Actually Sparse Variational Gaussian Processes

Gaussian processes (GPs) are typically criticised for their unfavourable scaling in both computational and memory requirements. For large datasets, sparse GPs reduce these demands by conditioning on a small set of inducing variables designed to summarise the data. In practice however, for large datasets requiring many inducing variables, such as low-lengthscale spatial data, even sparse GPs can become computationally expensive, limited by the number of inducing variables one can use. In this work, we propose a new class of inter-domain variational GP, constructed by projecting a GP onto a set of compactly supported B-spline basis functions. The key benefit of our approach is that the compact support of the B-spline basis functions admits the use of sparse linear algebra to significantly speed up matrix operations and drastically reduce the memory footprint. This allows us to very efficiently model fast-varying spatial phenomena with tens of thousands of inducing variables, where previous approaches failed

Habitat-use influences severe disease-mediated population declines in two of the most common garden bird species in Great Britain

The influence of supplementary feeding of wildlife on disease transmission and its consequent impacts on population dynamics are underappreciated. In Great Britain, supplementary feeding is hypothesised to have enabled the spread of the protozoan parasite, Trichomonas gallinae, from columbids to finches, leading to epidemic finch trichomonosis and a rapid population decline of greenfinch (Chloris chloris). More recently, chaffinch (Fringilla coelebs), has also declined markedly from the second to fifth commonest bird in Britain. Using citizen science data, we show that both declines were driven primarily by reduced adult survival, with the greatest reductions occurring in peri-domestic habitats, where supplementary food provision is common. Post-mortem examinations showed a proportional increase in chaffinch trichomonosis cases, near-contemporaneous with its population decline. Like greenfinches, chaffinches often use supplementary food, but are less associated with human habitation. Our results support the hypothesis that supplementary feeding can increase parasite transmission frequency within and between common species. However, the dynamics behind resultant population change can vary markedly, highlighting the need for integrating disease surveillance with demographic monitoring. Other species susceptible to T. gallinae infection may also be at risk. Supplementary feeding guidelines for wildlife should include disease mitigation strategies to ensure that benefits to target species outweigh risks

The Development of a Semtex-H Simulant for Terahertz Spectroscopy

The development and use of terahertz (THz) frequency spectroscopy systems for security screening has shown an increased growth over the past 15 years. In order to test these systems in real-world situations, safe simulants of illicit materials, such as Semtex-H, are required. Ideally, simulants should mimic key features of the material of interest, such that they at least resemble or even appear indistinguishable from the materials of interest to the interrogating technique(s), whilst not having hazardous or illicit properties. An ideal simulant should have similar physical properties (malleability, density, surface energy and volatility to the material of interest); be non-toxic and easy to clean and decontaminate from surfaces; be recyclable or disposable; and be useable in a public environment. Here, we present a method for developing such an explosive simulant (for Semtex-H) based on a database of THz spectra of common organic molecules, and the use of a genetic algorithm to select a mixture of compounds automatically to form such a simulant. Whilst we focus on a security application, this work could be applied to various other contexts, where the material of interest is dangerous, impractical or costly. We propose four mixtures that could then be used to test the spectral response of any instrument, working at terahertz frequencies, without the need for an explosive substance

Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity

Sulfatides and gangliosides are raft-associated glycolipids essential for maintaining myelinated nerve integrity. Mice deficient in sulfatide (cerebroside sulfotransferase knockout, CST-/- ) or complex gangliosides (β-1,4-N-acetylegalactosaminyltransferase1 knockout, GalNAc-T-/- ) display prominent disorganization of proteins at the node of Ranvier (NoR) in early life, and age-dependent neurodegeneration. Loss of neuronal rather than glial complex gangliosides underpins the GalNAc-T-/- phenotype, as shown by neuron or glial-specific rescue, whereas sulfatide is principally expressed and functional in glial membranes. The similarities in NoR phenotype of CST-/- , GalNAc-T-/- and axo-glial protein deficient mice suggests these glycolipids stabilise membrane proteins including neurofascin155 (NF155) and myelin-associated glycoprotein (MAG) at axo-glial junctions. To assess the functional interactions between sulfatide and gangliosides, CST-/- and GalNAc-T-/- genotypes were interbred. CST-/- x GalNAc-T-/- mice develop normally to P10, but all die between P20-P25, coinciding with peak myelination. Ultrastructural, immunohistological and biochemical analysis of either sex reveals widespread axonal degeneration and disruption to the axo-glial junction at the NoR. In addition to sulfatide-dependent loss of NF155, CST-/-x GalNAc-T-/- mice exhibited a major reduction in MAG protein levels in CNS myelin, compared to wild type and single lipid deficient mice. The CST-/- x GalNAc-T-/- phenotype was fully restored to that of CST-/- mice by neuron-specific expression of complex gangliosides, but not by their glial-specific expression nor by the global expression of a-series gangliosides. These data indicate that sulfatide and complex b-series gangliosides on the glial and neuronal membranes respectively act in concert to promote NF155 and MAG in maintaining the stable axo-glial interactions essential for normal nerve function.SIGNIFICANCE STATEMENTSulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalisation of multiple membrane proteins. The axo-glial adhesion molecules neurofascin 155 and myelin-associated glycoprotein require membrane microdomains containing either sulfatides or complex gangliosides to localise and function effectively. The co-operative roles of these microdomains and associated proteins are unknown. Here we show vital interdependent roles for sulfatides and complex gangliosides as double (but not single) deficiency causes a rapidly lethal phenotype in early age. These findings suggests that sulfatides and complex gangliosides on opposing axo-glial membranes are responsible for essential tethering of the axo-glial junction proteins, neurofascin155 and myelin-associated glycoprotein that interact to maintain the nodal complex

