First introduction of highly pathogenic H5N1 avian influenza A viruses in wild and domestic birds in Denmark, Northern Europe

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SLC35A2-related congenital disorder of glycosylation : Defining the phenotype

We aim to further delineate the phenotype associated with pathogenic variants in the SLC35A2 gene, and review all published literature to-date. This gene is located on the X chromosome and encodes a UDP-galactose transporter. Pathogenic variants in SLC35A2 cause a congenital disorder of glycosylation. The condition is rare, and less than twenty patients have been reported to-date. The phenotype is complex and has not been fully defined. Here, we present a series of five patients with de novo pathogenic variants in SLC35A2. The patients' phenotype includes developmental and epileptic encephalopathy with hypsarrhythmia, facial dysmorphism, severe intellectual disability, skeletal abnormalities, congenital cardiac disease and cortical visual impairment. Developmental and epileptic encephalopathy with hypsarrhythmia is present in most patients with SLC35A2 variants, and is drug-resistant in the majority of cases. Adrenocorticotropic hormone therapy may achieve partial or complete remission of seizures, but the effect is usually temporary. Isoelectric focusing of transferrins may be normal after infancy, therefore a congenital disorder of glycosylation should still be considered as a diagnosis in the presence of a suggestive phenotype. We also provide evidence that cortical visual impairment is part of the phenotypic spectrum. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.Peer reviewe

The GEF Trio controls endothelial cell size and arterial remodeling downstream of Vegf signaling in both zebrafish and cell models

Arterial networks enlarge in response to increase in tissue metabolism to facilitate flow and nutrient delivery. Typically, the transition of a growing artery with a small diameter into a large caliber artery with a sizeable diameter occurs upon the blood flow driven change in number and shape of endothelial cells lining the arterial lumen. Here, using zebrafish embryos and endothelial cell models, we describe an alternative, flow independent model, involving enlargement of arterial endothelial cells, which results in the formation of large diameter arteries. Endothelial enlargement requires the GEF1 domain of the guanine nucleotide exchange factor Trio and activation of Rho-GTPases Rac1 and RhoG in the cell periphery, inducing F-actin cytoskeleton remodeling, myosin based tension at junction regions and focal adhesions. Activation of Trio in developing arteries in vivo involves precise titration of the Vegf signaling strength in the arterial wall, which is controlled by the soluble Vegf receptor Flt1. Arterial flow regulates artery diameter but other mechanisms may also affect this. Here, the authors show that the guanine nucleotide exchange factor Trio and GTPases Rac1 and RhoG, triggers F-actin remodeling in arterial endothelial cells, independent of flow, to enhance lumen diameter in zebrafish and cell models.Peer reviewe

Investigation of the presence of human or bovine respiratory syncytial virus in the lungs of mink (Neovison vison) with hemorrhagic pneumonia due to Pseudomonas aeruginosa

<p>Abstract</p> <p>Background</p> <p>Hemorrhagic pneumonia is a disease of farmed mink (<it>Neovison vison</it>) caused by <it>Pseudomonas aeruginosa</it>. The disease is highly seasonal in Danish mink with outbreaks occurring almost exclusively in the autumn. Human respiratory syncytial virus (RSV) has been shown to augment infection with <it>P. aeruginosa</it> in mice and to promote adhesion of <it>P. aeruginosa</it> to human respiratory cells.</p> <p>Findings</p> <p>We tested 50 lung specimens from mink with hemorrhagic pneumonia for bovine RSV by reverse transcriptase polymerase chain reaction (PCR) and for human RSV by a commercial real-time PCR. RSV was not found.</p> <p>Conclusions</p> <p>This study indicates that human and bovine RSV is not a major co-factor for development of hemorrhagic pneumonia in Danish mink.</p

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy

Malaria eradication: the economic, financial and institutional challenge

Malaria eradication raises many economic, financial and institutional challenges. This paper reviews these challenges, drawing on evidence from previous efforts to eradicate malaria, with a special focus on resource-poor settings; summarizes more recent evidence on the challenges, drawing on the literature on the difficulties of scaling-up malaria control and strengthening health systems more broadly; and explores the implications of these bodies of evidence for the current call for elimination and intensified control