A Small-Molecule Inhibitor of Mps1 Blocks the Spindle-Checkpoint Response to a Lack of Tension on Mitotic Chromosomes

SummaryThe spindle checkpoint prevents chromosome loss by preventing chromosome segregation in cells with improperly attached chromosomes [1–3]. The checkpoint senses defects in the attachment of chromosomes to the mitotic spindle [4] and the tension exerted on chromosomes by spindle forces in mitosis [5–7]. Because many cancers have defects in chromosome segregation, this checkpoint may be required for survival of tumor cells and may be a target for chemotherapy. We performed a phenotype-based chemical-genetic screen in budding yeast and identified an inhibitor of the spindle checkpoint, called cincreasin. We used a genome-wide collection of yeast gene-deletion strains and traditional genetic and biochemical analysis to show that the target of cincreasin is Mps1, a protein kinase required for checkpoint function [8]. Despite the requirement for Mps1 for sensing both the lack of microtubule attachment and tension at kinetochores, we find concentrations of cincreasin that selectively inhibit the tension-sensitive branch of the spindle checkpoint. At these concentrations, cincreasin causes lethal chromosome missegregation in mutants that display chromosomal instability. Our results demonstrate that Mps1 can be exploited as a target and that inhibiting the tension-sensitive branch of the spindle checkpoint may be a way of selectively killing cancer cells that display chromosomal instability

Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury.

PRIMARY OBJECTIVE: To investigate functional improvement late (>6 months) after traumatic brain injury (TBI). To this end, we conducted a double-blind, placebo-controlled experimental medicine study to test the hypothesis that a widely used cognitive enhancer would benefit patients with TBI. RESEARCH DESIGN: We focused on motor control function using a sequential finger opposition fMRI paradigm in both patients and age-matched controls. METHODS AND PROCEDURES: Patients' fMRI and DTI scans were obtained after randomised administration of methylphenidate or placebo. Controls were scanned without intervention. To assess differences in motor speed, we compared reaction times from the baseline condition of a sustained attention task. MAIN OUTCOMES AND RESULTS: Patients' reaction times correlated with wide-spread motor-related white matter abnormalities. Administration of methylphenidate resulted in faster reaction times in patients, which were not significantly different from those achieved by controls. This was also reflected in the fMRI findings in that patients on methylphenidate activated the left inferior frontal gyrus significantly more than when on placebo. Furthermore, stronger functional connections between pre-/post-central cortices and cerebellum were noted for patients on methylphenidate. CONCLUSIONS: Our findings suggest that residual functionality in patients with TBI may be enhanced by a single dose of methylphenidate.The study was funded by the Evelyn Trust- grant number 06/20. C.D. was funded by the Clinical Academic Research Awards organized by the East of England Multi Professional Deanery. B.J.S. consults for Cambridge Cognition, Otsuka, Servier and Lundbeck. She holds a grant from Janssen/J&J and has share options in Cambridge Cognition. D.K.M. is supported by the Neuroscience Theme of the NIHR Cambridge Biomedical Research Centre and NIHR Senior Investigator awards, and by Framework Program 7 funding from the European Commission (TBIcare). He has received lecture and consultancy fees and support for research from Glaxo SmithKline, Solvay and Linde. E.A.S. is funded by the Stephen Erskine Fellowship, Queens' College, Cambridge, UK

Radiation pressure instability driven variability in the accreting black holes

The time dependent evolution of the accretion disk around black hole is computed. The classical description of the $\alpha$-viscosity is adopted so the evolution is driven by the instability operating in the innermost radiation-pressure dominated part of the accretion disk. We assume that the optically thick disk always extends down to the marginally stable orbit so it is never evacuated completely. We include the effect of the advection, coronal dissipation and vertical outflow. We show that the presence of the corona and/or the outflow reduce the amplitude of the outburst. If only about half of the energy is dissipated in the disk (with the other half dissipated in the corona and carried away by the outflow) the outburst amplitude and duration are consistent with observations of the microquasar GRS 1915+105. Viscous evolution explains in a natural way the lack of direct transitions from the state C to the state B in color-color diagram of this source. Further reduction of the fraction of energy dissipated in the optically thick disk switches off the outbursts which may explain why they are not seen in all high accretion rate sources being in the Very High State.Comment: 31 pages, 14 figures; accepted to Ap

