Over-expression of Dyrk1A affects bleeding by modulating plasma fibronectin and fibrinogen level in mice

Down syndrome is the most common chromosomal abnormality in humans. Patients with Down syndrome have hematologic disorders, including mild to moderate thrombocytopenia. In case of Down syndrome, thrombocytopenia is not associated with bleeding, and it remains poorly characterized regarding molecular mechanisms. We investigated the effects of overexpression of Dyrk1A, an important factor contributing to some major Down syndrome phenotypes, on platelet number and bleeding in mice. Mice overexpressing Dyrk1A have a decrease in platelet number by 20%. However, bleeding time was found to be reduced by 50%. The thrombocytopenia and the decreased bleeding time observed were not associated to an abnormal platelet receptors expression, to a defect of platelet activation by ADP, thrombin or convulxin, to the presence of activated platelets in the circulation or to an abnormal half-life of the platelets. To propose molecular mechanisms explaining this discrepancy, we performed a network analysis of Dyrk1A interactome and demonstrated that Dyrk1A, fibronectin and fibrinogen interact indirectly through two distinct clusters of proteins. Moreover, in mice overexpressing Dyrk1A, increased plasma fibronectin and fibrinogen levels were found, linked to an increase of the hepatic fibrinogen production. Our results indicate that overexpression of Dyrk1A in mice induces decreased bleeding consistent with increased plasma fibronectin and fibrinogen levels, revealing a new role of Dyrk1A depending on its indirect interaction with these two proteins.     

Climate change is predicted to cause population collapse in a cooperative breeder

It has been suggested that animals may have evolved cooperative breeding strategies in response to extreme climatic conditions. Climate change, however, may push species beyond their ability to cope with extreme climates, and reduce the group sizes in cooperatively breeding species to a point where populations are no longer viable. Predicting the impact of future climates on these species is challenging as modelling the impact of climate change on their population dynamics requires information on both group- and individual-level responses to climatic conditions. Using a single-sex individual-based model incorporating demographic responses to ambient temperature in an endangered species, the African wild dog Lycaon pictus, we show that there is a threshold temperature above which populations of the species are predicted to collapse. For simulated populations with carrying capacities equivalent to the median size of real-world populations (nine packs), extinction risk increases once temperatures exceed those predicted in the best-case climate warming scenario (Representative Concentration Pathway [RCP] 2.6). The threshold is higher (between RCP 4.5 and RCP 6.0) for larger simulated populations (30 packs), but 84% of real-world populations number <30 packs. Simulated populations collapsed because, at high ambient temperatures, juvenile survival was so low that packs were no longer recruiting enough individuals to persist, leading them to die out. This work highlights the importance of social dynamics in determining impacts of climatic variables on social species, and the critical role that recruitment can play in driving population-level impacts of climate change. Population models parameterised on long-term data are essential for predicting future population viability under climate change.     

A stimulatory role for the La-related protein 4B in translation

La-related proteins (LARPs) belong to an evolutionarily conserved family of factors with predicted roles in RNA metabolism. Here, we have analyzed the cellular interactions and function of LARP4B, a thus far uncharacterized member of the LARP family. We show that LARP4B is a cytosolic protein that accumulates upon arsenite treatment in cellular stress granules. Biochemical experiments further uncovered an interaction of LARP4B with the cytosolic poly(A) binding protein 1 (PABPC1) and the receptor for activated C Kinase (RACK1), a component of the 40S ribosomal subunit. Under physiological conditions, LARP4B co-sedimented with polysomes in cellular extracts, suggesting a role in translation. In agreement with this notion, overexpression of LARP4B stimulated protein synthesis, whereas knockdown of the factor by RNA interference impaired translation of a large number of cellular mRNAs. In sum, we identified LARP4B as a stimulatory factor of translation. We speculate that LARP4B exerts its function by bridging mRNA factors of the 3′ end with initiating ribosomes.     

Studies on the biological function of the nucleotide base of vitamin B12

Studies on the coenzyme activity of some nucleotide base analogues of adenosylcobalamine in the dioldehydratase and methyl-malonyl-CoA mutase systems resulted in fundamental differences: Contrary to dioldehydratase the coenzyme activity remains in the methyl-malonyl-CoA mutase system when adenosyl-cobamides with a strongly modified nucleotide base are studied. The analogues give a good growth response with Escherichia coli. In the growth test with Lactobacillus leichmanii only the cobamides that do not have substituted nucleotide bases in the positions 2 or 3 of their imidazole ring are active.     

NDNF interneurons in layer 1 gain-modulate whole cortical columns according to an animal’s behavioral state

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