21 research outputs found
An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansenâs Metaphyseal Chondrodysplasia
Jansenâs metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligandâindependent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cellâbased assays, we found that certain Nâterminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu11,dTrp12,Trp23,Tyr36]âPTHrP(7â36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1âH223R allele of JMC in osteoblastic cells via the collagenâ1α1 promoter (C1HR mice). We observed that after 2âweeks of twiceâdaily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proofâofâconcept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154322/1/jbmr3913-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154322/2/jbmr3913.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154322/3/jbmr3913_am.pd
The glial cell line-derived neurotrophic factor family receptor components are differentially regulated within sensory neurons after nerve injury.
Glial cell line-derived neurotrophic factor (GDNF) has potent trophic effects on adult sensory neurons after nerve injury and is one of a family of proteins that includes neurturin, persephin, and artemin. Sensitivity to these factors is conferred by a receptor complex consisting of a ligand binding domain (GFRalpha1-GFRalpha4) and a signal transducing domain RET. We have investigated the normal expression of GDNF family receptor components within sensory neurons and the response to nerve injury. In normal rats, RET and GFRalpha1 were expressed in a subpopulation of both small- and large-diameter afferents projecting through the sciatic nerve [60 and 40% of FluoroGold (FG)-labeled cells, respectively]. GFRalpha2 and GFRalpha3 were both expressed principally within small-diameter DRG cells (30 and 40% of FG-labeled cells, respectively). Two weeks after sciatic axotomy, the expression of GFRalpha2 was markedly reduced (to 12% of sciatic afferents). In contrast, the proportion of sciatic afferents that expressed GFRalpha1 increased (to 66% of sciatic afferents) so that virtually all large-diameter afferents expressed this receptor component, and the expression of GFRalpha3 also increased (to 66% of sciatic afferents) so that almost all of the small-diameter afferents expressed this receptor component after axotomy. There was little change in RET expression. The changes in the proportions of DRG cells expressing different receptor components were mirrored by alterations in the total RNA levels within the DRG. The changes in GFRalpha1 and GFRalpha2 expression after axotomy could be largely reversed by treatment with GDNF
GenGIS 2: geospatial analysis of traditional and genetic biodiversity, with new gradient algorithms and an extensible plugin framework
GenGIS is free and open source software designed to integrate biodiversity data with a digital map and information about geography and habitat. While originally developed with microbial community analyses and phylogeography in mind, GenGIS has been applied to a wide range of datasets. A key feature of GenGIS is the ability to test geographic axes that can correspond to routes of migration or gradients that influence community similarity. Here we introduce GenGIS version 2, which extends the linear gradient tests introduced in the first version to allow comprehensive testing of all possible linear geographic axes. GenGIS v2 also includes a new plugin framework that supports the development and use of graphically driven analysis packages: initial plugins include implementations of linear regression and the Mantel test, calculations of alpha-diversity (e.g., Shannon Index) for all samples, and geographic visualizations of dissimilarity matrices. We have also implemented a recently published method for biomonitoring reference condition analysis (RCA), which compares observed species richness and diversity to predicted values to determine whether a given site has been impacted. The newest version of GenGIS supports vector data in addition to raster files. We demonstrate the new features of GenGIS by performing a full gradient analysis of an Australian kangaroo apple data set, by using plugins and embedded statistical commands to analyze human microbiome sample data, and by applying RCA to a set of samples from Atlantic Canada. GenGIS release versions, tutorials and documentation are freely available at http://kiwi.cs.dal.ca/GenGIS, and source code is available at https://github.com/beiko-lab/gengis
Phylogeography of kangaroo apples.
<p>A) A longitudinal gradient resulting in 23 crossings. Each of the eight species within the kangaroo apple phylogeny is assigned a unique color, and the two most substantial subclades are labelled. B) A latitudinal gradient results in 57 crossings. C) Results of a linear axes analysis on the kangaroo apple dataset. The number of crossings is only shown for axes between 90° and 270° as the graph has a period of 180°. Under the null model, only 10 of 10,000 permutations resulted in fewer than 34 crossings which is depicted by the red line (i.e. αâ=â0.001). D) A linear axes analysis of the <i>Similia</i> subclade with the red line set to reflect a conservative critical value of αâ=â0.1. E) A linear axes analysis of the <i>Avicularia/Laciniata</i> subclades (αâ=â0.1).</p
Heatmap of frequencies of three taxonomic groups (Bacteroidia, Clostridia, and âUnclassified Bacteriaâ) from 24 fecal samples.
<p>Dark colors correspond to low frequencies, while yellow, tan and pink indicate high frequencies. Hierarchical clustering of samples and taxonomic groups are shown along both dimensions of the heatmap. Sample labels are explained in the legend of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0069885#pone-0069885-g002" target="_blank">Figure 2b</a>.</p