Radiation pressure instability as a variability mechanism in the microquasar GRS 1915+105

Physical mechanism responsible for high viscosity in accretion disks is still under debate. Parameterization of the viscous stress as $\alpha P$ proved to be a successful representation of this mechanism in the outer parts of the disk, explaining the dwarf novae and X-ray novae outbursts as due to ionization instability. We show that this parameterization can be also adopted in the innermost part of the disk where the adoption of the $\alpha$-viscosity law implies the presence of the instability in the radiation pressure dominated region. We study the time evolution of such disks. We show that the time-dependent behavior of GRS 1915+105 can be well reproduced if $\alpha$-viscosity disk model is calculated accurately (with proper numerical coefficients in vertically averaged equations and with advection included), and if the model is supplemented with (i) moderate corona dissipating 50% of energy (ii) jet carrying luminosity-dependent fraction of energy. These necessary modifications in the form of the presence of a corona and a jet are well justified observationally. The model predicts outbursts at luminosity larger than 0.16$\dot M_{Edd}$, as required, correct outburst timescales and amplitudes, including the effect of increasing outburst timescale with mean luminosity. This result strongly suggests that the $\alpha$-viscosity law is a good description of the actual mechanism responsible for angular momentum transfer also in the innermost, radiation pressure dominated part of the disk around a black hole.Comment: 6 pages, 2 figures; accepted for publication in ApJ Letter

Kondo-like transport and magnetic field effect of charge carrier fluctuations in granular aluminum oxide thin films

Granular aluminum oxide is an attractive material for superconducting quantum electronics. However, its low-temperature normal state transport properties are still not fully understood, while they could be related to the unconventional phenomenon of the superconductivity in this material. In order to obtain useful information on this aspect, a detailed study of charge carrier fluctuations has been performed in granular aluminum oxide films. The results of electric noise measurements indicate the presence of a Kondo-type spin-flip scattering mechanism for the conducting electrons in the normal state, at low temperatures. Moreover, the magnetic field dependence of the noise amplitude suggests that interface magnetic moments are the main source of fluctuations. The identification of the nature of fluctuation processes is a mandatory requirement for the improvement of quality and performance of quantum devices

Kondo-like transport and magnetic field effect of charge carrier fluctuations in granular aluminum oxide thin films

Granular aluminum oxide is an attractive material for superconducting quantum electronics. However, its low-temperature normal state transport properties are still not fully understood, while they could be related to the unconventional phenomenon of the superconductivity in this material. In order to obtain useful information on this aspect, a detailed study of charge carrier fluctuations has been performed in granular aluminum oxide films. The results of electric noise measurements indicate the presence of a Kondo-type spin-flip scattering mechanism for the conducting electrons in the normal state, at low temperatures. Moreover, the magnetic field dependence of the noise amplitude suggests that interface magnetic moments are the main source of fluctuations. The identification of the nature of fluctuation processes is a mandatory requirement for the improvement of quality and performance of quantum devices

The 'new majority' and the academization of journalism

The academization of journalism is reliant on the development of the field founded in scholarship demonstrated through the publication of research in peer-reviewed specialist journals. Given the profile of journalism faculty, this means inducting practitioners into a culture of critical research. In Australia at least, this cohort of neophytes is predominantly comprised of middle-aged women who were surveyed about their personal attitudes to research. They were mostly open to the idea of becoming researchers but were inclined to proceed cautiously without necessarily severing their ties with practice. There was evidence to suggest that a generally positive orientation to research was not capitalized on and that they remained uncertain about the role of research. On the other hand, they appeared not to have adopted the orthodoxy of implacable opposition to scholarly inquiry. The change in gender composition in the academy may provide, contrary to historical, but more in line with contemporary, evidence, a renewed impetus to the project of academizing the field