2,290 research outputs found

    Galactosemia: Towards Pharmacological Chaperones

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    Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia.ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency RTI2018-096246-B-I00FEDER/Junta de Andalucía - Consejería de Transformación Económica, Industria, Conocimiento y Universidades P18-RT-241

    Model-based 3D micro-navigation and bathymetry estimation for interferometric synthetic aperture sonar

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    Sub-wavelength navigation information is vital for the formation of all synthetic aperture sonar (SAS) data products. This challenging requirement can be achieved using the redundant phase centre (RPC) or displaced phase centre antenna (DPCA) micro-navigation algorithm, which uses cross-correlation of signals with inter-ping coherence to estimate time delays and hence make navigation estimates. In this paper a new approach to micro- navigation for interferometric synthetic aperture sonar is introduced. The algorithm makes 3D vehicle position estimates for each sonar ping by making use of time delays measured between all possible pairs of redundant phase centre arrays, using both interferometric arrays on each side of the vehicle. Simultaneous estimation of coarse bathymetry allows the SAS images to be projected onto ground-range. The method is based on non-linear minimization of the difference in modelled and measured time delays and surges between redundant phase centre arrays. The approach is demonstrated using data collected by the CMRE MUSCLE AUV using its 270-330 kHz SAS during the MANEX’14 experiment. SAS images have been projected onto the coarsely estimated bathymetry, and interferograms have been formed. The coarse bathymetry estimate and vehicle navigation estimate are validated by the quality of the image focussing and the near-zero phase of the interferogram. The method has the potential to improve through-the-sensor navigation aiding and to increase the accuracy of single-pass bathymetry estimation. Future development of the algorithm for repeat-pass operation has the potential to enable repeat-pass track registration in three dimensions. The method is therefore an important step towards improved coherent change detection and high resolution bathymetry estimation

    Phase wrap error correction by random sample consensus with application to synthetic aperture sonar micro-navigation

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    PhylOTU: a high-throughput procedure quantifies microbial community diversity and resolves novel taxa from metagenomic data.

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    Microbial diversity is typically characterized by clustering ribosomal RNA (SSU-rRNA) sequences into operational taxonomic units (OTUs). Targeted sequencing of environmental SSU-rRNA markers via PCR may fail to detect OTUs due to biases in priming and amplification. Analysis of shotgun sequenced environmental DNA, known as metagenomics, avoids amplification bias but generates fragmentary, non-overlapping sequence reads that cannot be clustered by existing OTU-finding methods. To circumvent these limitations, we developed PhylOTU, a computational workflow that identifies OTUs from metagenomic SSU-rRNA sequence data through the use of phylogenetic principles and probabilistic sequence profiles. Using simulated metagenomic data, we quantified the accuracy with which PhylOTU clusters reads into OTUs. Comparisons of PCR and shotgun sequenced SSU-rRNA markers derived from the global open ocean revealed that while PCR libraries identify more OTUs per sequenced residue, metagenomic libraries recover a greater taxonomic diversity of OTUs. In addition, we discover novel species, genera and families in the metagenomic libraries, including OTUs from phyla missed by analysis of PCR sequences. Taken together, these results suggest that PhylOTU enables characterization of part of the biosphere currently hidden from PCR-based surveys of diversity

    The Productivity of Wh- Prompts in Child Forensic Interviews.

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    Child witnesses are often asked wh- prompts (what, how, why, who, when, where) in forensic interviews. However, little research has examined the ways in which children respond to different wh- prompts, and no previous research has investigated productivity differences among wh- prompts in investigative interviews. This study examined the use and productivity of wh- prompts in 95 transcripts of 4- to 13-year-olds alleging sexual abuse in child investigative interviews. What-how questions about actions elicited the most productive responses during both the rapport building and substantive phases. Future research and practitioner training should consider distinguishing among different wh- prompts.This research was supported in part by the Nuffield Foundation, Jacobs Foundation, an NICHD Grant HD047290, and an ESRC studentship.This is the author accepted manuscript. The final version is available from SAGE via http://dx.doi.org/10.1177/088626051562108

    A qualitative investigation of obese men\u27s experiences with their weight

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    Objectives: To investigate obese men\u27s health behaviors and strategies for change. Methods: Qualitative interviews with 36 men (BMI 30 and over). Results: All men felt personally responsible for their weight gain. Sedentary lifestyles, stress, lack of worklife balance and weight-based stigma were all significant causes of weight gain and barriers to weight loss. These factors also contributed to men\u27s unwillingness to seek help for their overweight. Conclusion: Addressing the self-blame and stigma associated with obesity is important in developing strategies to improve the health and well-being of obese men
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