ORCID Profile
0000-0003-1717-2549
Current Organisation
Universiteit Leiden
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Publisher: Springer Science and Business Media LLC
Date: 20-07-2016
DOI: 10.1038/NCOMMS11387
Abstract: The poorly studied picornavirus, human parechovirus 3 (HPeV3) causes neonatal sepsis with no therapies available. Our 4.3-Å resolution structure of HPeV3 on its own and at 15 Å resolution in complex with human monoclonal antibody Fabs demonstrates the expected picornavirus capsid structure with three distinct features. First, 25% of the HPeV3 RNA genome in 60 sites is highly ordered as confirmed by asymmetric reconstruction, and interacts with conserved regions of the capsid proteins VP1 and VP3. Second, the VP0 N terminus stabilizes the capsid inner surface, in contrast to other picornaviruses where on expulsion as VP4, it forms an RNA translocation channel. Last, VP1’s hydrophobic pocket, the binding site for the antipicornaviral drug, pleconaril, is blocked and thus inappropriate for antiviral development. Together, these results suggest a direction for development of neutralizing antibodies, antiviral drugs based on targeting the RNA–protein interactions and dissection of virus assembly on the basis of RNA nucleation.
Publisher: American Diabetes Association
Date: 27-04-2015
DOI: 10.2337/DB14-1752
Abstract: Loss of pancreatic islet β-cell mass and β-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulin-containing β-cells can convert into glucagon-containing α-cells ex vivo. This loss of β-cell identity was characterized by the presence of β-cell transcription factors (Nkx6.1, Pdx1) in glucagon+ cells. Here, we investigated whether the loss of β-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin+ cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1+ but insulin− coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1+glucagon+insulin− cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1+glucagon+insulin− cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of β-cell identity occurs in T2DM and could contribute to the decrease of functional β-cell mass. Maintenance of β-cell identity is a potential novel strategy to preserve β-cell function in diabetes.
Location: United States of America
No related grants have been discovered for Abraham Koster.