Cytokine exposure mediates transcriptional activation of the orphan nuclear receptor Nur77 in hematopoietic cells

The orphan nuclear receptor Nur77 is an immediate-early response gene that based on tissue and cell context is implicated in a plethora of cellular processes, including proliferation, differentiation, apoptosis, metabolism, and inflammation. Nur77 has a ligand-binding pocket that is obstructed by hydrophobic side groups. Naturally occurring, cell-endogenous ligands have not been identified, and Nur77 transcriptional activity is thought to be regulated through posttranslational modification and modulation of protein levels. To determine whether Nur77 is transcriptionally active in hematopoietic cells in vivo, we used an upstream activating sequence (UAS)-GFP transgenic reporter. We found that Nur77 is transcriptionally inactive in vivo in hematopoietic cells under basal conditions, but that activation occurs following cytokine exposure by G-CSF or IL-3. We also identified a series of serine residues required for cytokine-dependent transactivation of Nur77. Moreover, a kinase inhibitor library screen and proximity labeling-based mass spectrometry identified overlapping kinase pathways that physically interacted with Nur77 and whose inhibition abrogated cytokine-induced activation of Nur77. We determined that transcriptional activation of Nur77 by G-CSF or IL-3 requires functional JAK and mTor signaling since their inhibition leads to Nur77 transcriptional inactivation. Thus, intracellular cytokine signaling networks appear to regulate Nur77 transcriptional activity in mouse hematopoietic cells

On the multiple Borsuk numbers of sets

The Borsuk number of a set S of diameter d >0 in Euclidean n-space is the smallest value of m such that S can be partitioned into m sets of diameters less than d. Our aim is to generalize this notion in the following way: The k-fold Borsuk number of such a set S is the smallest value of m such that there is a k-fold cover of S with m sets of diameters less than d. In this paper we characterize the k-fold Borsuk numbers of sets in the Euclidean plane, give bounds for those of centrally symmetric sets, smooth bodies and convex bodies of constant width, and examine them for finite point sets in the Euclidean 3-space.Comment: 16 pages, 3 figure

Eutactic quantum codes

We consider sets of quantum observables corresponding to eutactic stars. Eutactic stars are systems of vectors which are the lower dimensional ``shadow'' image, the orthogonal view, of higher dimensional orthonormal bases. Although these vector systems are not comeasurable, they represent redundant coordinate bases with remarkable properties. One application is quantum secret sharing.Comment: 6 page

Morphological characterization of shocked porous material

Morphological measures are introduced to probe the complex procedure of shock wave reaction on porous material. They characterize the geometry and topology of the pixelized map of a state variable like the temperature. Relevance of them to thermodynamical properties of material is revealed and various experimental conditions are simulated. Numerical results indicate that, the shock wave reaction results in a complicated sequence of compressions and rarefactions in porous material. The increasing rate of the total fractional white area $A$ roughly gives the velocity $D$ of a compressive-wave-series. When a velocity $D$ is mentioned, the corresponding threshold contour-level of the state variable, like the temperature, should also be stated. When the threshold contour-level increases, $D$ becomes smaller. The area $A$ increases parabolically with time $t$ during the initial period. The $A(t)$ curve goes back to be linear in the following three cases: (i) when the porosity $\delta$ approaches 1, (ii) when the initial shock becomes stronger, (iii) when the contour-level approaches the minimum value of the state variable. The area with high-temperature may continue to increase even after the early compressive-waves have arrived at the downstream free surface and some rarefactive-waves have come back into the target body. In the case of energetic material ... (see the full text)Comment: 3 figures in JPG forma

Improper colourings inspired by Hadwiger’s conjecture

Hadwiger’s Conjecture asserts that every Kt-minor-free graph has a proper (t − 1)-colouring. We relax the conclusion in Hadwiger’s Conjecture via improper colourings. We prove that every Kt-minor-free graph is (2t − 2)-colourable with monochromatic components of order at most 1/2 (t − 2). This result has no more colours and much smaller monochromatic components than all previous results in this direction. We then prove that every Kt-minor-free graph is (t − 1)-colourable with monochromatic degree at most t − 2. This is the best known degree bound for such a result. Both these theorems are based on a decomposition method of independent interest. We give analogous results for Ks,t-minorfree graphs, which lead to improved bounds on generalised colouring numbers for these classes. Finally, we prove that graphs containing no Kt-immersion are 2-colourable with bounded monochromatic degree

Extended morphometric analysis of neuronal cells with Minkowski valuations

Minkowski valuations provide a systematic framework for quantifying different aspects of morphology. In this paper we apply vector- and tensor-valued Minkowski valuations to neuronal cells from the cat's retina in order to describe their morphological structure in a comprehensive way. We introduce the framework of Minkowski valuations, discuss their implementation for neuronal cells and show how they can discriminate between cells of different types.Comment: 14 pages, 18 postscript figure

RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from those of two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacological antagonists, suggesting it may be ligand-independent. These data provide further evidence that activated retinoid X receptors can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of retinoid X receptors in other settings

Concentration of the intrinsic volumes of a convex body

The intrinsic volumes are measures of the content of a convex body. This paper applies probabilistic and information-theoretic methods to study the sequence of intrinsic volumes. The main result states that the intrinsic volume sequence concentrates sharply around a specific index, called the central intrinsic volume. Furthermore, among all convex bodies whose central intrinsic volume is fixed, an appropriately scaled cube has the intrinsic volume sequence with maximum entropy

RXRA DT448/9PP generates a dominant active variant capable of inducing maturation in acute myeloid leukemia cells.

RARA and RXRA contribute to myeloid maturation in both mice and humans, and deletion of Rxra and Rxrb augments leukemic growth in mice. While defining the domains of RXRA that are required for anti-leukemic effects in murine KMT2A-MLLT3 leukemia cells, we unexpectedly identified RXRA DT448/9PP as a constitutively active variant capable of inducing maturation and loss of their proliferative phenotype. RXRA DT448/9PP was associated with ligand-independent activity in reporter assays, with enhanced co-activator interactions, reduced engraftment in vivo, and activation of myeloid maturation transcriptional signatures that overlapped with those of cells treated with the potent RXRA agonist bexarotene, suggestive of constitutive activity that leads to leukemic maturation. Phenotypes of RXRA DT448/9PP appear to differ from those of two other RXRA mutations with forms of constitutive activity (F318A and S427F), in that DT448/9PP activity was resistant to mutations at critical ligand-interacting amino acids (R316A/L326A) and was resistant to pharmacological antagonists, suggesting it may be ligand-independent. These data provide further evidence that activated retinoid X receptors can regulate myeloid maturation and provide a novel constitutively active variant that may be germane for broader studies of retinoid X receptors in other settings.This work was supported by National Institutes of Health grant R01 HL128447 (JSW) , by the Siteman Investment Program (JSW) , the Washington University SPORE DRP (JSW and MAF) , the Children's Discovery Institute (JSW) , the Alex's Lemonade Stand Foundation Young Investigator Award (MAF) , the National Institutes of Health 5K12HD07622408 (MAF) , and grants from the Spanish Ministerio de Ciencia e Innovacion (MCI) (SAF2017-90604-REDT-NurCaMeIn, RTI2018-095928-BI00) (MR).S