Cataclysmic Variables in the First Year of the Zwicky Transient Facility

Using selection criteria based on amplitude, time, and color, we have identified 329 objects as known or candidate cataclysmic variables (CVs) during the first year of testing and operation of the Zwicky Transient Facility. Of these, 90 are previously confirmed CVs, 218 are strong candidates based on the shape and color of their light curves obtained during 3–562 days of observation, and the remaining 21 are possible CVs but with too few data points to be listed as good candidates. Almost half of the strong candidates are within 10 deg of the galactic plane, in contrast to most other large surveys that have avoided crowded fields. The available Gaia parallaxes are consistent with sampling the low mass transfer CVs, as predicted by population models. Our follow-up spectra have confirmed Balmer/helium emission lines in 27 objects, with four showing high-excitation He ii emission, including candidates for an AM CVn, a polar, and an intermediate polar. Our results demonstrate that a complete survey of the Galactic plane is needed to accomplish an accurate determination of the number of CVs existing in the Milky Way

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Restoring tumour selectivity of the bioreductive prodrug pr-104 by developing an analogue resistant to aerobic metabolism by human aldo-keto reductase 1c3

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes ‘off-target’ two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues. AKR1C3 expression in human myeloid progenitor cells probably accounts for the dose-limiting myelotoxicity of PR-104 documented in clinical trials, resulting in human PR-104A plasma exposure levels 3.4- to 9.6-fold lower than can be achieved in murine models. Structure-based design to eliminate AKR1C3 activation thus represents a strategy for restoring the therapeutic window of this class of agent in humans. Here, we identified SN29176, a PR-104A analogue resistant to human AKR1C3 activation. SN29176 retains hypoxia selectivity in vitro with aerobic/hypoxic IC(50) ratios of 9 to 145, remains a substrate for POR and triggers γH2AX induction and cell cycle arrest in a comparable manner to PR-104A. SN35141, the soluble phosphate pre-prodrug of SN29176, exhibited superior hypoxic tumour log cell kill (>4.0) to PR-104 (2.5–3.7) in vivo at doses predicted to be achievable in humans. Orthologues of human AKR1C3 from mouse, rat and dog were incapable of reducing PR-104A, thus identifying an underlying cause for the discrepancy in PR-104 tolerance in pre-clinical models versus humans. In contrast, the macaque AKR1C3 gene orthologue was able to metabolise PR-104A, indicating that this species may be suitable for evaluating the toxicokinetics of PR-104 analogues for clinical development. We confirmed that SN29176 was not a substrate for AKR1C3 orthologues across all four pre-clinical species, demonstrating that this prodrug analogue class is suitable for further development. Based on these findings, a prodrug candidate was subsequently identified for clinical trials

Mechanical Relaxation in Glasses and at the Glass Transition

The Gilroy-Phillips model of relaxational jumps in asymmetric double-well potentials, developed for the Arrhenius-type secondary relaxations of the glass phase, is extended to a formal description of the breakdown of the shear modulus at the glass transition, the flow process.Comment: 13 pages, 11 figures, 49 ref

Radiative Decays of the Upsilon(1S) to a Pair of Charged Hadrons

Using data obtained with the CLEO~III detector, running at the Cornell Electron Storage Ring (CESR), we report on a new study of exclusive radiative Upsilon(1S) decays into the final states gamma pi^+ pi^-, gamma K^+ K^-, and gamma p pbar.. We present branching ratio measurements for the decay modes Upsilon(1S) to gamma f_2(1270), Upsilon(1S) to gamma f_2'(1525), and Upsilon(1S) to gamma K^+K^-; helicity production ratios for f_2(1270) and f_2'(1525); upper limits for the decay Upsilon(1S) to gamma f_J(2200), with f_J(2220) to pi^+ pi^-, K^+ K^-, p pbar; and an upper limit for the decay Upsilon(1S) to gamma X(1860), with X(1860) to gamma p pbar.Comment: 17 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2005/, Submitted to PR

Search for X(3872) in gamma gamma Fusion and ISR at CLEO

We report on a search for the recently reported X(3872) state using 15.1 fb^{-1} e+ e- data taken in the \sqrt{s} = 9.46-11.30 GeV region. Separate searches for the production of X(3872) in untagged gamma-gamma fusion and e+ e- annihilation following initial state radiation (ISR) are made by taking advantage of the unique correlation of J/psi -> l+ l- in X(3872) decay to pi+ pi- J/psi. No signals are observed in either case, and 90% confidence upper limits are established as (2J+1)\Gamma_{\gamma\gamma}B(X -> pi+ pi- J/psi) < 12.9 eV and \Gamma_{ee}B(X -> pi+ pi- J/psi) < 8.3 eV.Comment: 8 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2004/, submitted to PR

Bright ligand-activatable fluorescent protein for high-quality multicolor live-cell super-resolution microscopy

