Knock-in of murine Calr del52 induces essential thrombocythemia with slow-rising dominance in mice and reveals key role of Calr exon 9 in cardiac development.

Frameshifting mutations (-1/+2) of the calreticulin (CALR) gene are responsible for the development of essential thrombocythemia (ET) and primary myelofibrosis (PMF). The mutant CALR proteins activate the thrombopoietin receptor (TpoR) inducing cytokine-independent megakaryocyte progenitor proliferation. Here, we generated via CRISPR/Cas9 technology two knock-in mouse models that are heterozygous for a type-I murine Calr mutation. These mice exhibit an ET phenotype with elevated circulating platelets compared with wild-type controls, consistent with our previous results showing that murine CALR mutants activate TpoR. We also show that the mutant CALR proteins can be detected in plasma. The phenotype of Calr del52 is transplantable, and the Calr mutated hematopoietic cells have a slow-rising advantage over wild-type hematopoiesis. Importantly, a homozygous state of a type-1 Calr mutation is lethal at a late embryonic development stage, showing narrowed ventricular myocardium walls, similar to the murine Calr knockout phenotype, pointing to the C terminus of CALR as crucial for heart development

The Design of Core 2: A Library for Exact Numeric Computation in Geometry and Algebra

There is a growing interest in numeric-algebraic techniques in the computer algebra community as such techniques can speed up many applications. This paper is concerned with one such approach called Exact Numeric Computation (ENC). The ENC approach to algebraic number computation is based on iterative verified approximations, combined with constructive zero bounds. This paper describesCore 2, the latest version of the Core Library, a package designed for applications such as non-linear computational geometry. The adaptive complexity of ENC combined with filters makes such libraries practical. Core 2 smoothly integrates our algebraic ENC subsystem with transcendental functions with ε-accurate comparisons. This paper describes how the design of Core 2 addresses key software issues such as modularity, extensibility, and efficiency in a setting that combines algebraic and transcendental elements. Our redesign preserves the original goals of the Core Library, namely, to provide a simple and natural interface for ENC computation to support rapid prototyping and exploration. We present examples, experimental results, and timings for our new system, released as Core Library 2.0