Dual Effects of Adp and Adenylylimidodiphosphate on Cftr Channel Kinetics Show Binding to Two Different Nucleotide Binding Sites

The CFTR chloride channel is regulated by phosphorylation by protein kinases, especially PKA, and by nucleotides interacting with the two nucleotide binding domains, NBD-A and NBD-B. Giant excised inside-out membrane patches from Xenopus oocytes expressing human epithelial cystic fibrosis transmembrane conductance regulator (CFTR) were tested for their chloride conductance in response to the application of PKA and nucleotides. Rapid changes in the concentration of ATP, its nonhydrolyzable analogue adenylylimidodiphosphate (AMP-PNP), its photolabile derivative ATP-P3-[1-(2-nitrophenyl)ethyl]ester, or ADP led to changes in chloride conductance with characteristic time constants, which reflected interaction of CFTR with these nucleotides. The conductance changes of strongly phosphorylated channels were slower than those of partially phosphorylated CFTR. AMP-PNP decelerated relaxations of conductance increase and decay, whereas ATP-P3-[1-(2-nitrophenyl)ethyl]ester only decelerated the conductance increase upon ATP addition. ADP decelerated the conductance increase upon ATP addition and accelerated the conductance decay upon ATP withdrawal. The results present the first direct evidence that AMP-PNP binds to two sites on the CFTR. The effects of ADP also suggest two different binding sites because of the two different modes of inhibition observed: it competes with ATP for binding (to NBD-A) on the closed channel, but it also binds to channels opened by ATP, which might either reflect binding to NBD-A (i.e., product inhibition in the hydrolysis cycle) or allosteric binding to NBD-B, which accelerates the hydrolysis cycle at NBD-A

Carcinoid heart disease: Two clinical cases and a review

We present two cases of metastatic carcinoid tumours, complicated by carcinoid syndrome and by cardiac valve involvement, a well-known, but infrequent, complication. Carcinoid tumours are generally more indolent than other cancers and may have a long asymptomatic phase. The symptoms of carcinoid syndrome generally manifest only once metastases to the liver have occurred. Cardiac involvement occurs in up to 50% of patients, and heralds a poor prognosis. However, a multidisciplinary team approach has improved the prognosis and quality of life for patients with carcinoid heart disease. Therapy includes somatostatin analogues and treatment for heart failure, removal of primary or metastatic tumour deposits, valve replacement in the presence of valvular involvement, and radioisotopes therapy

Off-line production of intense 7,10Be+^{7,10}Be^{+} beams

$^7$Be and $^{10}$Be were produced by 590~MeV proton bombardment of a graphite target at PSI. Parts of this graphite target were transferred into an ISOLDE target and ion source unit and ionized with the ISOLDE resonance ionization laser ion source (RILIS). Thus intense radioactive ion beams of 300~nA of $^{7,10}$Be$^+$ were produced off-line

genenames.org: the HGNC resources in 2011

The HUGO Gene Nomenclature Committee (HGNC) aims to assign a unique gene symbol and name to every human gene. The HGNC database currently contains almost 30 000 approved gene symbols, over 19 000 of which represent protein-coding genes. The public website, www.genenames.org, displays all approved nomenclature within Symbol Reports that contain data curated by HGNC editors and links to related genomic, phenotypic and proteomic information. Here we describe improvements to our resources, including a new Quick Gene Search, a new List Search, an integrated HGNC BioMart and a new Statistics and Downloads facility

In the absence of ATPase activity, pre-RC formation is blocked prior to MCM2-7 hexamer dimerization

The origin recognition complex (ORC) of Saccharomyces cerevisiae binds origin DNA and cooperates with Cdc6 and Cdt1 to load the replicative helicase MCM2–7 onto DNA. Helicase loading involves two MCM2–7 hexamers that assemble into a double hexamer around double-stranded DNA. This reaction requires ORC and Cdc6 ATPase activity, but it is unknown how these proteins control MCM2–7 double hexamer formation. We demonstrate that mutations in Cdc6 sensor-2 and Walker A motifs, which are predicted to affect ATP binding, influence the ORC–Cdc6 interaction and MCM2–7 recruitment. In contrast, a Cdc6 sensor-1 mutant affects MCM2–7 loading and Cdt1 release, similar as a Cdc6 Walker B ATPase mutant. Moreover, we show that Orc1 ATP hydrolysis is not involved in helicase loading or in releasing ORC from loaded MCM2–7. To determine whether Cdc6 regulates MCM2–7 double hexamer formation, we analysed complex assembly. We discovered that inhibition of Cdc6 ATPase restricts MCM2–7 association with origin DNA to a single hexamer, while active Cdc6 ATPase promotes recruitment of two MCM2–7 hexamer to origin DNA. Our findings illustrate how conserved Cdc6 AAA+ motifs modulate MCM2–7 recruitment, show that ATPase activity is required for MCM2–7 hexamer dimerization and demonstrate that MCM2–7 hexamers are recruited to origins in a consecutive process

