SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells

<p>Abstract</p> <p>Background</p> <p>The vertebrate pancreas contains islet, acinar and ductal cells. These cells derive from a transient pool of multipotent pancreatic progenitors during embryonic development. Insight into the genetic determinants regulating pancreatic organogenesis will help the development of cell-based therapies for the treatment of diabetes mellitus. <it>Suppressor enhancer lin12/Notch 1 like (Sel1l</it>) encodes a cytoplasmic protein that is highly expressed in the developing mouse pancreas. However, the morphological and molecular events regulated by <it>Sel1l </it>remain elusive.</p> <p>Results</p> <p>We have characterized the pancreatic phenotype of mice carrying a gene trap mutation in <it>Sel1l</it>. We show that <it>Sel1l </it>expression in the developing pancreas coincides with differentiation of the endocrine and exocrine lineages. Mice homozygous for the gene trap mutation die prenatally and display an impaired pancreatic epithelial morphology and cell differentiation. The pancreatic epithelial cells of <it>Sel1l </it>mutant embryos are confined to the progenitor cell state throughout the secondary transition. Pharmacological inhibition of Notch signaling partially rescues the pancreatic phenotype of <it>Sel1l </it>mutant embryos.</p> <p>Conclusions</p> <p>Together, these data suggest that <it>Sel1l </it>is essential for the growth and differentiation of endoderm-derived pancreatic epithelial cells during mouse embryonic development.</p

A triple action CDK4/6-PI3K-BET inhibitor with augmented cancer cell cytotoxicity

National Institutes of Health GM125195, GM135671, CA192656, FD00511

SN 2009bb: a Peculiar Broad-Lined Type Ic Supernova

Ultraviolet, optical, and near-infrared photometry and optical spectroscopy of the broad-lined Type Ic supernova (SN) 2009bb are presented, following the flux evolution from -10 to +285 days past B-band maximum. Thanks to the very early discovery, it is possible to place tight constraints on the SN explosion epoch. The expansion velocities measured from near maximum spectra are found to be only slightly smaller than those measured from spectra of the prototype broad-lined SN 1998bw associated with GRB 980425. Fitting an analytical model to the pseudo-bolometric light curve of SN 2009bb suggests that 4.1+-1.9 Msun of material was ejected with 0.22 +-0.06 Msun of it being 56Ni. The resulting kinetic energy is 1.8+-0.7x10^52 erg. This, together with an absolute peak magnitude of MB=-18.36+-0.44, places SN 2009bb on the energetic and luminous end of the broad-lined Type Ic (SN Ic) sequence. Detection of helium in the early time optical spectra accompanied with strong radio emission, and high metallicity of its environment makes SN 2009bb a peculiar object. Similar to the case for GRBs, we find that the bulk explosion parameters of SN 2009bb cannot account for the copious energy coupled to relativistic ejecta, and conclude that another energy reservoir (a central engine) is required to power the radio emission. Nevertheless, the analysis of the SN 2009bb nebular spectrum suggests that the failed GRB detection is not imputable to a large angle between the line-of-sight and the GRB beamed radiation. Therefore, if a GRB was produced during the SN 2009bb explosion, it was below the threshold of the current generation of gamma-ray instruments.Comment: Accepted for publication in Ap

ER stress and Rho kinase activation underlie the vasculopathy of CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) leads to premature stroke and vascular dementia. Mechanism-specific therapies for this aggressive cerebral small vessel disease are lacking. CADASIL is caused by NOTCH3 mutations that influence vascular smooth muscle cell (VSMC) function through unknown processes. We investigated molecular mechanisms underlying the vasculopathy in CADASIL focusing on endoplasmic reticulum (ER) stress and RhoA/Rho kinase (ROCK). Peripheral small arteries and VSMCs were isolated from gluteal biopsies of CADASIL patients and mesentery of TgNotch3R169C mice (CADASIL model). CADASIL vessels exhibited impaired vasorelaxation, blunted vasoconstriction, and hypertrophic remodeling. Expression of NOTCH3 and ER stress target genes was amplified and ER stress response, Rho kinase activity, superoxide production, and cytoskeleton-associated protein phosphorylation were increased in CADASIL, processes associated with Nox5 upregulation. Aberrant vascular responses and signaling in CADASIL were ameliorated by inhibitors of Notch3 (γ-secretase inhibitor), Nox5 (mellitin), ER stress (4-phenylbutyric acid), and ROCK (fasudil). Observations in human CADASIL were recapitulated in TgNotch3R169C mice. These findings indicate that vascular dysfunction in CADASIL involves ER stress/ROCK interplay driven by Notch3-induced Nox5 activation and that NOTCH3 mutation–associated vascular pathology, typical in cerebral vessels, also manifests peripherally. We define Notch3-Nox5/ER stress/ROCK signaling as a putative mechanism-specific target and suggest that peripheral artery responses may be an accessible biomarker in CADASIL

Type II-P Supernovae from the SDSS-II Supernova Survey and the Standardized Candle Method

We apply the Standardized Candle Method (SCM) for Type II Plateau supernovae (SNe II-P), which relates the velocity of the ejecta of a SN to its luminosity during the plateau, to 15 SNe II-P discovered over the three season run of the Sloan Digital Sky Survey - II Supernova Survey. The redshifts of these SNe - 0.027 < z < 0.144 - cover a range hitherto sparsely sampled in the literature; in particular, our SNe II-P sample contains nearly as many SNe in the Hubble flow (z > 0.01) as all of the current literature on the SCM combined. We find that the SDSS SNe have a very small intrinsic I-band dispersion (0.22 mag), which can be attributed to selection effects. When the SCM is applied to the combined SDSS-plus-literature set of SNe II-P, the dispersion increases to 0.29 mag, larger than the scatter for either set of SNe separately. We show that the standardization cannot be further improved by eliminating SNe with positive plateau decline rates, as proposed in Poznanski et al. (2009). We thoroughly examine all potential systematic effects and conclude that for the SCM to be useful for cosmology, the methods currently used to determine the Fe II velocity at day 50 must be improved, and spectral templates able to encompass the intrinsic variations of Type II-P SNe will be needed.Comment: Accepted for publication by ApJ; data used in this paper can be downloaded from http://sdssdp47.fnal.gov/sdsssn/photometry/SNIIp.tgz; citation errors correcte

Measurement of VH, H→bb¯ production as a function of the vector-boson transverse momentum in 13 TeV pp collisions with the ATLAS detector

Cross-sections of associated production of a Higgs boson decaying into bottom-quark pairs and an electroweak gauge boson, W or Z, decaying into leptons are measured as a function of the gauge boson transverse momentum. The measurements are performed in kinematic fiducial volumes defined in the `simplified template cross-section´ framework. The results are obtained using 79.8 fb−1 of proton-proton collisions recorded by the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 13 TeV. All measurements are found to be in agreement with the Standard Model predictions, and limits are set on the parameters of an effective Lagrangian sensitive to modifications of the Higgs boson couplings to the electroweak gauge bosons.Fil: Aaboud, M.. Université Mohamed; MarruecosFil: Aad, G.. Aix-Marseille Université; Francia. Centre National de la Recherche Scientifique; FranciaFil: Abbott, B.. University of Oklahoma; Estados UnidosFil: Abbott, D. C.. University of Oklahoma; Estados UnidosFil: Abdinov, O.. Azerbaijan Academy of Sciences; AzerbaiyánFil: Abed Abud, A.. Universita degli Studi di Pavia; Italia. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Abhayasinghe, D. K.. Royal Holloway University of London; Reino UnidoFil: Abidi, S. H.. University of Toronto; CanadáFil: AbouZeid, O. S.. Universidad de Copenhagen; DinamarcaFil: Abraham, N. L.. University of Sussex; Reino UnidoFil: Abramowicz, H.. Universitat Tel Aviv; IsraelFil: Abreu, H.. Technion - Israel Institute of Technology; IsraelFil: Abulaiti, Y.. Argonne National Laboratory; Estados UnidosFil: Acharya, B. S.. Istituto Nazionale di Fisica Nucleare; Italia. The Abdus Salam. International Centre for Theoretical Physics; Italia. King’s College London; Reino UnidoFil: Adachi, S.. University of Tokyo; JapónFil: Adam, L.. Universität Mainz; AlemaniaFil: Adam Bourdarios, C.. Université Paris-Sud; Francia. Universite Paris-Saclay; . Centre National de la Recherche Scientifique; FranciaFil: Adamczyk, L.. University of Science and Technology; PoloniaFil: Adamek, L.. University of Toronto; CanadáFil: Adelman, J.. Northern Illinois University; Estados UnidosFil: Adersberger, M.. Ludwig-Maximilians-Universität München; AlemaniaFil: Adiguzel, A.. Bogazici University; Turquía. Istanbul University; TurquíaFil: Adorni, S.. Université de Genève; FranciaFil: Adye, T.. Rutherford Appleton Laboratory; Reino UnidoFil: Affolder, A. A.. University of California Santa Cruz; Estados UnidosFil: Afik, Y.. Technion - Israel Institute of Technology; IsraelFil: Agapopoulou, C.. Université Paris-Sud; Francia. Centre National de la Recherche Scientifique; Francia. Universite Paris-Saclay;Fil: Agaras, M. N.. Université Clermont Auvergne; Francia. Centre National de la Recherche Scientifique; FranciaFil: Aggarwal, A.. Radboud Universiteit Nijmegen; Países BajosFil: Arduh, Francisco Anuar. Cern - European Organization for Nuclear Research; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; Argentin

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Background NADPH Oxidase 5 (Nox5) is a calcium‐sensitive superoxide‐generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro‐contractile signaling and vascular function. Methods and Results Transgenic mice expressing human Nox5 in a vascular smooth muscle cell–specific manner (Nox5 mice) and Rhodnius prolixus, an arthropod model that expresses Nox5 endogenoulsy, were studied. Reactive oxygen species generation was increased systemically and in the vasculature and heart in Nox5 mice. In Nox5‐expressing mice, agonist‐induced vasoconstriction was exaggerated and endothelium‐dependent vasorelaxation was impaired. Vascular structural and mechanical properties were not influenced by Nox5. Vascular contractile responses in Nox5 mice were normalized by N‐acetylcysteine and inhibitors of calcium channels, calmodulin, and endoplasmic reticulum ryanodine receptors, but not by GKT137831 (Nox1/4 inhibitor). At the cellular level, vascular changes in Nox5 mice were associated with increased vascular smooth muscle cell [Ca2+]i, increased reactive oxygen species and nitrotyrosine levels, and hyperphosphorylation of pro‐contractile signaling molecules MLC20 (myosin light chain 20) and MYPT1 (myosin phosphatase target subunit 1). Blood pressure was similar in wild‐type and Nox5 mice. Nox5 did not amplify angiotensin II effects. In R. prolixus, gastrointestinal smooth muscle contraction was blunted by Nox5 silencing, but not by VAS2870 (Nox1/2/4 inhibitor). Conclusions Nox5 is a pro‐contractile Nox isoform important in redox‐sensitive contraction. This involves calcium‐calmodulin and endoplasmic reticulum–regulated mechanisms. Our findings define a novel function for vascular Nox5, linking calcium and reactive oxygen species to the pro‐contractile molecular machinery in vascular smooth muscle cells

Discovery of Endangered Mexican Blindcat, Prietella phreatophila, in Texas: Implications for International Groundwater Management and Evolution of the Regional Karst Aquifer Biota

