326 research outputs found
Monoamine oxidase-A modulates apoptotic cell death induced by staurosporine in human neuroblastoma cells
Monoamine oxidases (MAOs) are mitochondrial enzymes which control the levels of neurotransmitters in the brain and dietary amines in peripheral tissues via oxidative deamination. MAO has also been implicated in cell signalling. In this study, we describe the MAO-A isoform as functional in apoptosis induced by staurosporine (STS) in human dopaminergic neuroblastoma cells (SH-SY5Y). Increased levels of MAO-A activity were induced by STS, accompanied by increased MAO-A protein and activation of the initiator of the intrinsic pathway, caspase 9, and the executioner caspase 3. MAO-A mRNA levels were unaffected by STS, suggesting that changes in MAO-A protein are due to post-transcriptional events. Two unrelated MAO-A inhibitors reduced caspase activation. STS treatment resulted in sustained activation of the mitogen-activated protein kinase pathway enzymes extracellular regulated kinase, c-jun terminal kinase and p38, and depletion of the anti-apoptotic protein Bcl-2. These changes were significantly reversed by MAO inhibition. Production of reactive oxygen species was increased following STS exposure, which was blocked by both MAO inhibition and the antioxidant N-acetylcysteine. Therefore our data provide evidence that MAO-A, through its production of reactive oxygen species as a by-product of its catalytic activity on the mitochondrial surface, is recruited by the cell to enhance apoptotic signalling
Linear modeling of possible mechanisms for parkinson tremor generation
The power of Parkinson tremor is expressed in terms of possibly changed frequency response functions between relevant variables in the neuromuscular system. The derivation starts out from a linear loopless equivalent model of mechanisms for general tremor generation. Hypothetical changes in this model from the substrate of the disease are indicated, and possible ones are inferred from literature about experiments on patients. The result indicates that in these patients tremor appears to have been generated in loops, which did not include the brain area which in surgery usually is inactivated. For some patients in the literature, these loops could involve muscle length receptors, the static sensitivity of which may have been enlarged by pathological brain activity
Unexpected effects of third-order cross-terms in heteronuclear spin systems under simultaneous radio-frequency irradiation and magic-angle spinning NMR
We recently noted [R. K. Harris, P. Hodgkinson, V. Zorin, J.-N. Dumez, B. Elena, L. Emsley, E. Salager, and R. Stein, Magn. Reson. Chem. 48, S103 (2010)10.1002/mrc.2636] anomalous shifts in apparent 1H chemical shifts in experiments using 1H homonuclear decoupling sequences to acquire high-resolution 1H NMR spectra for organic solids under magic-angle spinning (MAS). Analogous effects were also observed in numerical simulations of model 13C,1H spin systems under homonuclear decoupling and involving large 13C,1H dipolar couplings. While the heteronuclear coupling is generally assumed to be efficiently suppressed by sample spinning at the magic angle, we show that under conditions typically used in solid-state NMR, there is a significant third-order cross-term from this coupling under the conditions of simultaneous MAS and homonuclear decoupling for spins directly bonded to 1H. This term, which is of the order of 100 Hz under typical conditions, explains the anomalous behaviour observed on both 1H and 13C spins, including the fast dephasing observed in 13C{1H} heteronuclear spin-echo experiments under 1H homonuclear decoupling. Strategies for minimising the impact of this effect are also discussed
Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.
The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth
The Resolved Structure and Dynamics of an Isolated Dwarf Galaxy: A VLT and Keck Spectroscopic Survey of WLM
We present spectroscopic data for 180 red giant branch stars in the isolated
dwarf irregular galaxy WLM. Observations of the Calcium II triplet lines in
spectra of RGB stars covering the entire galaxy were obtained with FORS2 at the
VLT and DEIMOS on Keck II allowing us to derive velocities, metallicities, and
ages for the stars. With accompanying photometric and radio data we have
measured the structural parameters of the stellar and gaseous populations over
the full galaxy. The stellar populations show an intrinsically thick
configuration with . The stellar rotation in WLM is
measured to be km s, however the ratio of rotation to
pressure support for the stars is , in contrast to the gas
whose ratio is seven times larger. This, along with the structural data and
alignment of the kinematic and photometric axes, suggests we are viewing WLM as
a highly inclined oblate spheroid. Stellar rotation curves, corrected for
asymmetric drift, are used to compute a dynamical mass of M at the half light radius (
pc). The stellar velocity dispersion increases with stellar age in a manner
consistent with giant molecular cloud and substructure interactions producing
the heating in WLM. Coupled with WLM's isolation, this suggests that the
extended vertical structure of its stellar and gaseous components and increase
in stellar velocity dispersion with age are due to internal feedback, rather
than tidally driven evolution. These represent some of the first observational
results from an isolated Local Group dwarf galaxy which can offer important
constraints on how strongly internal feedback and secular processes modulate SF
and dynamical evolution in low mass isolated objects.Comment: 14 Pages, 17 figures, 3 tables. Accepted for publication in Ap
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