RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells: A HOMEOSTATIC RESPONSE?

Transcription factor tonicity-responsive enhancer-binding protein (TonEBP/NFAT5) is critical for osmo-adaptation and extracellular matrix homeostasis of nucleus pulposus (NP) cells in their hypertonic tissue niche. Recent studies implicate TonEBP signaling in inflammatory disease and rheumatoid arthritis pathogenesis. However, broader functions of TonEBP in the disc remain unknown. RNA sequencing was performed on NP cells with TonEBP knockdown under hypertonic conditions. 1140 TonEBP-dependent genes were identified and categorized using Ingenuity Pathway Analysis. Bioinformatic analysis showed enrichment of matrix homeostasis and cytokine/chemokine signaling pathways. C-C motif chemokine ligand 2 (CCL2), interleukin 6 (IL6), tumor necrosis factor (TNF), and nitric oxide synthase 2 (NOS2) were studied further. Knockdown experiments showed that TonEBP was necessary to maintain expression levels of these genes. Gain- and loss-of-function experiments and site-directed mutagenesis demonstrated that TonEBP binding to a specific site in the CCL2 promoter is required for hypertonic inducibility. Despite inhibition by dominant-negative TonEBP, IL6 and NOS2 promoters were not hypertonicity-inducible. Whole-disc response to hypertonicity was studied in an ex vivo organ culture model, using wild-type and haploinsufficient TonEBP mice. Pro-inflammatory targets were induced by hypertonicity in discs from wild-type but not TonEBP-haploinsufficient mice. Mechanistically, NF-κB activity increased with hypertonicity and was necessary for hypertonic induction of target genes IL6, TNF, and NOS2 but not CCL2 Although TonEBP maintains transcription of genes traditionally considered pro-inflammatory, it is important to note that some of these genes also serve anabolic and pro-survival roles. Therefore, in NP cells, this phenomenon may reflect a physiological adaptation to diurnal osmotic loading of the intervertebral disc

Near-optimum design of the InP homojunction solar cell

Using a fairly comprehensive model, researchers have done a parametric variation study of the InP n+p homojunction solar cell for AMO, 25 C operation. The results of this study are presented. These results indicate that an efficiency of about 25 percent should be realistically possible in a shallow homojunction InP solar cell with near-optimum design

Modeling Stable Matching Problems with Answer Set Programming

The Stable Marriage Problem (SMP) is a well-known matching problem first introduced and solved by Gale and Shapley (1962). Several variants and extensions to this problem have since been investigated to cover a wider set of applications. Each time a new variant is considered, however, a new algorithm needs to be developed and implemented. As an alternative, in this paper we propose an encoding of the SMP using Answer Set Programming (ASP). Our encoding can easily be extended and adapted to the needs of specific applications. As an illustration we show how stable matchings can be found when individuals may designate unacceptable partners and ties between preferences are allowed. Subsequently, we show how our ASP based encoding naturally allows us to select specific stable matchings which are optimal according to a given criterion. Each time, we can rely on generic and efficient off-the-shelf answer set solvers to find (optimal) stable matchings.Comment: 26 page

Synchronization of dynamical hypernetworks: dimensionality reduction through simultaneous block-diagonalization of matrices

We present a general framework to study stability of the synchronous solution for a hypernetwork of coupled dynamical systems. We are able to reduce the dimensionality of the problem by using simultaneous block-diagonalization of matrices. We obtain necessary and sufficient conditions for stability of the synchronous solution in terms of a set of lower-dimensional problems and test the predictions of our low-dimensional analysis through numerical simulations. Under certain conditions, this technique may yield a substantial reduction of the dimensionality of the problem. For example, for a class of dynamical hypernetworks analyzed in the paper, we discover that arbitrarily large networks can be reduced to a collection of subsystems of dimensionality no more than 2. We apply our reduction techique to a number of different examples, including a class of undirected unweighted hypermotifs of three nodes.Comment: 9 pages, 6 figures, accepted for publication in Phys. Rev.

Influence of inclination error in sedimentary rocks on the Triassic and Jurassic apparent pole wander path for North America and implications for Cordilleran tectonics

Because of paleomagnetic inclination error (I error) in sedimentary rocks, we argue that previous estimates of Triassic and Jurassic paleolatitudes of the North American craton have generally been too low, the record being derived mostly from sedimentary rocks. Using results from all major cratons, we construct a new composite apparent pole wander (APW) path for Triassic through Paleogene based on 69 paleopoles ranging in age from 243 to 43 Ma. The poles are from igneous rocks and certain sedimentary formations corrected for I error brought into North American coordinates using plate tectonic reconstructions. Key features of the new APW path are a 25° northward progression from 230 to 190 Ma to high latitudes (off northernmost Siberia) where the pole lingers until 160 Ma, a jump to the Aleutians followed by a hook in western Alaska by ~145 Ma that leads to the 130-60 Ma stillstand, after which the pole moves to its present position. As an example of the application of this new path we use paleomagnetic results to determine that southern Wrangellia and Stikinia (W/S), the two most westerly terranes in the Canadian Cordillera, lay 630 to 1650 km farther south than at present relative to the craton during the Late Triassic and Early Jurassic. This is consistent with an exotic Tethyan origin as paleontological and mantle geochemical evidences imply. During the Late Triassic through Early Cretaceous, W/S moved northward more slowly than the craton, implying oblique sinistral net convergence over this 130 Myr interval. This was followed by dextral shear in latest Cretaceous through Eocene

Lack of evidence for involvement of TonEBP and hyperosmotic stimulus in induction of autophagy in the nucleus pulposus.

Nucleus pulposus (NP) cells reside in a physiologically hyperosmotic environment within the intervertebral disc. TonEBP/NFAT5 is an osmo-sensitive transcription factor that controls expression of genes critical for cell survival under hyperosmotic conditions. A recent report on NP and studies of other cell types have shown that hyperosmolarity triggers autophagy. However, little is known whether such autophagy induction occurs through TonEBP. The goal of this study was to investigate the role of TonEBP in hyperosmolarity-dependent autophagy in NP. Loss-of-function studies showed that autophagy in NP cells was not TonEBP-dependent; hyperosmolarity did not upregulate autophagy as previously reported. NP tissue of haploinsufficient TonEBP mice showed normal pattern of LC3 staining. NP cells did not increase LC3-II or LC3-positive puncta under hyperosmotic conditions. Bafilomycin-A1 treatment and tandem mCherry-EGFP-LC3B reporter transfection demonstrated that the autophagic flux was unaffected by hyperosmolarity. Even under serum-free conditions, NP cells did not induce autophagy with increasing osmolarity. Hyperosmolarity did not change the phosphorylation of ULK1 by mTOR and AMPK. An ex vivo disc organ culture study supported that extracellular hyperosmolarity plays no role in promoting autophagy in the NP. We conclude that hyperosmolarity does not play a role in autophagy induction in NP cells

Transcriptional profiling of the nucleus pulposus: say yes to notochord

This editorial addresses the debate concerning the origin of adult nucleus pulposus cells in the light of profiling studies by Minogue and colleagues. In their report of several marker genes that distinguish nucleus pulposus cells from other related cell types, the authors provide novel insights into the notochordal nature of the former. Together with recently published work, their work lends support to the view that all cells present within the nucleus pulposus are derived from the notochord. Hence, the choice of an animal model for disc research should be based on considerations other than the cell loss and replacement by non-notochordal cells