Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death

The ability of the sulfonylurea receptor (SUR) 1 to suppress seizures and excitotoxic neuron damage was assessed in mice transgenically overexpressing this receptor. Fertilized eggs from FVB mice were injected with a construct containing SUR cDNA and a calcium-calmodulin kinase IIα promoter. The resulting mice showed normal gross anatomy, brain morphology and histology, and locomotor and cognitive behavior. However, they overexpressed the SUR1 transgene, yielding a 9- to 12-fold increase in the density of [3H]glibenclamide binding to the cortex, hippocampus, and striatum. These mice resisted kainic acid-induced seizures, showing a 36% decrease in average maximum seizure intensity and a 75% survival rate at a dose that killed 53% of the wild-type mice. Kainic acid-treated transgenic mice showed no significant loss of hippocampal pyramidal neurons or expression of heat shock protein 70, whereas wild-type mice lost 68–79% of pyramidal neurons in the CA1–3 subfields and expressed high levels of heat shock protein 70 after kainate administration. These results indicate that the transgenic overexpression of SUR1 alone in forebrain structures significantly protects mice from seizures and neuronal damage without interfering with locomotor or cognitive function.

Structure of Hjc, a Holliday junction resolvase, from Sulfolobus solfataricus

The 2.15-Å structure of Hjc, a Holliday junction-resolving enzyme from the archaeon Sulfolobus solfataricus, reveals extensive structural homology with a superfamily of nucleases that includes type II restriction enzymes. Hjc is a dimer with a large DNA-binding surface consisting of numerous basic residues surrounding the metal-binding residues of the active sites. Residues critical for catalysis, identified on the basis of sequence comparisons and site-directed mutagenesis studies, are clustered to produce two active sites in the dimer, about 29 Å apart, consistent with the requirement for the introduction of paired nicks in opposing strands of the four-way DNA junction substrate. Hjc displays similarity to the restriction endonucleases in the way its specific DNA-cutting pattern is determined but uses a different arrangement of nuclease subunits. Further structural similarity to a broad group of metal/phosphate-binding proteins, including conservation of active-site location, is observed. A high degree of conservation of surface electrostatic character is observed between Hjc and T4-phage endonuclease VII despite a complete lack of structural homology. A model of the Hjc–Holliday junction complex is proposed, based on the available functional and structural data.

Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: Direct correlation with clinical retinopathy of prematurity

Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel development. In vitro, low levels of IGF-I prevent vascular endothelial growth factor-induced activation of protein kinase B (Akt), a kinase critical for endothelial cell survival. Our results from studies in premature infants suggest that if the IGF-I level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic and vascular endothelial growth factor accumulates in the vitreous. As IGF-I increases to a critical level, retinal neovascularization is triggered. These data indicate that serum IGF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levels could prevent this disease.

Maintenance of TCR clonality in T cells expressing genes for two TCR heterodimers

T cell receptor (TCR) allelic exclusion is believed to be primarily mediated by suppression of further recombination at the TCR locus after the expression of a functional TCR protein. Genetic allelic exclusion has been shown to be leaky for the β chain and, more commonly, for the α chain. Here, we demonstrate an additional mechanism by which T cells can maintain monoclonality. T cells from double TCR transgenic mice express only one or the other of the two available TCRs at the cell surface. This “functional allelic exclusion” is apparently due to control of the TCR assembly process because these T cells express RNA and protein for all four transgenic TCR proteins. Lack of cell surface expression of the second TCR may be controlled by a failure to assemble the TCR heterodimer.

Mortal: A Mutant of White Clover Defective in Nodal Root Development

A monogenic dominant mutant of white clover (Trifolium repens L.), designated Mortal, which is defective in the formation of adventitious nodal roots, is described. Mortal plants grown at temperatures ranging from 10 to 25°C do not initiate nodal root primordium development. However, all other aspects of plant development are normal, including the formation of lateral roots and wound-induced adventitious roots. In some genetic backgrounds, the Mortal mutation has a temperature-sensitive conditional phenotype. Mortal plants shifted from growing conditions of 20 to 30°C for 2 to 3 d form nodal root meristems. However, new nodes that develop after plants are returned to 20°C exhibit the mutant phenotype. The capacity to form nodal roots on cuttings placed in water is also influenced by the genetic background of the Mortal mutation. Genetic analysis established that the physiological reversion of Mortal to nodal root formation is controlled by at least two separate dominant genetic loci, one for Nodal water response (Now) and one for Nodal temperature response (Not); the Now locus has a dominant epistatic interaction with the Not locus. The conditional nature of Mortal should provide opportunities for the identification of genetic and physiological mechanisms that influence the development of nodal roots.

