Noril'sk/Siberian plateau basalts and Bahama hot spot: Impact triggered?

Twenty-eight years after one of us argued that Sudbury was an astrobleme, this interpretation has only recently attained wide acceptance; not so for the view that the Sudbury Cu/Ni sulfide ores are cosmogenic. Other research has provided the triggering of plateau basalts by super-large impacts a modicum of respectability. The recent apparent successful tying in of the K/T extinctions to the Chicxulub astrobleme in the Yucatan encourages the search for an impact event that may have caused the other two major post-Paleozoic extinctions (P/Tr, Tr/J). This gives us heart to offer two further outrageous hypotheses. The cosmogenic concept for the Sudbury ore deposite remains viable because it is giant, nonultramafic, and unique (except for Noril'sk). The Triassic/Jurassic boundary catastrophic extinctions have been attributed to the Manicouagan asteroidal impact, but recent radiometric dating indicates these events are diachronous (Manicouagan astrobleme 212 +/- 2 Ma and Tr/J boundary 200 Ma)

microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions

Increased microRNA-10b (miR-10b) expression in the cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a marker of disease aggressiveness. In the present study, we determined that plasma miR-10b levels are significantly increased in PDAC patients by comparison with normal controls. By gene profiling, we identified potential targets downregulated by miR-10b, including Tat-interacting protein 30 (TIP30). Immunoblotting and luciferase reporter assays confirmed that TIP30 was a direct miR-10b target. Downregulation of TIP30 by miR-10b or siRNA-mediated silencing of TIP30 enhanced epidermal growth factor (EGF)-dependent invasion. The actions of miR-10b were abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. EGF-induced EGF receptor (EGFR) tyrosine phosphorylation and extracellular signal–regulated kinase phosphorylation were enhanced by miR-10b, and these effects were mimicked by TIP30 silencing. The actions of EGF in the presence of miR-10b were blocked by EGFR kinase inhibition with erlotinib and by dual inhibition of PI3K (phosphatidylinositol 3′-kinase) and MEK. Moreover, miR-10b, EGF and transforming growth factor-beta (TGF-β) combined to markedly increase cell invasion, and this effect was blocked by the combination of erlotinib and SB505124, a type I TGF-β receptor inhibitor. miR-10b also enhanced the stimulatory effects of EGF and TGF-β on cell migration and epithelial–mesenchymal transition (EMT) and decreased the expression of RAP2A, EPHB2, KLF4 and NF1. Moreover, miR-10b overexpression accelerated pancreatic cancer cell (PCC) proliferation and tumor growth in an orthotopic model. Thus, plasma miR-10b levels may serve as a diagnostic marker in PDAC, whereas intra-tumoral miR-10b promotes PCC proliferation and invasion by suppressing TIP30, which enhances EGFR signaling, facilitates EGF–TGF-β cross-talk and enhances the expression of EMT-promoting genes, whereas decreasing the expression of several metastasis-suppressing genes. Therefore, therapeutic targeting of miR-10b in PDAC may interrupt growth-promoting deleterious EGF–TGF-β interactions and antagonize the metastatic process at various levels

MOLECULAR BASIS AND MODIFICATION OF A NEURAL CREST DEFICIT IN A DOWN SYNDROME MOUSE MODEL

poster abstractTrisomy 21 occurs in 1/700 live births and leads to phenotypes associat-ed with Down syndrome (DS), including craniofacial dysmorphology and a small mandible. Ts65Dn mice are trisomic for approximately half the genes on human chromosome 21 and display DS-like craniofacial anomalies. Cells cultured from Ts65Dn and euploid 1st pharyngeal arch (PA1) and neural tube (NT) tissues were used to analyze the effects of genetic dysregulation on cell proliferation and migration. In vitro studies revealed a proliferation deficit in trisomic PA1 and migration deficits from trisomic NT originating at embryonic day 9.5 (E9.5). DYRK1A is a gene thought to be involved in DS craniofacial development and we hypothesized that dysregulation of Dyrk1a contributes to altered craniofacial development in Ts65Dn mice. We also hypothesized that Dyrk1a agonists could be used to ameliorate this phenotype. To test our hypotheses, we quantified expression of Dyrk1a using qPCR. At E9.5, Dyrk1a is upregulated in Ts65Dn as relative to euploid PA1. We also showed that cell proliferation and migration could be returned to near euploid levels with the green tea polyphenol epigallocatechin gallate (EGCG) and harmine (known Dyrk1a inhibitors) in vitro. To further test our hypothesis, pregnant Ts65Dn and euploid mothers were treated with EGCG on E7 and E8 and E9.5 trisomic and euploid embryos were assessed for embryonic volume, PA1 vol-ume, and NCC number. Preliminary evidence suggests in vivo treatment leads to an increase in embryonic volume, PA1 volume, and NCC number in both euploid and trisomic embryos. Trisomic EGCG-treated embryos had similar PA1 volumes and NCC numbers to euploid embryos treated with PBS. Gene expression analysis of EGCG-treated NCCs is currently underway to better understand the effects of EGCG in these studies. Our results provide information about the molecular basis of DS craniofacial abnormalities and may lead to evidenced-based therapeutic options