Paper presented July 15, 2017 at the annual Joint Meeting of Ichthyologists and Herpetologists in Austin, Texas, USA (http://conferences.k-state.edu/JMIH-Austin-2017/). The oral presentation of this content mentioned questions about the taxonomy and phylogenetic position of Prietella lundbergi and the only specimens attributed to P. lundbergi apart from the holotype. Since the presentation, we obtained high resolution CT scans of both the holotype and a specimen (TNHC 25767) from Cueva del Nacimiento del Río Frio, not far north of the type locality. The anatomy revealed in those CT scans suggests that these specimens represent a single species, and that P. lundbergi is only remotely related to Prietella phreatophila, which would be consistent with results of Wilcox, T.P., F.J. Garcı́a de León, Dean A. Hendrickson, and D.M. Hillis. 2004. “Convergence among Cave Catfishes: Long-Branch Attraction and a Bayesian Relative Rates Test.” Molecular Phylogenetics and Evolution 31 (3): 1101–13. doi:10.1016/j.ympev.2003.11.006). Thus, further research is in progress by Hendrickson, Lundberg, Luckenbill and Arce that may result in taxonomic revision removing P. lundbergi from Prietella.Mexican blindcat, Prietella phreatophila, described in 1954 from a cave system near the town of Múzquiz in central Coahuila state, and considered a Mexican endemic, was listed by the U.S. Fish and Wildlife Service as a foreign endangered species (protected "wherever found") in 1970. Explorations in the 1990s discovered many new localities extending nearly to the international border, and in 2016 the species was discovered in Amistad National Recreation Area (ANRA) in Texas, just north of the international border near Del Rio. Not only does the discovery support the aquifer of this fish being an internationally shared resource, but the stygobitic invertebrate biota found with the fish indicates a potentially large extent of the aquifer, and thus possibly the fish, in Texas. Invertebrate faunal connections (historic or current) extend from the Amistad Lake area of the new occurrence west into the Trans-Pecos region and east into the Edwards Aquifer of central Texas. We explore implications of this for both water management and evolutionary history of this and other blind ictalurids, and suggest that population genetic studies of both stygobitic fishes and invertebrates could help hydrogeologists better define often difficult to map aquifer extents and interconnections. While NPS is continuing to support the cave explorations of ANRA that produced the Texas discovery, we propose a broader bi-national sampling effort for both the fish and invertebrates extending well beyond the current known distribution of P. phreatophila. We also pointed out questions about phylogenetic relatedness of P. phreatophila and P. lundbergi further south, as well as the possibility of a monophyletic clade of blindcats, including those of the Edwards Aquifer, Satan and Trogloglanis. If substantiated, that evolutionary history would imply broader historic inter-aquifer connections ranging from the San Antonio area as far south as southernmost Tamaulipas. Finally, we report establishment of a small captive population of Prietella phreatophila at San Antonio Zoo for research and possibly eventual conservation applications.U.S. National Park Service; San Antonio Zoo; University of Texas at Austin College of Natural Sciences and Department of Integrative BiologyIntegrative Biolog

NADPH oxidase 5 is a pro‐contractile Nox isoform and a point of cross‐talk for calcium and redox signaling‐implications in vascular function

Background: NADPH Oxidase 5 (Nox5) is a calcium‐sensitive superoxide‐generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro‐contractile signaling and vascular function. Methods and Results: Transgenic mice expressing human Nox5 in a vascular smooth muscle cell–specific manner (Nox5 mice) and Rhodnius prolixus, an arthropod model that expresses Nox5 endogenoulsy, were studied. Reactive oxygen species generation was increased systemically and in the vasculature and heart in Nox5 mice. In Nox5‐expressing mice, agonist‐induced vasoconstriction was exaggerated and endothelium‐dependent vasorelaxation was impaired. Vascular structural and mechanical properties were not influenced by Nox5. Vascular contractile responses in Nox5 mice were normalized by N‐acetylcysteine and inhibitors of calcium channels, calmodulin, and endoplasmic reticulum ryanodine receptors, but not by GKT137831 (Nox1/4 inhibitor). At the cellular level, vascular changes in Nox5 mice were associated with increased vascular smooth muscle cell [Ca2+]i, increased reactive oxygen species and nitrotyrosine levels, and hyperphosphorylation of pro‐contractile signaling molecules MLC20 (myosin light chain 20) and MYPT1 (myosin phosphatase target subunit 1). Blood pressure was similar in wild‐type and Nox5 mice. Nox5 did not amplify angiotensin II effects. In R. prolixus, gastrointestinal smooth muscle contraction was blunted by Nox5 silencing, but not by VAS2870 (Nox1/2/4 inhibitor). Conclusions: Nox5 is a pro‐contractile Nox isoform important in redox‐sensitive contraction. This involves calcium‐calmodulin and endoplasmic reticulum–regulated mechanisms. Our findings define a novel function for vascular Nox5, linking calcium and reactive oxygen species to the pro‐contractile molecular machinery in vascular smooth muscle cells