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"Davis, Daniel M."
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The secret body : how the new science of the human body is changing the way we live
Traversing six key frontiers of human biology, Daniel Davis shows how these radical possibilities have been made real - thanks to the ingenious, decades-long work of scientists whose breakthrough discoveries are transforming our understanding of how the body works, what it is capable of and how we might manipulate it. By bringing together the latest understanding of the immune system, the brain, the microbiome, the interaction of cells and the development of the foetus, including developments such as optogenetics, super-resolution microscopy, the human cell atlas and systems biology, we arrive at a vision of the human body of dizzying complexity, wonder and possibility.
Book
Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity
Cytotoxic lymphocytes are critical in our immune defence against cancer and infection. Cytotoxic T lymphocytes and Natural Killer cells can directly lyse malignant or infected cells in at least two ways: granule-mediated cytotoxicity, involving perforin and granzyme B, or death receptor-mediated cytotoxicity, involving the death receptor ligands, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). In either case, a multi-step pathway is triggered to facilitate lysis, relying on active pro-death processes and signalling within the target cell. Because of this reliance on an active response from the target cell, each mechanism of cell-mediated killing can be manipulated by malignant and infected cells to evade cytolytic death. Here, we review the mechanisms of cell-mediated cytotoxicity and examine how cells may evade these cytolytic processes. This includes resistance to perforin through degradation or reduced pore formation, resistance to granzyme B through inhibition or autophagy, and resistance to death receptors through inhibition of downstream signalling or changes in protein expression. We also consider the importance of tumour necrosis factor (TNF)-induced cytotoxicity and resistance mechanisms against this pathway. Altogether, it is clear that target cells are not passive bystanders to cell-mediated cytotoxicity and resistance mechanisms can significantly constrain immune cell-mediated killing. Understanding these processes of immune evasion may lead to novel ideas for medical intervention.
Journal Article
Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro
Interleukin (IL)-18 and IL-1β are potent pro-inflammatory cytokines that contribute to inflammatory conditions such as rheumatoid arthritis and Alzheimer’s disease. They are produced as inactive precursors that are activated by large macromolecular complexes called inflammasomes upon sensing damage or pathogenic signals. NLRP3 inflammasome activation is regarded to require a priming step that causes NLRP3 and IL-1β gene upregulation, and also NLRP3 post-translational licencing. A subsequent activation step leads to the assembly of the complex and the cleavage of pro-IL-18 and pro-IL-1β by caspase-1 into their mature forms, allowing their release. Here we show that human monocytes, but not monocyte derived macrophages, are able to form canonical NLRP3 inflammasomes in the absence of priming. NLRP3 activator nigericin caused the processing and release of constitutively expressed IL-18 in an unprimed setting. This was mediated by the canonical NLRP3 inflammasome that was dependent on K + and Cl − efflux and led to ASC oligomerization, caspase-1 and Gasdermin-D (GSDMD) cleavage. IL-18 release was impaired by the NLRP3 inhibitor MCC950 and by the absence of NLRP3, but also by deficiency of GSDMD, suggesting that pyroptosis is the mechanism of release. This work highlights the readiness of the NLRP3 inflammasome to assemble in the absence of priming in human monocytes and hence contribute to the very early stages of the inflammatory response when IL-1β has not yet been produced. It is important to consider the unprimed setting when researching the mechanisms of NLRP3 activation, as to not overshadow the pathways that occur in the absence of priming stimuli, which might only enhance this response.
Journal Article
Self defence : a myth-busting guide to immune health
We are surrounded by big claims for how to enhance our immunity. But the one thing the science is clear on is that everyone's immune system is entirely unique. So how do we tell the myths from the facts? And is there anything we can actually do to benefit our immune health? World-leading immunologist Daniel M. Davis has the answers in this truly authoritative and highly accessible, myth-busting guide to the effects of stress, age, exercise, weight, nutrition, sleep and mental health on our immune health.
BOOK
Machine learning for cluster analysis of localization microscopy data
Quantifying the extent to which points are clustered in single-molecule localization microscopy data is vital to understanding the spatial relationships between molecules in the underlying sample. Many existing computational approaches are limited in their ability to process large-scale data sets, to deal effectively with sample heterogeneity, or require subjective user-defined analysis parameters. Here, we develop a supervised machine-learning approach to cluster analysis which is fast and accurate. Trained on a variety of simulated clustered data, the neural network can classify millions of points from a typical single-molecule localization microscopy data set, with the potential to include additional classifiers to describe different subtypes of clusters. The output can be further refined for the measurement of cluster area, shape, and point-density. We demonstrate this approach on simulated data and experimental data of the kinase Csk and the adaptor PAG in primary human T cell immunological synapses.
