Fusion of RVG or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disease caused by a mutation in the IDS gene, resulting in deficiency of the enzyme iduronate-2-sulfatase (IDS) causing heparan sulfate (HS) and dermatan sulfate (DS) accumulation in all cells. This leads to skeletal and cardiorespiratory disease with severe neurodegeneration in two thirds of sufferers. Enzyme replacement therapy is ineffective at treating neurological disease, as intravenously-delivered IDS is unable to cross the blood-brain barrier (BBB). Haematopoietic stem cell transplant is also unsuccessful, presumably due to insufficient IDS enzyme production from transplanted cells engrafting in the brain. We used two different peptide sequences (RVG and gh625), both previously published as BBB-crossing peptides, fused to IDS and delivered via haematopoietic stem cell gene therapy (HSCGT). HSCGT with LV.IDS.RVG and LV.IDS.gh625 was compared to LV.IDS.ApoEII and LV.IDS in MPSII mice at 6-months post-transplant. Levels of IDS enzyme activity in the brain and peripheral tissues were lower in LV.IDS.RVG and LV.IDS.gh625 treated mice than in LV.IDS.ApoEII and LV.IDS treated mice, despite comparable vector copy numbers. Microgliosis, astrocytosis and lysosomal swelling were partially normalised in MPSII mice treated with LV.IDS.RVG and LV.IDS.gh625. Skeletal thickening was normalised by both treatments to wild-type levels. Although reductions in skeletal abnormalities and neuropathology are encouraging, given the low levels of enzyme activity compared to control tissue from LV.IDS and LV.IDS.ApoEII transplanted mice, the RVG and gh625 peptides are unlikely to be ideal candidates for HSCGT in MPSII, and are inferior to the ApoEII peptide that we have previously demonstrated to be more effective at correcting MPSII disease than IDS alone

Exploiting a fast neutron mutant genetic resource in Pisum sativum (pea) for functional genomics

A fast neutron mutagenised population was generated in Pisum sativum L. (pea) to enable the identification and isolation of genes underlying traits and processes. Studies of a number of phenotypic traits have clearly demonstrated the utility of the resource by associating gene deletions with phenotype followed by functional tests exploiting additional mutant sources, from both induced and natural variant germplasm. For forward genetic screens next generation sequencing methodologies provide an opportunity for identifying genes associated with deletions rapidly and systematically. The application of rapid reverse genetic screens of the fast neutron mutant pea population supports conclusions on the frequency of deletions based on phenotype alone. These studies further suggest that large deletions affecting one or more loci can be non-deleterious to the pea genome, yielding mutants that could not be obtained by other means. Deletion mutants affecting genes associated with seed metabolism and storage are providing unique opportunities to identify the products of complex and related gene families, and to study the downstream consequences of such deletion

Learning in the European Union: Theoretical Lenses and Meta-Theory

notes: This paper is based on research carried out with the support of the European Research Council grant on Analysis of Learning in Regulatory Governance, ALREG http://centres.exeter.ac.uk/ceg/research/ALREG/index.php. The authors wish to express their gratitude to the other authors in this special edition and in particular its editor, Nikos Zaharaidis and X anonymous referees.publication-status: AcceptedThe European Union may well be a learning organization, yet there is still confusion about the nature of learning, its causal structure and the normative implications. In this article we select four perspectives that address complexity, governance, the agency-structure nexus, and how learning occurs or may be blocked by institutional features. They are transactional theory, purposeful opportunism, experimental governance, and the joint decision trap. We use the four cases to investigate how history and disciplinary traditions inform theory; the core causal arguments about learning; the normative implications of the analysis; the types of learning that are theoretically predicted; the meta-theoretical aspects and the lessons for better theories of the policy process and political scientists more generally

Correction to: The tree that hides the forest : cryptic diversity and phylogenetic relationships in the Palaearctic vector Obsoletus/Scoticus complex (Diptera: Ceratopogonidae) at the European level

An amendment to this paper has been published and can be accessed via the original article

The tree that hides the forest : cryptic diversity and phylogenetic relationships in the Palaearctic vector Obsoletus/Scoticus Complex (Diptera: Ceratopogonidae) at the European level