TREATMENT OF CRANIOFACIAL DEFICITS ASSOCIATED WITH DOWN SYN-DROME IN A MOUSE MODEL

poster abstractTrisomy 21 is the genetic source of the group of phenotypes commonly known as Down syndrome (DS). These phenotypes include cognitive im-pairment, heart defects and craniofacial abnormalities, including a small mandible. The Ts65Dn mouse model contains three copies of approximately half the genes found on human chromosome 21 and exhibits similar pheno-types to individuals with DS including a small, dysmorphic mandible. Our lab has traced this deficit to a smaller first branchial arch (BA1) consisting of fewer neural crest cells (NCCs) at embryonic day 9.5 (E9.5). At E9.5, Dyrk1a, a gene known to affect craniofacial development, is upregulated in the BA1, likely contributing to its cell deficit. Using epigallocatechin gallate (EGCG), an extract from green tea and a known inhibitor of Dyrk1a, we are attempting to rescue this deficit. We hypothesize the consumption of EGCG by pregnant mothers at E7 and E8 will rescue the mandibular deficit in de-veloping embryos by reducing the expression or activity of Dyrk1a. From our data we conclude the treatment of pregnant mothers with EGCG results in increased embryo size of trisomic embryos. Further analysis will be done to determine embryo volume, the volume of the BA1, and number of NCCs within the BA1 to determine the effects of EGCG in vivo. This research will better our understanding of craniofacial development and could lead to po-tential genetic-based therapies in the future

The Ursinus Weekly, April 10, 1916

Varsity nine wins and loses • Dr. Good delivers series of lectures • Two big events coming this week • Schaff prize essay: Our inefficient Army • YWCA elects officers • Among the colleges • Literary societies • On the campushttps://digitalcommons.ursinus.edu/weekly/2625/thumbnail.jp

The Ursinus Weekly, April 17, 1916

Orators contest for money prizes • Ursinus revenges football defeat • Junior class play pleases audience • Schaff prize essay: Our inefficient army • Literary societies • Varsity loses to Washington College • Ursinus defeats Norristownhttps://digitalcommons.ursinus.edu/weekly/2626/thumbnail.jp

Bandgap Profiling in CIGS Solar Cells Via Valence Electron Energy-Loss Spectroscopy

A robust, reproducible method for the extraction of relative bandgap trends from scanning transmission electron microscopy (STEM) based electron energy-loss spectroscopy (EELS) is described. The effectiveness of the approach is demonstrated by profiling the bandgap through a CuIn1-xGaxSe2 solar cell that possesses intentional Ga/(In + Ga) composition variation. The EELS-determined bandgap profile is compared to the nominal profile calculated from compositional data collected via STEM-based energy dispersive X-ray spectroscopy. The EELS based profile is found to closely track the calculated bandgap trends, with only a small, fixed offset difference. This method, which is particularly advantageous for relatively narrow bandgap materials and/or STEM systems with modest resolution capabilities (i.e., 100 meV), compromises absolute accuracy to provide a straightforward route for the correlation of local electronic structure trends with nanoscale chemical and physical structure/microstructure within semiconductor materials and devices. Published by AIP Publishing

Correction of Craniofacial Deficits using Epigallocatechin-3’-gallate Treatment in a Down Syndrome Mouse Model

poster abstractDown syndrome (DS) is caused by trisomy of human chromosome (HSA21). Individuals with DS display distinct craniofacial abnormalities including an undersized, dismorphic mandible which leads to difficulty with eating, breathing, and swallowing. Using the Ts65Dn DS mouse model (three copies of ~50% HSA21 homologs), we have traced the mandibular deficit to a neural crest cell (NCC) deficiency and reduction in first pharyngeal arch (PA1 or mandibular precursor) at embryonic day 9.5. Previous studies have shown that this deficit is caused when NCC fail to migrate from the neural tube to populate the PA1 and fail to proliferate in the PA1. At E9.5, Dyrk1A, a triplicated DS candidate gene, is overexpressed in the PA1 and may cause the NCC and PA1 deficits. We hypothesize that treatment of pregnant Ts65Dn mothers with Epigallocatechin-3’-gallate (EGCG), a known Dyrk1A inhibitor, will correct NCC deficits and rescue the undersized PA1 in trisomic E9.5 embryos. To test our hypothesis, we treated pregnant Ts65Dn mothers with EGCG, where embryos received treatment from either E7-E8 or E0-E9.5. Our preliminary study found variable increases in PA1 volume and NCC number between treatment regimens, with several treatment groups indicating EGCG treatment has the potential to rescue the NCC deficit in the mandibular precursor. We found an increase in NCC number and PA1 volume with E7-E8 EGCG treatment in 21-24 somite embryos from trisomic mothers and in euploid embryos from euploid mothers treated from E0-E9.5. With EGCG treatment, we also observed a decrease in the average somite number of embryos from trisomic mothers, but an increase in those mothers’ average litter size. This study is important because it helps define the specific dosage and timing of ECGC and how it may affect specific DS phenotypes. These findings provide preclinical testing for a potential therapy for craniofacial disorders linked to DS