Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms

Copy number variation (CNV) is known to cause all von Willebrand disease (VWD) types, although the associated pathogenic mechanisms involved have not been extensively studied. Notably, in-frame CNV provides a unique opportunity to investigate how specific von Willebrand factor (VWF) domains influence the processing and packaging of the protein. Using multiplex ligation-dependent probe amplification, this study determined the extent to which CNV contributed to VWD in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease cohort, highlighting in-frame deletions of exons 3, 4-5, 32-34, and 33-34. Heterozygous in vitro recombinant VWF expression demonstrated that, although deletion of exons 3, 32-34, and 33-34 all resulted in significant reductions in total VWF (P < .0001, P < .001, and P < .01, respectively), only deletion of exons 3 and 32-34 had a significant impact on VWF secretion (P < .0001). High-resolution microscopy of heterozygous and homozygous deletions confirmed these observations, indicating that deletion of exons 3 and 32-34 severely impaired pseudo-Weibel-Palade body (WPB) formation, whereas deletion of exons 33-34 did not, with this variant still exhibiting pseudo-WPB formation similar to wild-type VWF. In-frame deletions in VWD, therefore, contribute to pathogenesis via moderate or severe defects in VWF biosynthesis and secretion

Tellurium, the forgotten element: a review for the properties, processes and biomedical applications of the bulk and nanoscale metalloid

Tellurium (Te) is a brittle, mildly toxic, and rare metalloid with an extremely low abundance in the planet. The element has been used in both its bulk and nanoscale forms for several applications in solar cell industry, semiconductors, catalysis, or heavy metal removal, among others. The end of the last century witnessed an explosion in new strategies for synthesizing different Te nanostructures with controlled compositions, sizes, morphologies, and properties, which allow these structures to enhance their impact in numerous applications. Nanomedicine has recently taken advantage of the metalloid in its nanoscale, showing promising applications as antibacterial, anticancer, and imaging agents. Nevertheless, the biological role of Te within living organisms remains mostly unknown, and just a few reports appear working on this matter. In this chapter, the forgotten elements are extensively studied in terms of its chemical, physical, and geological properties, and its main applications are summarized and studied for both bulk and nanosized tellurium. At the end, tellurium’s most important biomedical applications are presented with the aim to establish a general concept of the metalloid as a powerful biomedical tool with a bright future yet to be discovered.Peer reviewe