Correction: Volume: 13 Issue: 1 Article Number: 483 DOI: 10.1186/s13071-020-04349-yBackgroundCulicoides obsoletus is an abundant and widely distributed Holarctic biting midge species, involved in the transmission of bluetongue virus (BTV) and Schmallenberg virus (SBV) to wild and domestic ruminants. Females of this vector species are often reported jointly with two morphologically very close species, C. scoticus and C. montanus, forming the Obsoletus/Scoticus Complex. Recently, cryptic diversity within C. obsoletus was reported in geographically distant sites. Clear delineation of species and characterization of genetic variability is mandatory to revise their taxonomic status and assess the vector role of each taxonomic entity. Our objectives were to characterize and map the cryptic diversity within the Obsoletus/Scoticus Complex.MethodsPortion of the cox1 mitochondrial gene of 3763 individuals belonging to the Obsoletus/Scoticus Complex was sequenced. Populations from 20 countries along a Palaearctic Mediterranean transect covering Scandinavia to Canary islands (North to South) and Canary islands to Turkey (West to East) were included. Genetic diversity based on cox1 barcoding was supported by 16S rDNA mitochondrial gene sequences and a gene coding for ribosomal 28S rDNA. Species delimitation using a multi-marker methodology was used to revise the current taxonomic scheme of the Obsoletus/Scoticus Complex.ResultsOur analysis showed the existence of three phylogenetic clades (C. obsoletus clade O2, C. obsoletus clade dark and one not yet named and identified) within C. obsoletus. These analyses also revealed two intra-specific clades within C. scoticus and raised questions about the taxonomic status of C. montanus.ConclusionsTo our knowledge, our study provides the first genetic characterization of the Obsoletus/Scoticus Complex on a large geographical scale and allows a revision of the current taxonomic classification for an important group of vector species of livestock viruses in the Palaearctic region.Peer reviewe

Effusive and explosive volcanism on the ultraslow-spreading Gakkel Ridge, 85°E

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 13 (2012): Q10005, doi:10.1029/2012GC004187.We use high-definition seafloor digital imagery and multibeam bathymetric data acquired during the 2007 Arctic Gakkel Vents Expedition (AGAVE) to evaluate the volcanic characteristics of the 85°E segment of the ultraslow spreading Gakkel Ridge (9 mm yr−1 full rate). Our seafloor imagery reveals that the axial valley is covered by numerous, small-volume (order ~1000 m3) lava flows displaying a range of ages and morphologies as well as unconsolidated volcaniclastic deposits with thicknesses up to 10 cm. The valley floor contains two prominent volcanic lineaments made up of axis-parallel ridges and small, cratered volcanic cones. The lava flows appear to have erupted from a number of distinct source vents within the ~12–15 km-wide axial valley. Only a few of these flows are fresh enough to have potentially erupted during the 1999 seismic swarm at this site, and these are associated with the Oden and Loke volcanic cones. We model the widespread volcaniclastic deposits we observed on the seafloor as having been generated by the explosive discharge of CO2 that accumulated in (possibly deep) crustal melt reservoirs. The energy released during explosive discharge, combined with the buoyant rise of hot fluid, lofted fragmented clasts of rapidly cooling magma into the water column, and they subsequently settled onto the seafloor as fall deposits surrounding the source vent.We gratefully acknowledge the financial support of the National Aeronautics and Space Administration, the National Science Foundation (N.S.F.), the International Polar Year 2007–2008, and Woods Hole Oceanographic Institution; and the graduate support provided by N.S.F., the NDSEG Fellowship, and WHOI Deep Ocean Exploration Institute.2013-04-0

Molecular Imaging of Pulmonary Tuberculosis in an Ex-Vivo Mouse Model Using Spectral Photon-Counting Computed Tomography and Micro-CT

Assessment of disease burden and drug efficacy is achieved preclinically using high resolution micro computed tomography (CT). However, micro-CT is not applicable to clinical human imaging due to operating at high dose. In addition, the technology differences between micro-CT and standard clinical CT prevent direct translation of preclinical applications. The current proof-of-concept study presents spectral photon-counting CT as a clinically translatable, molecular imaging tool by assessing contrast uptake in an ex-vivo mouse model of pulmonary tuberculosis (TB). Iodine, a common contrast used in clinical CT imaging, was introduced into a murine model of TB. The excised mouse lungs were imaged using a standard micro-CT subsystem (SuperArgus) and the contrast enhanced TB lesions quantified. The same lungs were imaged using a spectral photoncounting CT system (MARS small-bore scanner). Iodine and soft tissues (water and lipid) were materially separated, and iodine uptake quantified. The volume of the TB infection quantified by spectral CT and micro-CT was found to be 2.96 mm(3) and 2.83 mm(3), respectively. This proof-of-concept study showed that spectral photon-counting CT could be used as a predictive preclinical imaging tool for the purpose of facilitating drug discovery and development. Also, as this imaging modality is available for human trials, all applications are translatable to human imaging. In conclusion, spectral photon-counting CT could accelerate a deeper understanding of infectious lung diseases using targeted pharmaceuticals and intrinsic markers, and ultimately improve the efficacy of therapies by measuring drug delivery and response to treatment in animal models and later in humans