation. We report that, in mice with a conditional deletion of the essential autophagy gene Atg7 in the T-cell compartment (CD4 Cre-Atg7 ⁻/⁻), thymic iNKT cell development—unlike conventional T-cell development—is blocked at an early stage and mature iNKT cells are absent in peripheral lymphoid organs. The defect is not due to altered loading of intracellular iNKT cell agonists; rather, it is T-cell–intrinsic, resulting in enhanced susceptibility of iNKT cells to apoptosis. We show that autophagy increases during iNKT cell thymic differentiation and that it developmentally regulates mitochondrial content through mitophagy in the thymus of mice and humans. Autophagy defects result in the intracellular accumulation of mitochondrial superoxide species and subsequent apoptotic cell death. Although autophagy-deficient conventional T cells develop normally, they show impaired peripheral survival, particularly memory CD8 ⁺ T cells. Because iNKT cells, unlike conventional T cells, differentiate into memory cells while in the thymus, our results highlight a unique autophagy-dependent metabolic regulation of adaptive and innate T cells, which is required for transition to a quiescent state after population expansion.
Journal Article
Inhibition of the Niemann-Pick C1 protein is a conserved feature of multiple strains of pathogenic mycobacteria
Mycobacterium tuberculosis
(
Mtb
) survives and replicates within host macrophages (MΦ) and subverts multiple antimicrobial defense mechanisms. Previously, we reported that lipids shed by pathogenic mycobacteria inhibit NPC1, the lysosomal membrane protein deficient in the lysosomal storage disorder Niemann-Pick disease type C (NPC). Inhibition of NPC1 leads to a drop in lysosomal calcium levels, blocking phagosome-lysosome fusion leading to mycobacterial survival. We speculated that the production of specific cell wall lipid(s) that inhibit NPC1 could have been a critical step in the evolution of pathogenicity. We therefore investigated whether lipid extracts from clinical
Mtb
strains from multiple
Mtb
lineages,
Mtb
complex (MTBC) members and non-tubercular mycobacteria (NTM) inhibit the NPC pathway. We report that inhibition of the NPC pathway was present in all clinical isolates from
Mtb
lineages 1, 2, 3 and 4,
Mycobacterium bovis
and the NTM,
Mycobacterium abscessus
and
Mycobacterium avium
. However, lipid extract from
Mycobacterium canettii
, which is considered to resemble the common ancestor of the MTBC did not inhibit the NPC1 pathway. We conclude that the evolution of NPC1 inhibitory mycobacterial cell wall lipids evolved early and post divergence from
Mycobacterium canettii
-related mycobacteria and that this activity contributes significantly to the promotion of disease.
Lipids shed by pathogenic mycobacteria have been shown to inhibit NPC1, a lysosomal membrane protein deficient in most cases of a rate inherited lysosomal storage disorder Niemann-Pick disease type C (NPC). Here, authors utilise lipid extracts from clinical
Mycobacterium tuberculosis
strains, and non-tubercular mycobacteria to investigate their ability to inhibit the NPC pathway.
Journal Article
Building relationships
Building Relationships uses an apparatus approach to media analysis in order to determine whether the synchronic logic of online dating is compatible with the historically diachronic logic of marriage.
eBook
Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing
Core–shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Herein, we report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood–brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain.
Journal Article
Modulation of Human Natural Killer T Cell Ligands on TLR-Mediated Antigen-Presenting Cell Activation
Invariant natural killer T (iNKT) cells are a subset of nonconventional T cells recognizing endogenous and/or exogenous glycolipid antigens in the context of CD1d molecules. It remains unclear whether innate stimuli can modify the profile of endogenous lipids recognized by iNKT cells on the surface of antigen-presenting cells (APCs). We report that activation of human APCs by Toll-like receptor ligands (TLR-L) modulates the lipid biosynthetic pathway, resulting in enhanced recognition of CD1d-associated lipids by iNKT cells, as defined by IFN-γ secretion. APC-derived soluble factors further increase CD1d-restricted iNKT cell activation. Finally, using soluble tetrameric iNKT T cell receptors (TCR) as a staining reagent, we demonstrate specific up-regulation of CD1d-bound ligand(s) on TLR-mediated APC maturation. The ability of innate stimuli to modulate the lipid profile of APCs resulting in iNKT cell activation and APC maturation underscores the role of iNKT cells in assisting priming of antigen-specific immune responses.
Journal Article
Molecular basis for a new bovine model of Niemann-Pick type C disease
Niemann-Pick type C disease is a lysosomal storage disease affecting primarily the nervous system that results in premature death. Here we present the first report and investigation of Niemann-Pick type C disease in Australian Angus/Angus-cross calves. After a preliminary diagnosis of Niemann-Pick type C, samples from two affected calves and two obligate carriers were analysed using single nucleotide polymorphism genotyping and homozygosity mapping, and NPC1 was considered as a positional candidate gene. A likely causal missense variant on chromosome 24 in the NPC1 gene (NM_174758.2:c.2969C>G) was identified by Sanger sequencing of cDNA. SIFT analysis, protein alignment and protein modelling predicted the variant to be deleterious to protein function. Segregation of the variant with disease was confirmed in two additional affected calves and two obligate carrier dams. Genotyping of 403 animals from the original herd identified an estimated allele frequency of 3.5%. The Niemann-Pick type C phenotype was additionally confirmed via biochemical analysis of Lysotracker Green, cholesterol, sphingosine and glycosphingolipids in fibroblast cell cultures originating from two affected calves. The identification of a novel missense variant for Niemann-Pick type C disease in Angus/Angus-cross cattle will enable improved breeding and management of this disease in at-risk populations. The results from this study offer a unique opportunity to further the knowledge of human Niemann-Pick type C disease through the potential availability of a bovine model of disease.
Journal Article
Correction: Molecular basis for a new bovine model of Niemann-Pick type C disease
[This corrects the article DOI: 10.1371/journal.pone.0238697.].
Journal Article
Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease
Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS and periphery. The NLRP3 inflammasome is an important coordinator of pro-inflammatory responses, and we have investigated its regulation in murine SD. The NLRP3 inflammasome requires two signals, lipopolysaccharide (LPS) and ATP, to prime and activate the complex, respectively, leading to IL-1β secretion. Peritoneal, but not bone-marrow-derived, macrophages from symptomatic SD mice, but not those from pre-symptomatic animals, secrete the cytokine following priming with LPS with no requirement for activation with ATP, suggesting that such NLRP3 deregulation is related to the extent of glycosphingolipid storage. Dysregulated production of IL-1β was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1β in SD pathology using two approaches: the creation of hexb−/−Il1r1−/− double knockout mice or by treating hexb−/− animals with anakinra, a recombinant form of the IL-1 receptor antagonist, IL-1Ra. Both resulted in modest but significant extensions in lifespan and improvement of neurological function. These data demonstrate that IL-1β actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1β may provide benefits to patients.
Journal Article