413 research outputs found
Structural characterization of copper(II) binding to α-Synuclein: Insights into the bioinorganic chemistry of Parkinson's disease
The aggregation of α -synuclein (AS) is characteristic of Parkinson’s disease and other neurodegenerative synucleinopathies. We demonstrate here that Cu(II) ions are effective in accelerating AS aggregation at physiologically relevant concentrations without altering the resultant fibrillar structures. By using numerous spectroscopic techniques (absorption, CD, EPR, and NMR), we have located the primary binding for Cu(II) to a specific site in the N terminus, involving His-50 as the anchoring residue and other nitrogen oxygen donor atoms in a square planar or distorted tetragonal geometry. The carboxylate-rich C terminus, originally thought to drive copper binding, is able to coordinate a second Cu(II) equivalent, albeit with a 300-fold reduced affinity. The NMR analysis of AS–Cu(II) complexes reveals the existence of conformational restrictions in the native state of the protein. The metallobiology of Cu(II) in Parkinson’s disease is discussed by a comparative analysis with other Cu(II)-binding proteins involved in neurodegenerative disorders
Bound pair states beyond the condensate for Fermi systems below T_c: the pseudogap as a necessary condition
As is known, the 1/q^2 theorem of Bogoliubov asserts that the mean density of
the fermion pair states with the total momentum q obeys the inequality n_q >
C/q^2 (q \to 0) in the case of the Fermi system taken at nonzero temperature
and in the superconducting state provided the interaction term of its
Hamiltonian is locally gauge invariant. With the principle of correlation
weakening it is proved in this paper that the reason for the mentioned singular
behaviour of n_q is the presence of the bound states of particle pairs with
nonzero total momenta. Thus, below the temperature of the superconducting phase
transition there always exist the bound states of the fermion couples beyond
the pair condensate. If the pseudogap observed in the normal phase of the
high-T_c superconductors is stipulated by the presence of the electron bound
pairs, then the derived result suggests, in a model-independent manner, that
the pseudogap survives below T_c.Comment: REVTeX, 8 pages, no figures, submitted to Phys. Rev.
Theory of superfluidity and drag force in the one-dimensional Bose gas
The one-dimensional Bose gas is an unusual superfluid. In contrast to higher
spatial dimensions, the existence of non-classical rotational inertia is not
directly linked to the dissipationless motion of infinitesimal impurities.
Recently, experimental tests with ultracold atoms have begun and quantitative
predictions for the drag force experienced by moving obstacles have become
available. This topical review discusses the drag force obtained from linear
response theory in relation to Landau's criterion of superfluidity. Based upon
improved analytical and numerical understanding of the dynamical structure
factor, results for different obstacle potentials are obtained, including
single impurities, optical lattices and random potentials generated from
speckle patterns. The dynamical breakdown of superfluidity in random potentials
is discussed in relation to Anderson localization and the predicted
superfluid-insulator transition in these systems.Comment: 17 pages, 12 figures, mini-review prepared for the special issue of
Frontiers of Physics "Recent Progresses on Quantum Dynamics of Ultracold
Atoms and Future Quantum Technologies", edited by Profs. Lee, Ueda, and
Drummon
Morphine and alternative opioids in cancer pain: the EAPC recommendations: Expert Working Group of the Research Network of the European Association for Palliative Care
An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated. © 2001 Cancer Research Campaig
Stoichiometry of a regulatory splicing complex revealed by single-molecule analyses
Splicing is regulated by complex interactions of numerous RNA-binding proteins. The molecular mechanisms involved remain elusive, in large part because of ignorance regarding the numbers of proteins in regulatory complexes. Polypyrimidine tract-binding protein (PTB), which regulates tissue-specific splicing, represses exon 3 of α-tropomyosin through distant pyrimidine-rich tracts in the flanking introns. Current models for repression involve either PTB-mediated looping or the propagation of complexes between tracts. To test these models, we used single-molecule approaches to count the number of bound PTB molecules both by counting the number of bleaching steps of GFP molecules linked to PTB within complexes and by analysing their total emissions. Both approaches showed that five or six PTB molecules assemble. Given the domain structures, this suggests that the molecules occupy primarily multiple overlapping potential sites in the polypyrimidine tracts, excluding propagation models. As an alternative to direct looping, we propose that repression involves a multistep process in which PTB binding forms small local loops, creating a platform for recruitment of other proteins that bring these loops into close proximity
The ESR1 (6q25) locus is associated with calcaneal ultrasound parameters and radial volumetric bone mineral density in European men
<p><b>Purpose:</b> Genome-wide association studies (GWAS) have identified 6q25, which incorporates the oestrogen receptor alpha gene (ESR1), as a quantitative trait locus for areal bone mineral density (BMD(a)) of the hip and lumbar spine. The aim of this study was to determine the influence of this locus on other bone health outcomes; calcaneal ultrasound (QUS) parameters, radial peripheral quantitative computed tomography (pQCT) parameters and markers of bone turnover in a population sample of European men.</p>
<p><b>Methods:</b> Eight single nucleotide polymorphisms (SNP) in the 6q25 locus were genotyped in men aged 40-79 years from 7 European countries, participating in the European Male Ageing Study (EMAS). The associations between SNPs and measured bone parameters were tested under an additive genetic model adjusting for centre using linear regression.</p>
<p><b>Results:</b> 2468 men, mean (SD) aged 59.9 (11.1) years had QUS measurements performed and bone turnover marker levels measured. A subset of 628 men had DXA and pQCT measurements. Multiple independent SNPs showed significant associations with BMD using all three measurement techniques. Most notably, rs1999805 was associated with a 0.10 SD (95%CI 0.05, 0.16; p = 0.0001) lower estimated BMD at the calcaneus, a 0.14 SD (95%CI 0.05, 0.24; p = 0.004) lower total hip BMD(a), a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMD(a) and a 0.18 SD (95%CI 0.06, 0.29; p = 0.003) lower trabecular BMD at the distal radius for each copy of the minor allele. There was no association with serum levels of bone turnover markers and a single SNP which was associated with cortical density was also associated with cortical BMC and thickness.</p>
<p><b>Conclusions:</b> Our data replicate previous associations found between SNPs in the 6q25 locus and BMD(a) at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.</p>
Natural Orbitals and BEC in traps, a diffusion Monte Carlo analysis
We investigate the properties of hard core Bosons in harmonic traps over a
wide range of densities. Bose-Einstein condensation is formulated using the
one-body Density Matrix (OBDM) which is equally valid at low and high
densities. The OBDM is calculated using diffusion Monte Carlo methods and it is
diagonalized to obtain the "natural" single particle orbitals and their
occupation, including the condensate fraction. At low Boson density, , where and is the hard core diameter, the condensate is
localized at the center of the trap. As increases, the condensate moves
to the edges of the trap. At high density it is localized at the edges of the
trap. At the Gross-Pitaevskii theory of the condensate
describes the whole system within 1%. At corrections are
3% to the GP energy but 30% to the Bogoliubov prediction of the condensate
depletion. At , mean field theory fails. At , the Bosons behave more like a liquid He droplet than a trapped Boson
gas.Comment: 13 pages, 14 figures, submitted Phys. Rev.
Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families.
The CHRM2 gene is thought to be involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release and has previously been implicated in higher cognitive processing. In a sample of 667 individuals from 304 families, we genotyped three singlenucleotide polymorphisms (SNPs) in the CHRM2 gene on 7q31–35. From all individuals, standardized intelligence measures were available. Using a test of within-family association, which controls for the possible effects of population stratification, a highly significant association was found between the CHRM2 gene and intelligence. The strongest association was between rs324650 and performance IQ (PIQ), where the T allele was associated with an increase of 4.6 PIQ points. In parallel with a large familybased association, we observed an attenuated – although still significant – population-based association, illustrating that population stratification may decrease our chances of detecting allele–trait associations. Such a mechanism has been predicted earlier, and this article is one of the first to empirically show that family-based association methods are not only needed to guard against false positives, but are also invaluable in guarding against false negatives
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