420 research outputs found
De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.
Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders
Azimuthal Anisotropy of Photon and Charged Particle Emission in Pb+Pb Collisions at 158 A GeV/c
The azimuthal distributions of photons and charged particles with respect to
the event plane are investigated as a function of centrality in Pb + Pb
collisions at 158 A GeV/c in the WA98 experiment at the CERN SPS. The
anisotropy of the azimuthal distributions is characterized using a Fourier
analysis. For both the photon and charged particle distributions the first two
Fourier coefficients are observed to decrease with increasing centrality. The
observed anisotropies of the photon distributions compare well with the
expectations from the charged particle measurements for all centralities.Comment: 8 pages and 6 figures. The manuscript has undergone a major revision.
The unwanted correlations were enhanced in the random subdivision method used
in the earlier version. The present version uses the more established method
of division into subevents separated in rapidity to minimise short range
correlations. The observed results for charged particles are in agreement
with results from the other experiments. The observed anisotropy in photons
is explained using flow results of pions and the correlations arising due to
the decay of the neutral pion
Sufficiency and duality in nondifferentiable multiobjective programming involving higher order strong invexity
Engendering harm: a critique of sex selection for 'family balancing'
The most benign rationale for sex-selection is deemed to be “family balancing.” On this view, provided the sex-distribution of an existing offspring group is “unbalanced,” one may legitimately use reproductive technologies to select the sex of the next child. I present four novel concerns with granting “family balancing” as a justification for sex-selection: (a) families or family subsets should not be subject to medicalization; (b) sex selection for “family balancing” entrenches heteronormativity, inflicting harm in at least three specific ways; (c) the logic of affirmative action is appropriated; (d) the moral mandate of reproductive autonomy is misused. I conclude that the harms caused by “family balancing” are sufficiently substantive to over-ride any claim arising from a supposed right to sex selection as an instantiation of procreative autonomy
Multiplicity Distributions and Charged-neutral Fluctuations
Results from the multiplicity distributions of inclusive photons and charged
particles, scaling of particle multiplicities, event-by-event multiplicity
fluctuations, and charged-neutral fluctuations in 158 GeV Pb+Pb
collisions are presented and discussed. A scaling of charged particle
multiplicity as and photons as have been observed, indicating violation of naive wounded nucleon model.
The analysis of localized charged-neutral fluctuation indicates a
model-independent demonstration of non-statistical fluctuations in both charged
particles and photons in limited azimuthal regions. However, no correlated
charged-neutral fluctuations are observed.Comment: Talk given at the International Symposium on Nuclear Physics
(ISNP-2000), Mumbai, India, 18-22 Dec 2000, Proceedings to be published in
Pramana, Journal of Physic
Sufficiency and duality in multiobjective fractional programming problems involving generalized type I functions
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