Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment

www.cs.uu.nl Region Intervisibility in Terrains

A polyhedral terrain is the graph of a continuous piecewise linear function defined over the triangles of a triangulation in the xy-plane. Two points on or above a terrain are visible to each other if the line-of-sight does not intersect the space below the terrain. In this paper, we look at three related visibility problems in terrains. Suppose we are given a terrain T with n triangles and two regions R1 and R2 on T, i.e., two simply connected subsets of at most m triangles. First, we present an algorithm that determines, for any constant ɛ> 0, within O(n 1+ɛ m) time and storage whether or not R1 and R2 are completely intervisible. We also give an O(m 3 n 4) time algorithm to determine whether every point in R1 sees at least one point in R2. Finally, we present an O(m 2 n 2 log n) time algorithm to determine whether there exists a pair of points p ∈ R1 and q ∈ R2, such that p and q see each other.

Facility location on terrains

Given a terrain defined as a piecewise-linear function with n triangles, and m point sites on it, we would like to identify the location on the terrain that minimizes the maximum distance to the sites. The distance is measured as the length of the Euclidean shortest path along the terrain. To simplify the problem somewhat, we extend the terrain to (the surface of) a polyhedron. To compute the optimum placement, we compute the furthest-site Voronoi diagram of the sites on the polyhedron. The diagram has maximum combinatorial complexity Θ(mn²), and the algorithm runs in O(mn² log² mlogn) time

Simple Traversal of a Subdivision Without Extra Storage

In this paper we show how to traverse a subdivision and to report all cells, edges and vertices, without making use of mark bits in the structure or a stack. We do this by performing a depth-first search on the subdivision, using local criteria for deciding what is the next cell to visit. Our method is extremely simple and provably correct. The algorithm has applications in the field of Geographic Information Systems (GIS), where traversing subdivisions is a common operation, but modifying the database is unwanted or impossible. We show how to adapt our algorithm to answer related queries, such as windowing queries and reporting connected subsets of cells that have a common attribute. Finally, we show how to extend our algorithm such that it can handle convex 3-dimensional subdivisions. Keywords: Subdivisions, traversal algorithms, topological data structure, windowing, three dimensions. 1 Introduction The basic spatial vector data structure in any geographic information system is the..

Fc gamma receptors are expressed in the developing rat brain and activate downstream signaling molecules upon cross-linking with immune complex

Background Exposure of the developing brain to immune mediators, including antibodies, is postulated to increase risk for neurodevelopmental disorders and neurodegenerative disease. It has been suggested that immunoglobulin G-immune complexes (IgG-IC) activate Fc gamma receptors (FcγR) expressed on neurons to modify signaling events in these cells. However, testing this hypothesis is hindered by a paucity of data regarding neuronal FcγR expression and function. Methods FcγR transcript expression in the hippocampus, cortex, and cerebellum of neonatal male and female rats was investigated ex vivo and in mixed cultures of primary hippocampal and cortical neurons and astrocytes using quantitative PCR analyses. Expression at the protein level in mixed cultures of primary hippocampal and cortical neurons and astrocytes was determined by immunocytochemistry, western blotting, proteotype analysis, and flow cytometry. The functionality of these receptors was assessed by measuring changes in intracellular calcium levels, Erk phosphorylation, and IgG internalization following stimulation with IgG-immune complexes. Results FcgrIa, FcgrIIa, FcgrIIb, FcgrIIIa, and Fcgrt transcripts were detectable in the cortex, hippocampus, and cerebellum at postnatal days 1 and 7. These transcripts were also present in primary hippocampal and cortical cell cultures, where their expression was modulated by IFNγ. Expression of FcγRIa, FcγRIIb, and FcγRIIIa, but not FcγRIIa or FcRn proteins, was confirmed in cultured hippocampal and cortical neurons and astrocytes at the single cell level. A subpopulation of these cells co-expressed the activating FcγRIa and the inhibitory FcγRIIb. Functional analyses demonstrated that exposure of hippocampal and cortical cell cultures to IgG-IC increases intracellular calcium and Erk phosphorylation and triggers FcγR-mediated internalization of IgG. Conclusions Our data demonstrate that developing neurons and astrocytes in the hippocampus and the cortex express signaling competent FcγR. These findings suggest that IgG antibodies may influence normal neurodevelopment or function via direct interactions with FcγR on non-immune cells in the brain

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