Estimating the Accuracy of Spectral Learning for HMMs

Hidden Markov models (HMMs) are usually learned using the expectation maximisation algorithm which is, unfortunately, subject to local optima. Spectral learning for HMMs provides a unique, optimal solution subject to availability of a sufficient amount of data. However, with access to limited data, there is no means of estimating the accuracy of the solution of a given model. In this paper, a new spectral evaluation method has been proposed which can be used to assess whether the algorithm is converging to a stable solution on a given dataset. The proposed method is designed for real-life datasets where the true model is not available. A number of empirical experiments on synthetic as well as real datasets indicate that our criterion is an accurate proxy to measure quality of models learned using spectral learning

Growth of fat slits and dispersionless KP hierarchy

A "fat slit" is a compact domain in the upper half plane bounded by a curve with endpoints on the real axis and a segment of the real axis between them. We consider conformal maps of the upper half plane to the exterior of a fat slit parameterized by harmonic moments of the latter and show that they obey an infinite set of Lax equations for the dispersionless KP hierarchy. Deformation of a fat slit under changing a particular harmonic moment can be treated as a growth process similar to the Laplacian growth of domains in the whole plane. This construction extends the well known link between solutions to the dispersionless KP hierarchy and conformal maps of slit domains in the upper half plane and provides a new, large family of solutions.Comment: 26 pages, 6 figures, typos correcte

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

BACKGROUND: For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. METHODS: Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. RESULTS: HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. CONCLUSION: These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored

Coevolution with bacteriophages drives genome-wide host evolution and constrains the acquisition of abiotic-beneficial mutations

This is the author accepted manuscript. The final version is available from OUP via the DOI in this record.Studies of antagonistic coevolution between hosts and parasites typically focus on resistance and infectivity traits. However, coevolution could also have genome-wide effects on the hosts due to pleiotropy, epistasis, or selection for evolvability. Here, we investigate these effects in the bacterium Pseudomonas fluorescens SBW25 during approximately 400 generations of evolution in the presence or absence of bacteriophage (coevolution or evolution treatments, respectively). Coevolution resulted in variable phage resistance, lower competitive fitness in the absence of phages, and greater genome-wide divergence both from the ancestor and between replicates, in part due to the evolution of increased mutation rates. Hosts from coevolution and evolution treatments had different suites of mutations. A high proportion of mutations observed in coevolved hosts were associated with a known phage target binding site, the lipopolysaccharide (LPS), and correlated with altered LPS length and phage resistance. Mutations in evolved bacteria were correlated with higher fitness in the absence of phages. However, the benefits of these growth-promoting mutations were completely lost when these bacteria were subsequently coevolved with phages, indicating that they were not beneficial in the presence of resistance mutations (consistent with negative epistasis). Our results show that in addition to affecting genome-wide evolution in loci not obviously linked to parasite resistance, coevolution can also constrain the acquisition of mutations beneficial for growth in the abiotic environment.This work was funded by European Research Council and NERC (UK)

Contemporary medical television and crisis in the NHS

This article maps the terrain of contemporary UK medical television, paying particular attention to Call the Midwife as its centrepiece, and situating it in contextual relation to the current crisis in the NHS. It provides a historical overview of UK and US medical television, illustrating how medical television today has been shaped by noteworthy antecedents. It argues that crisis rhetoric surrounding healthcare leading up to the passing of the Health and Social Care Act 2012 has been accompanied by a renaissance in medical television. And that issues, strands and clusters have emerged in forms, registers and modes with noticeable regularity, especially around the value of affective labour, the cultural politics of nostalgia and the neoliberalisation of healthcare

Self-similarity in Laplacian Growth

We consider Laplacian Growth of self-similar domains in different geometries. Self-similarity determines the analytic structure of the Schwarz function of the moving boundary. The knowledge of this analytic structure allows us to derive the integral equation for the conformal map. It is shown that solutions to the integral equation obey also a second order differential equation which is the one dimensional Schroedinger equation with the sinh inverse square potential. The solutions, which are expressed through the Gauss hypergeometric function, characterize the geometry of self-similar patterns in a wedge. We also find the potential for the Coulomb gas representation of the self-similar Laplacian growth in a wedge and calculate the corresponding free energy.Comment: 16 pages, 9 figure

Recombinant expression of Streptococcus pneumoniae capsular polysaccharides in Escherichia coli.

Currently, Streptococcus pneumoniae is responsible for over 14 million cases of pneumonia worldwide annually, and over 1 million deaths, the majority of them children. The major determinant for pathogenesis is a polysaccharide capsule that is variable and is used to distinguish strains based on their serotype. The capsule forms the basis of the pneumococcal polysaccharide vaccine (PPV23) that contains purified capsular polysaccharide from 23 serotypes, and the pneumococcal conjugate vaccine (PCV13), containing 13 common serotypes conjugated to CRM197 (mutant diphtheria toxin). Purified capsule from S. pneumoniae is required for pneumococcal conjugate vaccine production, and costs can be prohibitively high, limiting accessibility of the vaccine in low-income countries. In this study, we demonstrate the recombinant expression of the capsule-encoding locus from four different serotypes of S. pneumoniae within Escherichia coli. Furthermore, we attempt to identify the minimum set of genes necessary to reliably and efficiently express these capsules heterologously. These E. coli strains could be used to produce a supply of S. pneumoniae serotype-specific capsules without the need to culture pathogenic bacteria. Additionally, these strains could be applied to synthetic glycobiological applications: recombinant vaccine production using E. coli outer membrane vesicles or coupling to proteins using protein glycan coupling technology

Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure