A Software Architecture for Reconstructability Analysis

Software packages for reconstructability analysis (RA), as well as for related log linear modeling, generally provide a fixed set of functions. Such packages are suitable for end‐users applying RA in various domains, but do not provide a platform for research into the RA methods themselves. A new software system, Occam3, is being developed which is intended to address three goals which often conflict with one another to provide: a general and flexible infrastructure for experimentation with RA methods and algorithms; an easily‐configured system allowing methods to be combined in novel ways, without requiring deep software expertise; and a system which can be easily utilized by domain researchers who are not computer specialists. Meeting these goals has led to an architecture which strictly separates functions into three layers: the core, which provides representation of data sets, relations, and models; the management layer, which provides extensible objects for development of new algorithms; and the script layer, which allows the other facilities to be combined in novel ways to address a particular domain analysis problem

What not to write:an intervention in written communication skills for accounting students

Abstract: This study considers the evidence that many accounting students struggle to write accurately and appropriately, which in turn has negative implications on their wider employability. Using an intervention approach, initiatives were taken to address this problem for first year accounting undergraduates at the University of Portsmouth. The results indicate that some improvements are possible and students' self-awareness of the issue was raised, but that in order to sustain any improvements an increased focus on the teaching of writing skills would be required. This may have resource implications but the potential benefits to students in the wider realm could be significant. The initiative is targeted specifically at the enhancement of employability and, although based around extracts from the accounting literature, could readily be transferred to other subject areas. 126 word

Similarity-based virtual screening using 2D fingerprints

This paper summarises recent work at the University of Sheffield on virtual screening methods that use 2D fingerprint measures of structural similarity. A detailed comparison of a large number of similarity coefficients demonstrates that the well-known Tanimoto coefficient remains the method of choice for the computation of fingerprint-based similarity, despite possessing some inherent biases related to the sizes of the molecules that are being sought. Group fusion involves combining the results of similarity searches based on multiple reference structures and a single similarity measure. We demonstrate the effectiveness of this approach to screening, and also describe an approximate form of group fusion, turbo similarity searching, that can be used when just a single reference structure is available

Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV) following in vivo escape from neutralising antibody

<b>BACKGROUND:</b> In the acute phase of infection with feline immunodeficiency virus (FIV), the virus targets activated CD4+ T cells by utilising CD134 (OX40) as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs) 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo.<p></p> <b>RESULTS:</b> Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134.<p></p> <b>CONCLUSIONS:</b> The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.<p></p&gt

Graph theoretic methods for the analysis of structural relationships in biological macromolecules

Subgraph isomorphism and maximum common subgraph isomorphism algorithms from graph theory provide an effective and an efficient way of identifying structural relationships between biological macromolecules. They thus provide a natural complement to the pattern matching algorithms that are used in bioinformatics to identify sequence relationships. Examples are provided of the use of graph theory to analyze proteins for which three-dimensional crystallographic or NMR structures are available, focusing on the use of the Bron-Kerbosch clique detection algorithm to identify common folding motifs and of the Ullmann subgraph isomorphism algorithm to identify patterns of amino acid residues. Our methods are also applicable to other types of biological macromolecule, such as carbohydrate and nucleic acid structures

Selective expansion of viral variants following experimental transmission of a reconstituted feline immunodeficiency virus quasispecies

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development

Rapid Quantification of Molecular Diversity for Selective Database Acquisition

There is an increasing need to expand the structural diversity of the molecules investigated in lead-discovery programs. One way in which this can be achieved is by acquiring external datasets that will enhance an existing database. This paper describes a rapid procedure for the selection of external datasets using a measure of structural diversity that is calculated from sums of pairwise intermolecular structural similarities

Spaces of Graphs, Boundary Groupoids and the Coarse Baum-Connes Conjecture

We introduce a new variant of the coarse Baum-Connes conjecture designed to tackle coarsely disconnected metric spaces called the boundary coarse Baum-Connes conjecture. We prove this conjecture for many coarsely disconnected spaces that are known to be counterexamples to the coarse Baum-Connes conjecture. In particular, we give a geometric proof of this conjecture for spaces of graphs that have large girth and bounded vertex degree. We then connect the boundary conjecture to the coarse Baum-Connes conjecture using homological methods, which allows us to exhibit all the current uniformly discrete counterexamples to the coarse Baum-Connes conjecture in an elementary way.Comment: 27 pages, added a new section concerned with counterexamples to the conjectur

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

Host and Viral Determinants of Feline Immunodeficiency Virus Pathogenicity

Background Infection with feline immunodeficiency virus (FIV) is mediated by attachment to CD134 (OX40) followed by a second interaction with CXCR4, the sole co-receptor for infection. However, the in vivo cell tropism of FIV expands with time post-infection, analogous to the shift in cell tropism observed with HIV-1 as co-receptor usage switches from CCR5 to CXCR4. Here, we ask whether alterations in the Env-CD134 interaction underpin the shift in FIV cell tropism and whether this is associated with disease progression. Results Experimental transmission of a reconstituted quasispecies comprising viral variants with distinct modes of interaction with CD134 [1,2] revealed the selective expansion of variants bearing Envs typical of “early”, acute infection, binding CD134 through determinants in both cysteine rich domains (CRDs) 1 and 2. In contrast, variants with Envs typical of “late”, chronic infection (binding via CRD1 only) failed to thrive following experimental transmission. The basis for the defective replication of “late” variants did not lie in suppression by the humoral or cellular immune responses, but correlated with the nature of the virus-receptor interaction. In order to assess whether our experimental observations on CD134 usage extended to natural infection of free-ranging cats, we characterized the receptor usage of viruses from two groups of cats naturally infected with FIV (n=44). Cats displaying clinical signs were more likely to harbour viral variants with a “late” phenotype (CRD1-dependent) than healthy cats. The emergence of CRD1-dependent variants coincided with declining health status, lower CD4 lymphocyte counts and led to shorter survival times. However, it was apparent that the shift from a CRD1&2 to CRD1-dependent interaction with CD134 was not a prerequisite for disease progression, as 25% of the cats that died during the study did not harbour Env variants displaying the “late” phenotype. Conclusions The shift in CD134 usage observed following natural infection with FIV aligns with a model whereby transmitted viruses switch from CRD1&2-dependent binding to CD134, to a CRD1-dependent interaction as disease progresses. Whether this shift in receptor usage is a cause or consequence of disease progression remains to be established, however, receptor usage may serve as a prognostic indicator for disease progression