Revising the Language Map of Korea

As linguists develop a deeper understanding of the properties of individual varieties of speech, they often find it necessary to reclassify dialects as independent languages, based on the criterion of intelligibility. This criterion is applied here to Jejueo, the traditional variety of speech used on Jeju Island, a province of the Republic of Korea. Although Jejueo has long been classified as a nonstandard dialect of Korean, evidence from an intelligibility experiment shows that it is not comprehensible to monolingual speakers of Korean and therefore should be treated as a separate language, in accordance with the usual practice within linguistics. This finding calls for a revision to the standard language map of Kore

Nonlinear acousto-electric transport in a two-dimensional electron system

We study both theoretically and experimentally the nonlinear interaction between an intense surface acoustic wave and a two-dimensional electron plasma in semiconductor-piezocrystal hybrid structures. The experiments on hybrid systems exhibit strongly nonlinear acousto-electric effects. The plasma turns into moving electron stripes, the acousto-electric current reaches its maximum, and the sound absorption strongly decreases. To describe the nonlinear phenomena, we develop a coupled-amplitude method for a two-dimensional system in the strongly nonlinear regime of interaction. At low electron densities the absorption coefficient decreases with increasing sound intensity, whereas at high electron density the absorption coefficient is not a monotonous function of the sound intensity. High-harmonic generation coefficients as a function of the sound intensity have a nontrivial behavior. Theory and experiment are found to be in a good agreement.Comment: 27 pages, 6 figure

Maximally-localized generalized Wannier functions for composite energy bands

We discuss a method for determining the optimally-localized set of generalized Wannier functions associated with a set of Bloch bands in a crystalline solid. By ``generalized Wannier functions'' we mean a set of localized orthonormal orbitals spanning the same space as the specified set of Bloch bands. Although we minimize a functional that represents the total spread sum_n [ _n - _n^2 ] of the Wannier functions in real space, our method proceeds directly from the Bloch functions as represented on a mesh of k-points, and carries out the minimization in a space of unitary matrices U_mn^k describing the rotation among the Bloch bands at each k-point. The method is thus suitable for use in connection with conventional electronic-structure codes. The procedure also returns the total electric polarization as well as the location of each Wannier center. Sample results for Si, GaAs, molecular C2H4, and LiCl will be presented.Comment: 22 pages, two-column style with 4 postscript figures embedded. Uses REVTEX and epsf macros. Also available at http://www.physics.rutgers.edu/~dhv/preprints/index.html#nm_wan

Influenza vaccine effectiveness in adults 65 years and older, Denmark, 2015/16:a rapid epidemiological and virological assessment

In Denmark, both influenza A(H1N1)pdm09 and influenza B co-circulated in the 2015/16 season. We estimated the vaccine effectiveness (VE) of the trivalent influenza vaccine in patients 65 years and older using the test-negative case–control design. The adjusted VE against influenza A(H1N1)pdm09 was 35.0% (95% confidence interval (CI): 11.1–52.4) and against influenza B 4.1% (95% CI: −22.0 to 24.7). The majority of influenza A(H1N1)pdm09 circulating in 2015/16 belonged to the new genetic subgroup subclade 6B.1.</jats:p

Canalization of the evolutionary trajectory of the human influenza virus

Since its emergence in 1968, influenza A (H3N2) has evolved extensively in genotype and antigenic phenotype. Antigenic evolution occurs in the context of a two-dimensional 'antigenic map', while genetic evolution shows a characteristic ladder-like genealogical tree. Here, we use a large-scale individual-based model to show that evolution in a Euclidean antigenic space provides a remarkable correspondence between model behavior and the epidemiological, antigenic, genealogical and geographic patterns observed in influenza virus. We find that evolution away from existing human immunity results in rapid population turnover in the influenza virus and that this population turnover occurs primarily along a single antigenic axis. Thus, selective dynamics induce a canalized evolutionary trajectory, in which the evolutionary fate of the influenza population is surprisingly repeatable and hence, in theory, predictable.Comment: 29 pages, 5 figures, 10 supporting figure