Polarity and permeation profiles in lipid membranes

The isotropic 14N-hyperfine coupling constant, a\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{o}^{N}}}\end{equation*}\end{document}, of nitroxide spin labels is dependent on the local environmental polarity. The dependence of a\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{o}^{N}}}\end{equation*}\end{document} in fluid phospholipid bilayer membranes on the C-atom position, n, of the nitroxide in the sn-2 chain of a spin-labeled diacyl glycerophospholipid therefore determines the transmembrane polarity profile. The polarity variation in phospholipid membranes, with and without equimolar cholesterol, is characterized by a sigmoidal, trough-like profile of the form {1 + exp [(n − no)/λ]}−1, where n = no is the point of maximum gradient, or polarity midpoint, beyond which the free energy of permeation decreases linearly with n, on a characteristic length-scale, λ. Integration over this profile yields a corresponding expression for the permeability barrier to polar solutes. For fluid membranes without cholesterol, no ≈ 8 and λ ≈ 0.5–1 CH2 units, and the permeability barrier introduces an additional diffusive resistance that is equivalent to increasing the effective membrane thickness by 35–80%, depending on the lipid. For membranes containing equimolar cholesterol, no ≈ 9–10, and the total change in polarity is greater than for membranes without cholesterol, increasing the permeability barrier by a factor of 2, whereas the decay length remains similar. The permeation of oxygen into fluid lipid membranes (determined by spin-label relaxation enhancements) displays a profile similar to that of the transmembrane polarity but of opposite sense. For fluid membranes without cholesterol no ≈ 8 and λ ≈ 1 CH2 units, also for oxygen. The permeation profile for polar paramagnetic ion complexes is closer to a single exponential decay, i.e., no lies outside the acyl-chain region of the membrane. These results are relevant not only to the permeation of water and polar solutes into membranes and their permeabilities, but also to depth determinations of site-specifically spin-labeled protein residues by using paramagnetic relaxation agents.

Underuse of beta-blockers in heart failure and chronic obstructive pulmonary disease

Acknowledgments The data in this article have been partly presented in preliminary abstract form as a poster at the winter meeting of the British Thoracic Society, London, 2 December 2015 (10.1136/thoraxjnl-2015-207770.161).

The Foundations of the Artists’ Community of Estes Park

"Estes Park lies in a beautiful location amongst the Rocky Mountains, sixty-five miles from Denver. Settlers came to the region in the second half of the nineteenth century. Among them in 1898 was artist R.H. Tallant who became a prominent landscape painter of the Rocky Mountains. Settling shortly after him was well-known painter Charles Partridge Adams. While Tallant and Adams founded the artists’ community, renowned artist Birger Sandzén and soon to be popular Dave Stirling were the mainstays pushing the artists’ community to new heights through the 1920s and 1930s. The establishment of a thriving artists’ community by Tallant, Adams, Sandzén and Stirling made Estes Park a recognizable place for attracting numerous artists throughout its history"

Manchester, Chetham's Library MS 8009 (Mun. A.6.31): A Codicological Description

This article presents a complete codicological description of Manchester, Chetham's Library, MS 8009 (Mun.A.6.31), a late fifteenth-century production that contains a combination of secular and religious texts. The manuscript's significance for both the literary and textual scholar was recognized by Derek Pearsall when he suggested its suitability for a facsimile edition. The restrictions imposed by the Governors of the Library for reproduction under the present conditions, however, suggest that Pearsall's recommendation may have to wait for some time. The purpose of this paper is to fill that void by correcting some inaccuracies in previous descriptions and completing them with supporting visual evidence.

The emblematic statement of the Nobel Peace Prize. Jean Monnet/Robert Schuman Paper Series Vol. 13 No. 1, January 2013

From the Introduction. On October 12th the Nobel Committee announced that the annual Nobel Peace Prize would be awarded to the European Union for, “promoting peace, democracy and human rights over six decades”.1 This was a bit of good news for the EU who had produced nothing but bad press with the Euro Crisis, the bailouts of struggling countries like Greece, and protests in the southern member states of Spain, Portugal, and Italy. At such a momentous occasion the EU’s next challenge was to figure out who would be the rightful head of the EU to accept the award. The EU has made their decision by opting to send its top three officials Jose Manuel Barroso the President of the European Commission, Herman Van Rompuy the President of the European Council, and Martin Schulz the President of the European Parliament2 as a sign that the EU is not headed by one person but instead is an supranational economic and political bloc that seeks to unify the European continent. Their symbolic acceptance of the award is in response to what Geir Lundestad, the Secretary of the Norwegian Nobel Committee, called, “an accumulated record.”3 This record has ushered the EU into the international spotlight as a beacon for countries in the EU’s periphery to want to join the bloc.