We introduce UnaG as a green-to-dark photoswitching fluorescent protein capable of high-quality super-resolution imaging with photon numbers equivalent to the brightest photoswitchable red protein. UnaG only fluoresces upon binding of a fluorogenic metabolite, bilirubin, enabling UV-free reversible photoswitching with easily controllable kinetics and low background under Epi illumination. The on- and off-switching rates are controlled by the concentration of the ligand and the excitation light intensity, respectively, where the dissolved oxygen also promotes the off-switching. The photo-oxidation reaction mechanism of bilirubin in UnaG suggests that the lack of ligand-protein covalent bond allows the oxidized ligand to detach from the protein, emptying the binding cavity for rebinding to a fresh ligand molecule. We demonstrate super-resolution single-molecule localization imaging of various subcellular structures genetically encoded with UnaG, which enables facile labeling and simultaneous multicolor imaging of live cells. UnaG has the promise of becoming a default protein for high-performance super-resolution imaging. Photoconvertible proteins occupy two color channels thereby limiting multicolour localisation microscopy applications. Here the authors present UnaG, a new green-to-dark photoswitching fluorescent protein for super-resolution imaging, whose activation is based on a noncovalent binding with bilirubin

Observation of a Narrow Resonance of Mass 2.46 GeV/c^2 Decaying to D_s^*+ pi^0 and Confirmation of the D_sJ^* (2317) State

Using 13.5 inverse fb of e+e- annihilation data collected with the CLEO II detector we have observed a narrow resonance in the Ds*+pi0 final state, with a mass near 2.46 GeV. The search for such a state was motivated by the recent discovery by the BaBar Collaboration of a narrow state at 2.32 GeV, the DsJ*(2317)+ that decays to Ds+pi0. Reconstructing the Ds+pi0 and Ds*+pi0 final states in CLEO data, we observe peaks in both of the corresponding reconstructed mass difference distributions, dM(Dspi0)=M(Dspi0)-M(Ds) and dM(Ds*pi0)=M(Ds*pi0)-M(Ds*), both of them at values near 350 MeV. We interpret these peaks as signatures of two distinct states, the DsJ*(2317)+ plus a new state, designated as the DsJ(2463)+. Because of the similar dM values, each of these states represents a source of background for the other if photons are lost, ignored or added. A quantitative accounting of these reflections confirms that both states exist. We have measured the mean mass differences = 350.0 +/- 1.2 [stat] +/- 1.0 [syst] MeV for the DsJ*(2317) state, and = 351.2 +/- 1.7 [stat] +/- 1.0 [syst] MeV for the new DsJ(2463)+ state. We have also searched, but find no evidence, for decays of the two states via the channels Ds*+gamma, Ds+gamma, and Ds+pi+pi-. The observations of the two states at 2.32 and 2.46 GeV, in the Ds+pi0 and Ds*+pi0 decay channels respectively, are consistent with their interpretations as (c anti-strange) mesons with orbital angular momentum L=1, and spin-parities of 0+ and 1+.Comment: 16 pages postscript, also available through http://w4.lns.cornell.edu/public/CLNS, version to be published in Physical Review D; minor modifications and fixes to typographical errors, plus an added section on production properties. The main results are unchanged; they supersede those reported in hep-ex/030501

Observation of the ^1P_1 State of Charmonium

The spin-singlet P-wave state of charmonium, hc(1P1), has been observed in the decay psi(2S) -> pi0 hc followed by hc -> gamma etac. Inclusive and exclusive analyses of the M(hc) spectrum have been performed. Two complementary inclusive analyses select either a range of energies for the photon emitted in hc -> gamma etac or a range of values of M(etac). These analyses, consistent with one another within statistics, yield M(h_c) =[3524.9 +/- 0.7 (stat) +/- 0.4 (sys)]MeV/c^2 and a product of the branching ratios B_psi(psi(2S) -> pi0 hc) x B_h(hc -> gamma etac) = [3.5 +/- 1.0 (stat) +/- 0.7 (sys)] x 10^{-4}. When the etac is reconstructed in seven exclusive decay modes, 17.5 +/- 4.5 hc events are seen with an average mass M(hc) = [3523.6 +/- 0.9 (stat) +/- 0.5 (sys)] MeV/c^2, and B_psi x B_h = [5.3 +/- 1.5 (stat) +/- 1.0 (sys)] x 10^{-4}. Because the inclusive and exclusive data samples are largely independent they are combined to yield an overall mass M(hc) = [3524.4 +/- 0.6 (stat) +/- 0.4 (sys)]MeV/c^2 and product of branching ratios B_psi x B_h = [4.0 +/- 0.8 (stat) +/- 0.7 (sys)] x 10^{-4}. The hc mass implies a P-wave hyperfine splitting Delta M_{HF}(1P) \equiv M(1^3P)-M(1^1P_1) = [1.0 +/- 0.6 (stat) +/- 0.4 (sys)] MeV/c^2.Comment: 38 pages postscript,also available through http://www.lns.cornell.edu/public/CLNS/2005/, Submitted to PR