Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss

Centromere-associated protein-E (CENP-E) is an essential mitotic kinesin that is required for efficient, stable microtubule capture at kinetochores. It also directly binds to BubR1, a kinetochore-associated kinase implicated in the mitotic checkpoint, the major cell cycle control pathway in which unattached kinetochores prevent anaphase onset. Here, we show that single unattached kinetochores depleted of CENP-E cannot block entry into anaphase, resulting in aneuploidy in 25% of divisions in primary mouse fibroblasts in vitro and in 95% of regenerating hepatocytes in vivo. Without CENP-E, diminished levels of BubR1 are recruited to kinetochores and BubR1 kinase activity remains at basal levels. CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. Thus, CENP-E is required for enhancing recruitment of its binding partner BubR1 to each unattached kinetochore and for stimulating BubR1 kinase activity, implicating it as an essential amplifier of a basal mitotic checkpoint signal

Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients

BackgroundClostridium difficile infection (CDI) is a common complication of lung and allogeneic hematopoietic cell (HCT) transplant, but the epidemiology and outcomes of CDI after transplant are poorly described.MethodsWe performed a prospective, multicenter study of CDI within 365 days post‐allogeneic HCT or lung transplantation. Data were collected via patient interviews and medical chart review. Participants were followed weekly in the 12 weeks post‐transplant and while hospitalized and contacted monthly up to 18 months post‐transplantation.ResultsSix sites participated in the study with 614 total participants; 4 enrolled allogeneic HCT (385 participants) and 5 enrolled lung transplant recipients (229 participants). One hundred and fifty CDI cases occurred within 1 year of transplantation; the incidence among lung transplant recipients was 13.1% and among allogeneic HCTs was 31.2%. Median time to CDI was significantly shorter among allogeneic HCT than lung transplant recipients (27 days vs 90 days; P = .037). CDI was associated with significantly higher mortality from 31 to 180 days post‐index date among the allogeneic HCT recipients (Hazard ratio [HR] = 1.80; P = .007). There was a trend towards increased mortality among lung transplant recipients from 120 to 180 days post‐index date (HR = 4.7, P = .09).ConclusionsThe epidemiology and outcomes of CDI vary by transplant population; surveillance for CDI should continue beyond the immediate post‐transplant period.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143790/1/tid12855_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143790/2/tid12855.pd

The role of aneuploidy in promoting and suppressing tumors

Impaired mitotic checkpoint signaling can both promote and suppress tumors. The mitotic checkpoint targets Cdc20, the specificity factor of the ubiquitin ligase that promotes anaphase by targeting cyclin B and securin for destruction. In this issue, Li et al. (2009. J. Cell Biol. doi:10.1083/jcb.200904020) use gene replacement to produce mice expressing a Cdc20 mutant that cannot be inhibited by the mitotic checkpoint. In addition to the expected aneuploidy, these animals have a high tumor incidence that is likely caused by persistent aneuploidy coupled with nonmitotic functions of mutant Cdc20

Nonlinear Lattice Waves in Random Potentials

Localization of waves by disorder is a fundamental physical problem encompassing a diverse spectrum of theoretical, experimental and numerical studies in the context of metal-insulator transition, quantum Hall effect, light propagation in photonic crystals, and dynamics of ultra-cold atoms in optical arrays. Large intensity light can induce nonlinear response, ultracold atomic gases can be tuned into an interacting regime, which leads again to nonlinear wave equations on a mean field level. The interplay between disorder and nonlinearity, their localizing and delocalizing effects is currently an intriguing and challenging issue in the field. We will discuss recent advances in the dynamics of nonlinear lattice waves in random potentials. In the absence of nonlinear terms in the wave equations, Anderson localization is leading to a halt of wave packet spreading. Nonlinearity couples localized eigenstates and, potentially, enables spreading and destruction of Anderson localization due to nonintegrability, chaos and decoherence. The spreading process is characterized by universal subdiffusive laws due to nonlinear diffusion. We review extensive computational studies for one- and two-dimensional systems with tunable nonlinearity power. We also briefly discuss extensions to other cases where the linear wave equation features localization: Aubry-Andre localization with quasiperiodic potentials, Wannier-Stark localization with dc fields, and dynamical localization in momentum space with kicked rotors.Comment: 45 pages, 19 figure

Additional Nucleon Current Contributions to Neutrinoless Double Beta Decay

We have examined the importance of momentum dependent induced nucleon currents such as weak-magnetism and pseudoscalar couplings to the amplitude of neutrinoless double beta decay in the mechanisms of light and heavy Majorana neutrino as well as in that of Majoron emission. Such effects are expected to occur in all nuclear models in the direction of reducing the light neutrino matrix elements by about 30%. To test this we have performed a calculation of the nuclear matrix elements of the experimentally interesting nuclei A = 76, 82, 96, 100, 116, 128, 130, 136 and 150 within the pn-RQRPA. We have found that indeed such corrections vary somewhat from nucleus to nucleus, but in all cases they are greater than 25 percent. In the case of heavy neutrino the effect is much larger (a factor of 3). Combining out results with the best presently available experimental limits on the half-life of the neutrinoless double beta decay we have extracted new limits on the effective neutrino mass (light and heavy) and the effective Majoron coupling constant.Comment: 31 pages, RevTex, 3 Postscript figures, submitted to Phys. Rev.

