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Comparative Genomics Identifies the Mouse BMP3 Promoter and an Upstream Evolutionary Conserved Region (ECR) in Mammals.
Get PDFThe Bone Morphogenetic Protein (BMP) pathway is a multi-member signaling cascade whose basic components are found in all animals. One member, BMP3, which arose more recently in evolution and is found only in deuterostomes, serves a unique role as an antagonist to both the canonical BMP and Activin pathways. However, the mechanisms that control BMP3 expression, and the cis-regulatory regions mediating this regulation, remain poorly defined. With this in mind, we sought to identify the Bmp3 promoter in mouse (M. musculus) through functional and comparative genomic analyses. We found that the minimal promoter required for expression in resides within 0.8 kb upstream of Bmp3 in a region that is highly conserved with rat (R. norvegicus). We also found that an upstream region abutting the minimal promoter acts as a repressor of the minimal promoter in HEK293T cells and osteoblasts. Strikingly, a portion of this region is conserved among all available eutherian mammal genomes (47/47), but not in any non-eutherian animal (0/136). We also identified multiple conserved transcription factor binding sites in the Bmp3 upstream ECR, suggesting that this region may preserve common cis-regulatory elements that govern Bmp3 expression across eutherian mammals. Since dysregulation of BMP signaling appears to play a role in human health and disease, our findings may have application in the development of novel therapeutics aimed at modulating BMP signaling in humans
Quirks of Stirling\u27s Approximation
No full textStirling\u27s approximation to ln n! is typically introduced to physical chemistry students as a step in the derivation-of the statistical expression for the entropy. However, naive application of this approximation leads to incorrect conclusions. In this article, the problem is first illustrated using a familiar toy model example, the two-state system of N classical spins, where it is shown that two different physical situations lead to the same computed value of the entropy. Retention of additional terms in the approximation of the factorial is required to yield an accurate expression for the statistical weight of the most probable configuration in such model systems, but generates only a little extra accuracy in entropy calculations, and then only in the limit of very small numbers of particles. Additionally, inclusion of these terms makes the entropy nonextensive. We show here that, in the standard derivation of the entropy of the microcanonical ensemble, it is the freedom to allow the ensemble size to be infinite that makes the Boltzmann entropy expression S = k(B) lnW exact, a fact that is not widely understood
Comparative Genomics Identifies the Mouse Bmp3 Promoter and an Upstream Evolutionary Conserved Region (ECR) in Mammals
No full textJohn Capreolus on Names Said Analogously of God and Creatures
No full textThe writings of John Capreolus (ca. 1380-1444), the Prince of Thomists, have come down to us exclusively through his great work, the Defense of the Theology of Thomas Aquinas (abbreviated in this article as the Defensiones), completed about the year 1442
DSG3 as a biomarker for the ultrasensitive detection of occult lymph node metastasis in oral cancer using nanostructured immunoarrays.
No full textOBJECTIVES: The diagnosis of cervical lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) patients constitutes an essential requirement for clinical staging and treatment selection. However, clinical assessment by physical examination and different imaging modalities, as well as by histological examination of routine lymph node cryosections can miss micrometastases, while false positives may lead to unnecessary elective lymph node neck resections. Here, we explored the feasibility of developing a sensitive assay system for desmoglein 3 (DSG3) as a predictive biomarker for lymph node metastasis in HNSCC.
MATERIALS AND METHODS: DSG3 expression was determined in multiple general cancer- and HNSCC-tissue microarrays (TMAs), in negative and positive HNSCC metastatic cervical lymph nodes, and in a variety of HNSCC and control cell lines. A nanostructured immunoarray system was developed for the ultrasensitive detection of DSG3 in lymph node tissue lysates.
RESULTS: We demonstrate that DSG3 is highly expressed in all HNSCC lesions and their metastatic cervical lymph nodes, but absent in non-invaded lymph nodes. We show that DSG3 can be rapidly detected with high sensitivity using a simple microfluidic immunoarray platform, even in human tissue sections including very few HNSCC invading cells, hence distinguishing between positive and negative lymph nodes.
CONCLUSION: We provide a proof of principle supporting that ultrasensitive nanostructured assay systems for DSG3 can be exploited to detect micrometastatic HNSCC lesions in lymph nodes, which can improve the diagnosis and guide in the selection of appropriate therapeutic intervention modalities for HNSCC patients
The novel tumor suppressor NOL7 post-transcriptionally regulates thrombospondin-1 expression.
No full textThrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis whose expression suppresses tumor growth in vivo. Like many angiogenesis-related genes, TSP-1 expression is tightly controlled by various mechanisms, but there is little data regarding the contribution of post-transcriptional processing to this regulation. NOL7 is a novel tumor suppressor that induces an antiangiogenic phenotype and suppresses tumor growth, in part through upregulation of TSP-1. Here we demonstrate that NOL7 is an mRNA-binding protein that must localize to the nucleoplasm to exert its antiangiogenic and tumor suppressive effects. There, it associates with the RNA-processing machinery and specifically interacts with TSP-1 mRNA through its 3\u27UTR. Reintroduction of NOL7 into SiHa cells increases luciferase expression through interaction with the TSP-1 3\u27UTR at both the mRNA and protein levels. NOL7 also increases endogenous TSP-1 mRNA half-life. Further, NOL7 post-transcriptional stabilization is observed in a subset of angiogenesis-related mRNAs, suggesting that the stabilization of TSP-1 may be part of a larger novel mechanism. These data demonstrate that NOL7 significantly alters TSP-1 expression and may be a master regulator that coordinates the post-transcriptional expression of key signaling factors critical for the regulation of the angiogenic phenotype
Abnormal Trafficking of Endogenously Expressed BMPR2 Mutant Allelic Products in Patients with Heritable Pulmonary Arterial Hypertension
Get PDFMore than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 (ΔEx2/+) mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 (ΔEx2/+) mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations
New Results for the Formation of a Muoniated Radical in the Mu+Br-2 System: a van der Waals Complex or Evidence for Vibrational Bonding in Br-Mu-Br?
No full textNew evidence is presented for the observation of a muoniated radical in the Mu + Br-2 system, from mu SR longitudinal field (LF) repolarisation studies in thegas phase, at Br-2 concentrations of 0.1 bar in a Br-2/N-2 mixture at 300 K and at 10 bar total pressure. The LF repolarisation curve, up to a field of 4.5 kG, reveals two paramagnetic components, one for the Mu atom, formed promptly during the slowing-down process of the positive muon, with a known Mu hyperfine coupling constant (hfcc) of 4463 MHz, and one for a muoniated radical formed by fast Mu addition. From model fits to the Br-2/N-2 data, the radicalcomponent is found to have an unusually high muon hfcc, assessed to be similar to 3300 MHz with an overall error due to systematics expected to exceed 10%. This high muon hfcc is taken as evidence for the observation of either the Br-Mu-Br radical, and hence of vibrational bonding in this H-L-H system, or ofa Mu center dot center dot center dot Br-2 van der Waals complex formed in the entrance channel. Preliminary ab initio electronic structure calculations suggest the latter is more likely but fully rigorous calculations of the effect of dynamics on the hfcc for either system have yet to be carried out