Improvement of speech recognition by nonlinear noise reduction

The success of nonlinear noise reduction applied to a single channel recording of human voice is measured in terms of the recognition rate of a commercial speech recognition program in comparison to the optimal linear filter. The overall performance of the nonlinear method is shown to be superior. We hence demonstrate that an algorithm which has its roots in the theory of nonlinear deterministic dynamics possesses a large potential in a realistic application.Comment: see urbanowicz.org.p

Independent Orbiter Assessment (IOA): CIL issues resolution report, volume 1

The results of the Independent Orbiter Assessment (IOA) of the Failure Modes and Effects Analysis (FMEA) and Critical Items List (CIL) are presented. This report contains IOA assessment worksheets showing resolution of outstanding IOA CIL issues that were summarized in the IOA FMEA/CIL Assessment Interim Report, dated 9 March 1988. Each assessment worksheet has been updated with CIL issue resolution and rationale. The NASA and Prime Contractor post 51-L FMEA/CIL documentation assessed is believed to be technically accurate and complete. No assessment issues remain that has safety implications. Volume 1 contain worksheets for the following sybsystems: Landing and Deceleration Subsystem; Purge, Vent and Drain Subsystem; Active Thermal Control and Life Support Systems; Crew Equipment Subsystem; Instrumentation Subsystem; Data Processing Subsystem; Atmospheric Revitalization Pressure Control Subsystem; Hydraulics and Water Spray Boiler Subsystem; and Mechanical Actuation Subsystem

Evaluation of a Tree-based Pipeline Optimization Tool for Automating Data Science

As the field of data science continues to grow, there will be an ever-increasing demand for tools that make machine learning accessible to non-experts. In this paper, we introduce the concept of tree-based pipeline optimization for automating one of the most tedious parts of machine learning---pipeline design. We implement an open source Tree-based Pipeline Optimization Tool (TPOT) in Python and demonstrate its effectiveness on a series of simulated and real-world benchmark data sets. In particular, we show that TPOT can design machine learning pipelines that provide a significant improvement over a basic machine learning analysis while requiring little to no input nor prior knowledge from the user. We also address the tendency for TPOT to design overly complex pipelines by integrating Pareto optimization, which produces compact pipelines without sacrificing classification accuracy. As such, this work represents an important step toward fully automating machine learning pipeline design.Comment: 8 pages, 5 figures, preprint to appear in GECCO 2016, edits not yet made from reviewer comment

Hepatitis C virus vaccine: Challenges and prospects

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The hepatitis C virus (HCV) causes both acute and chronic infection and continues to be a global problem despite advances in antiviral therapeutics. Current treatments fail to prevent reinfection and remain expensive, limiting their use to developed countries, and the asymptomatic nature of acute infection can result in individuals not receiving treatment and unknowingly spreading HCV. A prophylactic vaccine is therefore needed to control this virus. Thirty years since the discovery of HCV, there have been major gains in understanding the molecular biology and elucidating the immunological mechanisms that underpin spontaneous viral clearance, aiding rational vaccine design. This review discusses the challenges facing HCV vaccine design and the most recent and promising candidates being investigated

Novel functional hepatitis C virus glycoprotein isolates identified using an optimised viral pseudotype entry assay

Retrovirus pseudotypes are a highly tractable model used to study the entry pathways of enveloped viruses. This model has been extensively applied to the study of the hepatitis C virus (HCV) entry pathway, pre-clinical screening of antiviral antibodies and for assessing the phenotype of patient-derived viruses using HCV pseudoparticles (HCVpp) possessing the HCV E1 and E2 glycoproteins. However, not all patient-isolated clones produce particles that are infectious in this model. This study investigated factors that might limit phenotyping of patient-isolated HCV glycoproteins. Genetically related HCV glycoproteins from individual patient quasispecies were discovered to behave very differently in this entry model. Empirical optimisation of the ratio of packaging construct and glycoprotein-encoding plasmid was required for successful HCVpp genesis for different clones. The selection of retroviral packaging construct also influenced the function of HCV pseudoparticles. Some glycoprotein constructs tolerated a wide range of assay parameters, while others were much more sensitive to alterations. Furthermore, glycoproteins previously characterised as unable to mediate entry were found to be functional. These findings were validated using chimeric cell-cultured HCV bearing these glycoproteins. Using the same empirical approach we demonstrated that generation of infectious ebolavirus pseudoviruses (EBOVpv) were also sensitive to the amount, and ratio, of plasmids used, and that protocols for optimal production of these pseudoviruses is dependent on the exact virus glycoprotein construct. These findings demonstrate that it is crucial for studies utilising pseudoviruses to conduct empirical optimisation of pseudotype production for each specific glycoprotein sequence to achieve optimal titres and facilitate accurate phenotyping

Flexible and rapid construction of viral chimeras applied to Hepatitis C Virus

A novel and broadly applicable strategy combining site directed mutagenesis and DNA assembly for constructing seamless viral chimeras is described using Hepatitis C Virus as an exemplar. Full-length HCV genomic cloning cassettes, which contained flexibly situated restriction endonuclease sites, were prepared via a single site-directed mutagenesis reaction and digested to receive PCR amplified virus envelope genes by In-Fusion cloning. Using this method we were able to construct gene-shuttle cassettes for generation of cell culture-infectious JFH-1-based chimeras containing genotype 1-3 E1E2 genes. Importantly, using this method we also show that E1E2 clones that were not able to support cell entry in the HCV pseudoparticle assay did confer entry when shuttled into the chimeric cell culture chimera system. This method can be easily applied to other genes of study and other viruses and, as such, will greatly simplify reverse genetics studies of variable viruses

Immunization with a synthetic consensus hepatitis C virus E2 glycoprotein ectodomain elicits virus-neutralizing antibodies

Global eradication of hepatitis C virus (HCV) infection will require an efficacious vaccine capable of eliciting protective immunity against genetically diverse HCV strains. Natural spontaneous resolution of HCV infection is associated with production of broadly neutralizing antibodies targeting the HCV glycoproteins E1 and E2. As such, production of cross-neutralizing antibodies is an important endpoint for experimental vaccine trials. Varying success generating cross-neutralizing antibodies has been achieved with immunogens derived from naturally-occurring HCV strains. In this study the challenge of minimising the genetic diversity between the vaccine strain and circulating HCV isolates was addressed. Two novel synthetic E2 glycoprotein immunogens (NotC1 and NotC2) were derived from consensus nucleotide sequences deduced from samples of circulating genotype 1 HCV strains. These two synthetic sequences differed in their relative positions in the overall genotype 1a/1b phylogeny. Expression of these constructs in Drosophila melanogaster S2 cells resulted in high yields of correctly-folded, monomeric E2 protein, which were recognised by broadly neutralizing monoclonal antibodies. Immunization of guinea pigs with either of these consensus immunogens, or a comparable protein representing a circulating genotype 1a strain resulted in high titres of cross-reactive anti-E2 antibodies. All immunogens generated antibodies capable of neutralizing the H77 strain, but NotC1 elicited antibodies that more potently neutralized virus entry. These vaccine-induced antibodies neutralized some viruses representing genotype 1, but not strains representing genotype 2 or genotype 3. Thus, while this approach to vaccine design resulted in correctly folded, immunogenic protein, cross-neutralizing epitopes were not preferentially targeted by the host immune response generated by this immunogen. Greater immunofocussing by vaccines to common epitopes is necessary to successfully elicit broadly neutralizing antibodies