Fast Neutron Detection with 6Li-loaded Liquid Scintillator

We report on the development of a fast neutron detector using a liquid scintillator doped with enriched Li-6. The lithium was introduced in the form of an aqueous LiCl micro-emulsion with a di-isopropylnaphthalene-based liquid scintillator. A Li-6 concentration of 0.15 % by weight was obtained. A 125 mL glass cell was filled with the scintillator and irradiated with fission-source neutrons. Fast neutrons may produce recoil protons in the scintillator, and those neutrons that thermalize within the detector volume can be captured on the Li-6. The energy of the neutron may be determined by the light output from recoiling protons, and the capture of the delayed thermal neutron reduces background events. In this paper, we discuss the development of this 6Li-loaded liquid scintillator, demonstrate the operation of it in a detector, and compare its efficiency and capture lifetime with Monte Carlo simulations. Data from a boron-loaded plastic scintillator were acquired for comparison. We also present a pulse-shape discrimination method for differentiating between electronic and nuclear recoil events based on the Matusita distance between a normalized observed waveform and nuclear and electronic recoil template waveforms. The details of the measurements are discussed along with specifics of the data analysis and its comparison with the Monte Carlo simulation

The semiology of changing brand image

This article considers the attempted change to the image of an established brand by studying the semiotics within the brand’s historical advertising campaigns. The use of semiotics to study the interpretation of messages is discussed, and the link between interpretation of messages and advertising effectiveness in changing brand image is explored. The authors deconstruct advertisements of a brand to provide a model containing opposing dialectics that may aid managers by highlighting alternative symbolic messages contained in advertisements. Oncwe identified, these alternative symbolic messages may be used to help change brand image and influence advertising effectiveness. Although the study focuses upon a major brand of beer, this is an industry in which there are numerous small firms, and many of those have constrained marketing budgets, and thus need to make sure that their advertising is effective. Equally, entrepreneurial marketing is not to found only in the small firm, and the case study discusses a radical and imaginative brand repositioning of a well established product

The Sudbury Neutrino Observatory

The Sudbury Neutrino Observatory is a second generation water Cherenkov detector designed to determine whether the currently observed solar neutrino deficit is a result of neutrino oscillations. The detector is unique in its use of D2O as a detection medium, permitting it to make a solar model-independent test of the neutrino oscillation hypothesis by comparison of the charged- and neutral-current interaction rates. In this paper the physical properties, construction, and preliminary operation of the Sudbury Neutrino Observatory are described. Data and predicted operating parameters are provided whenever possible.Comment: 58 pages, 12 figures, submitted to Nucl. Inst. Meth. Uses elsart and epsf style files. For additional information about SNO see http://www.sno.phy.queensu.ca . This version has some new reference

Study of cosmogenic activation above ground for the DarkSide-20k experiment

The activation of materials due to exposure to cosmic rays may become an important background source for experiments investigating rare event phenomena. DarkSide-20k, currently under construction at the Laboratori Nazionali del Gran Sasso, is a direct detection experiment for galactic dark matter particles, using a two-phase liquid-argon Time Projection Chamber (TPC) filled with 49.7 tonnes (active mass) of Underground Argon (UAr) depleted in 39Ar. Despite the outstanding capability of discriminating / background in argon TPCs, this background must be considered because of induced dead time or accidental coincidences mimicking dark-matter signals and it is relevant for low-threshold electron-counting measurements. Here, the cosmogenic activity of relevant long-lived radioisotopes induced in the experiment has been estimated to set requirements and procedures during preparation of the experiment and to check that it is not dominant over primordial radioactivity; particular attention has been paid to the activation of the 120 t of UAr used in DarkSide-20k. Expected exposures above ground and production rates, either measured or calculated, have been considered in detail. From the simulated counting rates in the detector due to cosmogenic isotopes, it is concluded that activation in copper and stainless steel is not problematic. The activity of 39Ar induced during extraction, purification and transport on surface is evaluated to be 2.8% of the activity measured in UAr by DarkSide-50 experiment, which used the same underground source, and thus considered acceptable. Other isotopes in the UAr such as 37Ar and 3H are shown not to be relevant due to short half-life and assumed purification methods