65 research outputs found
Data integration for large-scale models of species distributions
With the expansion in the quantity and types of biodiversity data being collected, there is a need to find ways to combine these different sources to provide cohesive summaries of species’ potential and realized distributions in space and time. Recently, model-based data integration has emerged as a means to achieve this by combining datasets in ways that retain the strengths of each. We describe a flexible approach to data integration using point process models, which provide a convenient way to translate across ecological currencies. We highlight recent examples of large-scale ecological models based on data integration and outline the conceptual and technical challenges and opportunities that arise
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
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Development of an integrated collagen gel system for studying cellular interfaces following spinal cord injury
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Modelling of the injured spinal cord using 3-dimensional cell cultures; strategies for improving tissue engineered repair
Traumatic injuries to the spinal cord and dorsal root entry zone (DREZ) are debilitating and often lead to paralysis and loss of sensation for the patient. At the cellular and molecular level, the repair site microenvironment is inhibitory for axon growth due to formation of a glial scar. A common finding of current strategies aimed at bridging CNS lesions, in particular recent tissue engineering approaches using fibronectin (Phillips et al., Biomaterials 2004), is that whilst axons readily enter and traverse the bridging graft, they are less likely to exit the graft and reconnect with their targets. The aim of this work was to develop a cell culture model to investigate reactive gliosis following damage to the spinal cord.
Astrocytes in the CNS under physiological conditions express low levels of GFAP, but following trauma exhibit a reactive phenotype characterised by GFAP up-regulation. Primary glial cell cultures were analysed in 2D monolayers and 3D collagen gels for GFAP expression. In 2D cultures approximately twice the number of cells were positive for GFAP compared to those cultured in 3D collagen gels. As 3D astrocyte cultures more closely modelled the in vivo situation, we used this model to investigate the response of astrocytes to cells found at the inhibitory interface following damage. The preliminary model involved placing dorsal root ganglia (DRG) explants into the centre of astrocyte gels. Classification of astrocyte morphology revealed significantly more ramified cells in DRG-adjacent regions (6 fold higher), than in control areas away from the DRG. A more advanced model was then developed in which dissociated DRGs were labelled with CellTrackerTM, seeded onto astrocyte-populated collagen gels and maintained in culture for 5 days. Astrocytes near the DRG interface showed marked GFAP up-regulation and adopted a reactive morphology which was observed up to 1mm away. Intensity of GFAP fluorescence at this interface was 3 fold higher than that seen away from the interface or in controls (astrocyte only gels).
Astrocytes in 3D culture exhibit a lower basal level of reactivity than cells grown in monolayer. This model provides a useful tool for investigating triggers of reactive gliosis, as demonstrated by the response observed to cells found at the inhibitory interfaces formed following damage to the spinal cord and could be used as a way to improve existing therapies and develop new strategies aimed at CNS repair
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Plastic compression of aligned cellular collagen gels for nervous system repair
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Schwann cells in collagen gels survive plastic compression and maintain their alignment: development of a cellular biomaterial for peripheral nerve repair
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