640 research outputs found
Dopamine Agonists and Pathologic Behaviors
The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson's disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics
A Distribution of Large Particles in the Coma of Comet 103P/Hartley 2
The coma of comet 103P/Hartley 2 has a significant population of large
particles observed as point sources in images taken by the Deep Impact
spacecraft. We measure their spatial and flux distributions, and attempt to
constrain their composition. The flux distribution of these particles implies a
very steep size distribution with power-law slopes ranging from -6.6 to -4.7.
The radii of the particles extend up to 20 cm, and perhaps up to 2 m, but their
exact sizes depend on their unknown light scattering properties. We consider
two cases: bright icy material, and dark dusty material. The icy case better
describes the particles if water sublimation from the particles causes a
significant rocket force, which we propose as the best method to account for
the observed spatial distribution. Solar radiation is a plausible alternative,
but only if the particles are very low density aggregates. If we treat the
particles as mini-nuclei, we estimate they account for <16-80% of the comet's
total water production rate (within 20.6 km). Dark dusty particles, however,
are not favored based on mass arguments. The water production rate from bright
icy particles is constrained with an upper limit of 0.1 to 0.5% of the total
water production rate of the comet. If indeed icy with a high albedo, these
particles do not appear to account for the comet's large water production rate.
production rate.
Erratum: We have corrected the radii and masses of the large particles of
comet 103P/Hartley 2 and present revised conclusions in the attached erratum.Comment: Original article: 46 pages, 17 figures, 5 tables, published in
Icarus. Erratum: 5 pages, 1 table, accepted for publication in Icaru
Performance of the NINDS-CSN 5-Minute Protocol in a National Population-Based Sample
Background In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors. Methods Cross-sectional analysis of 7,199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score. Results Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values<0.001). Higher cerebrovascular risk on the Framingham Stroke Risk Profile (FSRP) was associated with lower total 5-Minute Protocol scores (p<0.001). The 5-Minute Protocol also differentiated between participants with and without confirmed stroke and with and without stroke symptom histories (p<0.001). Conclusions The NINDS-CSN 5-Minute Protocol is a brief, easily administered screening measure that is sensitive to cerebrovascular risk and offers a valid method of screening for cognitive impairment in populations at risk for VCI
Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis
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Molecular insights of p47phox phosphorylation dynamics in the regulation of NADPH oxidase activation and superoxide production
Phagocyte superoxide production by a multicomponent NADPH oxidase is important in host defense against microbial invasion. However inappropriate NADPH oxidase activation causes inflammation. Endothelial cells express NADPH oxidase and endothelial oxidative stress due to prolonged NADPH oxidase activation predisposes many diseases. Discovering the mechanism of NADPH oxidase activation is essential for developing novel treatment of these diseases. The p47phox is a key regulatory subunit of NADPH oxidase; however, due to the lack of full protein structural information, the mechanistic insight of
p47phox phosphorylation in NADPH oxidase activation remains incomplete. Based on crystal structures of three functional domains, we generated a computational structural model of the full p47phox protein. Using a combination of in silico phosphorylation, molecular dynamics simulation and protein/protein docking, we discovered that the C-terminal tail of p47phox is critical for stabilizing its autoinhibited structure. Ser-379 phosphorylation disrupts H-bonds that link the C-terminal tail to the autoinhibitory region (AIR) and the tandem Src homology 3 (SH3) domains, allowing the AIR to undergo phosphorylation to expose the SH3 pocket for p22phox binding. These findings were confirmed by site-directed mutagenesis and gene transfection of p47phox_/_ coronary microvascular cells. Compared with wild-type p47phoxcDNAtransfected cells, the single mutation of S379A completely blocked p47phox membrane translocation, binding to p22phox and endothelial O2 . production in response to acute stimulation of PKC. p47phox C-terminal tail plays a key role in stabilizing intramolecular interactions at rest. Ser-379 phosphorylation is a molecular switch which initiates p47phox conformational changes and NADPH oxidase-dependent superoxide production by cells
HIV and adolescents: focus on young key populations