Artificial Shear Stress Effects on Leukocytes at a Biomaterial Interface

Medical devices, such as ventricular assist devices (VADs), introduce both foreign materials and artificial shear stress to the circulatory system. The effects these have on leukocytes and the immune response are not well understood. Understanding how these two elements combine to affect leukocytes may reveal why some patients are susceptible to recurrent device-related infections and provide insight into the development of pump thrombosis. Biomaterials - DLC: diamond-like carbon coated stainless steel; Sap: single-crystal sapphire; and Ti: titanium alloy (Ti6Al4V) were attached to the parallel plates of a rheometer. Whole human blood was left between the two discs for 5 min at +37°C with or without the application of shear stress (0s-1 or 1000s-1). Blood was removed and used for: complete blood cell counts; flow cytometry (leukocyte activation; cell death; microparticle generation; phagocytic ability; and reactive oxygen species (ROS) production); and the production of pro-inflammatory cytokines. L-selectin expression on monocytes was decreased when blood was exposed to the biomaterials both with and without shear. Applying shear stress to blood on a Sap and Ti surface led to activation of neutrophils shown as decreased L-selectin expression. Sap and Ti blunted the LPS-stimulated macrophage migration inhibitory factor (MIF) production, most notably when sheared on Ti.The biomaterials used here have been shown to activate leukocytes in a static environment. The introduction of shear appears to exacerbate this activation. Interestingly, a widely accepted biocompatible material (Ti) utilised in many different types of devices, has the capacity for immune cell activation and inhibition of MIF secretion when combined with shear stress. These findings contribute to our understanding of the contribution of biomaterials and shear stress to recurrent infections and vulnerability to sepsis in some VAD patients as well as pump thrombosis

Signal transduction pathways involved in proteolysis-inducing factor induced proteasome expression in murine myotubes

The proteolysis-inducing factor (PIF) is produced by cachexia-inducing tumours and initiates protein catabolism in skeletal muscle. The potential signalling pathways linking the release of arachidonic acid (AA) from membrane phospholipids with increased expression of the ubiquitin-proteasome proteolytic pathway by PIF has been studied using C2C12 murine myotubes as a surrogate model of skeletal muscle. The induction of proteasome activity and protein degradation by PIF was blocked by quinacrine, a nonspecific phospholipase A2 (PLA2) inhibitor and trifluroacetyl AA, an inhibitor of cytosolic PLA2. PIF was shown to increase the expression of calcium-independent cytosolic PLA2, determined by Western blotting, at the same concentrations as those inducing maximal expression of 20S proteasome α-subunits and protein degradation. In addition, both U-73122, which inhibits agonist-induced phospholipase C (PLC) activation and D609, a specific inhibitor of phosphatidylcholine-specific PLC also inhibited PIF-induced proteasome activity. This suggests that both PLA 2 and PLC are involved in the release of AA in response to PIF, and that this is important in the induction of proteasome expression. The two tyrosine kinase inhibitors genistein and tryphostin A23 also attenuated PIF-induced proteasome expression, implicating tyrosine kinase in this process. PIF induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) at the same concentrations as that inducing proteasome expression, and the effect was blocked by PD98059, an inhibitor of MAPK kinase, as was also the induction of proteasome expression, suggesting a role for MAPK activation in PIF-induced proteasome expression. © 2003 Cancer Research UK

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

Proteolysis-inducing factor, a cachexia-inducing tumour product, is an N-glycosylated peptide with homology to the unglycosylated neuronal survival peptide Y-P30 and a predicted product of the dermcidin gene, a pro-survival oncogene in breast cancer. We aimed to investigate whether dermcidin is pro-survival in liver cells, in which proteolysis-inducing factor induces catabolism, and to determine the role of potentially glycosylated asparagine residues in this function. Reverse cloning of proteolysis-inducing factor demonstrated ∼100% homology with the dermcidin cDNA. This cDNA was cloned into pcDNA3.1+ and both asparagine residues removed using site-directed mutagenesis. In vitro translation demonstrated signal peptide production, but no difference in molecular weight between the products of native and mutant vectors. Immunocytochemistry of HuH7 cells transiently transfected with V5-His-tagged dermcidin confirmed targeting to the secretory pathway. Stable transfection conferred protection against oxidative stress. This was abrogated by mutation of both asparagines in combination, but not by mutation of either asparagine alone. These findings suggest that dermcidin may function as an oncogene in hepatic as well as breast cells. Glycosylation does not appear to be required, but the importance of asparagine residues suggests a role for the proteolysis-inducing factor core peptide domain

P-Element Homing Is Facilitated by engrailed Polycomb-Group Response Elements in Drosophila melanogaster

P-element vectors are commonly used to make transgenic Drosophila and generally insert in the genome in a nonselective manner. However, when specific fragments of regulatory DNA from a few Drosophila genes are incorporated into P-transposons, they cause the vectors to be inserted near the gene from which the DNA fragment was derived. This is called P-element homing. We mapped the minimal DNA fragment that could mediate homing to the engrailed/invected region of the genome. A 1.6 kb fragment of engrailed regulatory DNA that contains two Polycomb-group response elements (PREs) was sufficient for homing. We made flies that contain a 1.5kb deletion of engrailed DNA (enΔ1.5) in situ, including the PREs and the majority of the fragment that mediates homing. Remarkably, homing still occurs onto the enΔ1. 5 chromosome. In addition to homing to en, P[en] inserts near Polycomb group target genes at an increased frequency compared to P[EPgy2], a vector used to generate 18,214 insertions for the Drosophila gene disruption project. We suggest that homing is mediated by interactions between multiple proteins bound to the homing fragment and proteins bound to multiple areas of the engrailed/invected chromatin domain. Chromatin structure may also play a role in homing