Indirect inference for survival data

In this paper we describe the so-called “indirect” method of inference, originally developed from the econometric literature, and apply it to survival analyses of two data sets with repeated events. This method is often more convenient computationally than maximum likelihood estimation when handling such model complexities as random effects and measurement error, for example; and it can also serve as a basis for robust inference with less stringent assumptions on the data generating mechanism. The first data set concerns recurrence times of mammary tumors in rats and is modeled using a Poisson process model with covariates and frailties. The second data set involves times of recurrences of skin tumors in individual patients in a clinical trial. The methodology is applied in both parametric and semi-parametric regression analyses to accommodate random effects and covariate measurement error.Peer Reviewe

Indirect inference for survival data

In this paper we describe the so-called "indirect" method of inference, originally developed from the econometric literature, and apply it to survival analyses of two data sets with repeated events. This method is often more convenient computationally than maximum likelihood estimation when handling such model complexities as random effects and measurement error, for example; and it can also serve as a basis for robust inference with less stringent assumptions on the data generating mechanism. The first data set concerns recurrence times of mammary tumors in rats and is modeled using a Poisson process model with covariates and frailties. The second data set involves times of recurrences of skin tumors in individual patients in a clinical trial. The methodology is applied in both parametric and semi-parametric regression analyses to accommodate random effects and covariate measurement error

Synthesis of ganglioside analogues as biological probes for enzymes that modify sialic acids

Ganglioside GM3, a glycosphingolipid found in the outer membrane of all mammalian cells, is expressed at much higher concentrations than normal in cancer cells. It has been reported that GM3 can inhibit signal transduction via the EGF receptor kinase, ultimately down regulating cell growth. In contrast to this, de-N-acetyl GM3, another ganglioside that has been found in a number of cancer cell lines, is reported to be a potent promoter of cell growth. Evidence suggests that GM3 and de-N-acetyl GM3 are inter-converted by enzymes that remove and replace the N-acetyl group on sialic acid. In this thesis, the syntheses of a number of simplified analogues of gangliosides are described, including some in which an inter-glycosidic oxygen atom is replaced by sulfur. Synthesis of O-linked ganglioside analogues was achieved by both a totally chemical route and also by a chemo-enzymatic route, involving the use of a recombinant construct of trypanosoma cruzi trans-sialidase for glycosylation with sialic acid. A novel strategy for the synthesis of ganglioside analogues that contain a sialic acid α(2-->3) galactose thioglycosidic linkage, is also described. These compounds were evaluated as substrates and inhibitors for Clostridium perfringens neuraminidase and Trypanosoma cruzi trans-sialidase. Some of the ganglioside analogues described herein were used to develop biochemical assays for detecting the putatative de-N-acetylase and N-acetyltransferase activities that would be required for the inter-conversion of gangliosides GM3 and de-N-acetyl GM3

Patient and public involvement in the ongoing applied artificial intelligence and complex health interventions co-design work

This briefing paper describes how we involved Patient and Public Involvement (PPI) methods in the ongoing applied artificial intelligence (AI) and complex interventions co-design project seeking to improve pathways of care for people with multiple long-term conditions (MLTCs) in Scotland. This project is part of the wider NIHR-funded programme called AIM-CISC (www.aim-cisc) which aims to use AI and state-of-the-art data science, social science, genomics, and health service research methods to understand the clustering of MLTCs within individuals, communities, and in key clinical contexts

C-type cytochrome-initiated reduction of bacterial lytic polysaccharide monooxygenases

The release of glucose from lignocellulosic waste for subsequent fermentation into biofuels holds promise for securing humankind's future energy needs. The discovery of a set of copper-dependent enzymes known as lytic polysaccharide monooxygenases (LPMOs) has galvanised new research in this area. LPMOs act by oxidatively introducing chain breaks into cellulose and other polysaccharides, boosting the ability of cellulases to act on the substrate. Although several proteins have been implicated as electron sources in fungal LPMO biochemistry, no equivalent bacterial LPMO electron donors have been previously identified, although the proteins Cbp2D and E from Cellvibrio japonicus have been implicated as potential candidates. Here we analyse a small c-type cytochrome (CjX183) present in Cellvibrio japonicus Cbp2D, and show that it can initiate bacterial CuII/I LPMO reduction and also activate LPMO-catalyzed cellulose-degradation. In the absence of cellulose, CjX183-driven reduction of the LPMO results in less H2O2 production from O2, and correspondingly less oxidative damage to the enzyme than when ascorbate is used as the reducing agent. Significantly, using CjX183 as the activator maintained similar cellulase boosting levels relative to the use of an equivalent amount of ascorbate. Our results therefore add further evidence to the impact that the choice of electron source can have on LPMO action. Furthermore, the study of Cbp2D and other similar proteins may yet reveal new insight into the redox processes governing polysaccharide degradation in bacteria

Aminooxy-BCN glycoconjugates

NMR spectroscopy data for aminooxybicyclononyne derivatives and glycan conjugates and protein mass spectrometry data for protein ligation reaction

Chemically Defined Sialoside Scaffolds for Investigation of Multivalent Interactions with Sialic Acid Binding Proteins

Four glycodendrons and a glycocluster were synthesized from carbohydrate building blocks to form paucivalent (di- to tetravalent) structures of controlled scaffold architectures. Enzymatic sialylation of the functionalized cluster and dendrons, terminated in lactose residues, generated a library of paucivalent synthetic sialosides displaying sialic acids with different dispositions. These newly constructed bioactive sialic acid-based structures were differentially recognized by sialoadhesin, a mammalian macrophage sialic acid binding protein. The binding of the sialosides to sialoadhesin was evaluated by an enzyme-linked immunosorbant assay to investigate the complementarity of scaffold structure and binding to sialoadhesin. Modulating the interaction between sialoadhesin and its sialic acid ligands has important implications in immunobiology

Bacterial toxin inhibitors based on multivalent scaffolds.

Protein toxins released by certain intestinal bacteria are the cause of many diarrhoeal diseases including cholera and travellers' diarrhoea. The toxins enter their target cells by first binding to specific glycolipids in the cell membrane. Inhibition of these protein-carbohydrate interactions has the potential to prevent the toxins from reaching their site of action, and thus avoid the ensuing diarrhoea. Simple oligosaccharides typically have low affinities for the protein toxins, therefore inhibitor design has focussed on exploiting the principles of multivalency: multiple weak interactions acting in concert can enhance the overall binding interaction. The major classes of multivalent inhibitors investigated to date will be discussed; these include glycopolymers, glycodendrimers, tailored glycoclusters and inhibitors exploiting templated assembly