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138345/1/jia20076.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138345/2/jia20076-sup-0001.pd
The NANOGrav 15-year Data Set: Search for Anisotropy in the Gravitational-Wave Background
The North American Nanohertz Observatory for Gravitational Waves (NANOGrav)
has reported evidence for the presence of an isotropic nanohertz gravitational
wave background (GWB) in its 15 yr dataset. However, if the GWB is produced by
a population of inspiraling supermassive black hole binary (SMBHB) systems,
then the background is predicted to be anisotropic, depending on the
distribution of these systems in the local Universe and the statistical
properties of the SMBHB population. In this work, we search for anisotropy in
the GWB using multiple methods and bases to describe the distribution of the
GWB power on the sky. We do not find significant evidence of anisotropy, and
place a Bayesian upper limit on the level of broadband anisotropy such
that . We also derive conservative estimates on the
anisotropy expected from a random distribution of SMBHB systems using
astrophysical simulations conditioned on the isotropic GWB inferred in the
15-yr dataset, and show that this dataset has sufficient sensitivity to probe a
large fraction of the predicted level of anisotropy. We end by highlighting the
opportunities and challenges in searching for anisotropy in pulsar timing array
data.Comment: 19 pages, 11 figures; submitted to Astrophysical Journal Letters as
part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave
Background. For questions or comments, please email [email protected]
The NANOGrav 15-Year Data Set: Detector Characterization and Noise Budget
Pulsar timing arrays (PTAs) are galactic-scale gravitational wave detectors.
Each individual arm, composed of a millisecond pulsar, a radio telescope, and a
kiloparsecs-long path, differs in its properties but, in aggregate, can be used
to extract low-frequency gravitational wave (GW) signals. We present a noise
and sensitivity analysis to accompany the NANOGrav 15-year data release and
associated papers, along with an in-depth introduction to PTA noise models. As
a first step in our analysis, we characterize each individual pulsar data set
with three types of white noise parameters and two red noise parameters. These
parameters, along with the timing model and, particularly, a piecewise-constant
model for the time-variable dispersion measure, determine the sensitivity curve
over the low-frequency GW band we are searching. We tabulate information for
all of the pulsars in this data release and present some representative
sensitivity curves. We then combine the individual pulsar sensitivities using a
signal-to-noise-ratio statistic to calculate the global sensitivity of the PTA
to a stochastic background of GWs, obtaining a minimum noise characteristic
strain of at 5 nHz. A power law-integrated analysis shows
rough agreement with the amplitudes recovered in NANOGrav's 15-year GW
background analysis. While our phenomenological noise model does not model all
known physical effects explicitly, it provides an accurate characterization of
the noise in the data while preserving sensitivity to multiple classes of GW
signals.Comment: 67 pages, 73 figures, 3 tables; published in Astrophysical Journal
Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational
Wave Background. For questions or comments, please email
[email protected]
The NANOGrav 12.5 yr Data Set: Search for Gravitational Wave Memory
We present the results of a Bayesian search for gravitational wave (GW) memory in the NANOGrav 12.5 yr data set. We find no convincing evidence for any gravitational wave memory signals in this data set. We find a Bayes factor of 2.8 in favor of a model that includes a memory signal and common spatially uncorrelated red noise (CURN) compared to a model including only a CURN. However, further investigation shows that a disproportionate amount of support for the memory signal comes from three dubious pulsars. Using a more flexible red-noise model in these pulsars reduces the Bayes factor to 1.3. Having found no compelling evidence, we go on to place upper limits on the strain amplitude of GW memory events as a function of sky location and event epoch. These upper limits are computed using a signal model that assumes the existence of a common, spatially uncorrelated red noise in addition to a GW memory signal. The median strain upper limit as a function of sky position is approximately 3.3 Ă 10â14. We also find that there are some differences in the upper limits as a function of sky position centered around PSR J0613â0200. This suggests that this pulsar has some excess noise that can be confounded with GW memory. Finally, the upper limits as a function of burst epoch continue to improve at later epochs. This improvement is attributable to the continued growth of the pulsar timing array
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