The characterization of clusters in single-molecule microscopy data is vital to reconstruct emerging spatial patterns. Here, the authors present a fast and accurate machine-learning approach to clustering, to address the issues related to the size of the data and to sample heterogeneity.
Journal Article
Coupled influence of tectonics, climate, and surface processes on landscape evolution in southwestern North America
The Cenozoic landscape evolution in southwestern North America is ascribed to crustal isostasy, dynamic topography, or lithosphere tectonics, but their relative contributions remain controversial. Here we reconstruct landscape history since the late Eocene by investigating the interplay between mantle convection, lithosphere dynamics, climate, and surface processes using fully coupled four-dimensional numerical models. Our quantified depth-dependent strain rate and stress history within the lithosphere, under the influence of gravitational collapse and sub-lithospheric mantle flow, show that high gravitational potential energy of a mountain chain relative to a lower Colorado Plateau can explain extension directions and stress magnitudes in the belt of metamorphic core complexes during topographic collapse. Profound lithospheric weakening through heating and partial melting, following slab rollback, promoted this extensional collapse. Landscape evolution guided northeast drainage onto the Colorado Plateau during the late Eocene-late Oligocene, south-southwest drainage reversal during the late Oligocene-middle Miocene, and southwest drainage following the late Miocene.
Cenozoic landscape evolution of southwestern North America remains debated. Here, the authors reconstruct landscape using 4-D numerical models, which can explain extensional collapse and superficial geological record for the Basin and Range Province
Journal Article
TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation
TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions
in cis
or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.
CD226 provides a co-stimulatory signal to the T cell receptor during activation, and TIGIT is believed to inhibit this process by competing for the CD226 ligand CD155. Here authors show that ligand binding induces dense nanocluster formation by TIGIT which initiates intrinsic, CD226 independent inhibitory signals, proximal to T cell receptor signalling.
Journal Article
Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells
Intercellular communication within the bone marrow niche significantly promotes leukemogenesis and provides protection of leukemic cells from therapy. Secreted factors, intercellular transfer of mitochondria and the receptor–ligand interactions have been shown as mediators of this protection. Here we report that tunneling nanotubes (TNTs)—long, thin membranous structures, which have been identified as a novel mode of intercellular cross-talk—are formed in the presence of stroma and mediate transfer of cellular vesicles from stroma to leukemic cells. Importantly, transmission of vesicles via TNTs from stromal cells increases resistance of leukemic cells to the tyrosine kinase inhibitor, imatinib. Using correlative light-electron microscopy and electron tomography we show that stromal TNTs contain vesicles, provide membrane continuity with the cell bodies and can be open-ended. Moreover, trans-SILAC studies to reveal the non-autonomous proteome showed that specific sets of proteins are transferred together with cellular vesicles from stromal to leukemic cells, with a potential role in survival and adaptation. Altogether, our findings provide evidence for the biological role of the TNT-mediated vesicle exchange between stromal and leukemic cells, implicating the direct vesicle and protein transfer in the stroma-provided protection of leukemic cells.
Journal Article
Remodelling of Cortical Actin Where Lytic Granules Dock at Natural Killer Cell Immune Synapses Revealed by Super-Resolution Microscopy
Natural Killer (NK) cells are innate immune cells that secrete lytic granules to directly kill virus-infected or transformed cells across an immune synapse. However, a major gap in understanding this process is in establishing how lytic granules pass through the mesh of cortical actin known to underlie the NK cell membrane. Research has been hampered by the resolution of conventional light microscopy, which is too low to resolve cortical actin during lytic granule secretion. Here we use two high-resolution imaging techniques to probe the synaptic organisation of NK cell receptors and filamentous (F)-actin. A combination of optical tweezers and live cell confocal microscopy reveals that microclusters of NKG2D assemble into a ring-shaped structure at the centre of intercellular synapses, where Vav1 and Grb2 also accumulate. Within this ring-shaped organisation of NK cell proteins, lytic granules accumulate for secretion. Using 3D-structured illumination microscopy (3D-SIM) to gain super-resolution of ~100 nm, cortical actin was detected in a central region of the NK cell synapse irrespective of whether activating or inhibitory signals dominate. Strikingly, the periodicity of the cortical actin mesh increased in specific domains at the synapse when the NK cell was activated. Two-colour super-resolution imaging revealed that lytic granules docked precisely in these domains which were also proximal to where the microtubule-organising centre (MTOC) polarised. Together, these data demonstrate that remodelling of the cortical actin mesh occurs at the central region of the cytolytic NK cell immune synapse. This is likely to occur for other types of cell secretion and also emphasises the importance of emerging super-resolution imaging technology for revealing new biology.
Journal Article