New gene functions in megakaryopoiesis and platelet formation

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.     

Plant ribosome-inactivating proteins type II induce the unfolded protein response in human cancer cells

Cytotoxic ribosome-inactivating proteins (RIPs) of type II such as ricin were investigated as anti-cancer agents, but also pose a threat as biological weapons. The molecular mechanism leading to their toxic effects is, however, not yet clear. The current paradigm, which states that the irreversible depurination of 28S rRNA results in a general translational arrest eventually leading to cell death, has been questioned. Using micro-array, qRT-PCR and Western blot, we identified the unfolded protein response (UPR), a cellular mechanism activated in response to endoplasmic reticulum stress, that is induced in HCT116 and MDA-MB-231 cells exposed to the plant type II RIPs ricin, riproximin and volkensin. Apoptosis was induced by concentrations at which translation of UPR-related genes still occurred, despite concomitant ribosomal depurination. We conclude that UPR induction represents a model that better describes the cellular effects of RIP exposure at concentrations at which selected proteins are translated despite ribosomal depurination.     

Effect of potassium on isolated bovine facial and human saphenous veins

Summary A moderate elevation of external (K ₀ ⁺ ) (5–10 mM) induces relaxation in bovine facial and human saphenous veins. A further increase of (K ₀ ⁺ ) leads to biphasic reactions (relaxation followed by contraction). Concentrations of (K ₀ ⁺ ) higher than about 15 mM cause contractions only. The potassium-induced relaxation may be explained by the stimulation of an electrogenic sodium pump.     

Orientation to learning context modulates retrieval processing for unrecognized words

Explicit memory errors may occur when individuals fail to retrieve information about items previously studied (item memory) or about the learning context (source memory). We examined electrophysiological measures during recognition failure in order to determine the influence of retrieval orientation for item versus source information. Recognition failure was associated with brain potentials distinct from those associated with success. Furthermore, source-memory failures were associated with earlier-onset brain potentials with a more anterior distribution compared to item-memory failures. Neurocognitive processing was thus modulated by retrieval orientation so as to differentially influence neural correlates of successful versus unsuccessful retrieval.