418 research outputs found
Performance of the CMS Cathode Strip Chambers with Cosmic Rays
The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device
in the CMS endcaps. Their performance has been evaluated using data taken
during a cosmic ray run in fall 2008. Measured noise levels are low, with the
number of noisy channels well below 1%. Coordinate resolution was measured for
all types of chambers, and fall in the range 47 microns to 243 microns. The
efficiencies for local charged track triggers, for hit and for segments
reconstruction were measured, and are above 99%. The timing resolution per
layer is approximately 5 ns
Remote loading of liposomes with a <sup>124</sup>I-radioiodinated compound and their in vivo evaluation by PET/CT in a murine tumor model
Performance and Operation of the CMS Electromagnetic Calorimeter
The operation and general performance of the CMS electromagnetic calorimeter
using cosmic-ray muons are described. These muons were recorded after the
closure of the CMS detector in late 2008. The calorimeter is made of lead
tungstate crystals and the overall status of the 75848 channels corresponding
to the barrel and endcap detectors is reported. The stability of crucial
operational parameters, such as high voltage, temperature and electronic noise,
is summarised and the performance of the light monitoring system is presented
Endothelial Function: The Impact of Objective and Subjective Socioeconomic Status on Flow-Mediated Dilation
Although objective and subjective indicators of socioeconomic status (SES) are linked to cardiovascular disease (CVD), little is known about their relationship to endothelial dysfunction, which often precedes CVD.
This study examined how objective and subjective SES relate to brachial artery flow-mediated dilation (FMD).
FMD was assessed in 72 healthy adults (mean age 36 years). The MacArthur Scale of Subjective Social Status assessed perceived social standing in the USA (SSS-USA) and local community (SSS-Community). Objective SES measures included income and the Hollingshead Two-Factor Index of Social Position (education, occupation).
Adjusted regressions revealed that SSS-Community positively correlated with FMD (p < 0.05) and explained 8% of the variance. No other SES measures were significant for FMD. The association between FMD and SSS-Community remained significant (p < 0.01) after adjustment for objective SES and other covariates.
Lower subjective social status in one’s community may be linked to CVD via impaired vasodilation
Protonation States of Remote Residues Affect Binding-Release Dynamics of the Ligand but not the Conformation of apo Ferric Binding Protein
We have studied the apo (Fe3+ free) form of periplasmic ferric binding
protein (FbpA) under different conditions and we have monitored the changes in
the binding and release dynamics of H2PO4- that acts as a synergistic anion in
the presence of Fe3+. Our simulations predict a dissociation constant of
2.20.2 mM which is in remarkable agreement with the experimentally
measured value of 2.30.3 mM under the same ionization strength and pH
conditions. We apply perturbations relevant for changes in environmental
conditions as (i) different values of ionic strength (IS), and (ii) protonation
of a group of residues to mimic a different pH environment. Local perturbations
are also studied by protonation or mutation of a site distal to the binding
region that is known to mechanically manipulate the hinge-like motions of FbpA.
We find that while the average conformation of the protein is intact in all
simulations, the H2PO4- dynamics may be substantially altered by the changing
conditions. In particular, the bound fraction which is 20 for the wild type
system is increased to 50 with a D52A mutation/protonation and further to
over 90 at the protonation conditions mimicking those at pH 5.5. The change
in the dynamics is traced to the altered electrostatic distribution on the
surface of the protein which in turn affects hydrogen bonding patterns at the
active site. The observations are quantified by rigorous free energy
calculations. Our results lend clues as to how the environment versus single
residue perturbations may be utilized for regulation of binding modes in hFbpA
systems in the absence of conformational changes.Comment: 26 pages, 4 figure
Pharmacotherapy of elderly patients in everyday anthroposophic medical practice: a prospective, multicenter observational study
Short-Term Striatal Gene Expression Responses to Brain-Derived Neurotrophic Factor Are Dependent on MEK and ERK Activation
BACKGROUND: Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity. CONCLUSIONS: These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression
Decreased Striatal RGS2 Expression Is Neuroprotective in Huntington's Disease (HD) and Exemplifies a Compensatory Aspect of HD-Induced Gene Regulation
The molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity.We used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only RGS2 and RASD2 modified mutant htt fragment toxicity in cultured rat primary striatal neurons. In both cases, disease modulation was in the opposite of the predicted direction: whereas decreased expression of RGS2 and RASD2 was associated with the HD condition, restoring expression enhanced degeneration of striatal cells. Conversely, silencing of RGS2 or RASD2 enhanced disease-related changes in gene expression and resulted in significant neuroprotection. These results indicate that RGS2 and RASD2 downregulation comprises a compensatory response that allows neurons to better tolerate huntingtin toxicity. Assessment of the possible mechanism of RGS2-mediated neuroprotection showed that RGS2 downregulation enhanced ERK activation. These results establish a novel link between the inhibition of RGS2 and neuroprotective modulation of ERK activity.Our findings both identify RGS2 downregulation as a novel compensatory response in HD neurons and suggest that RGS2 inhibition might be considered as an innovative target for neuroprotective drug development
Treatment and long-term outcome in primary nephrogenic diabetes insipidus
Background:
Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome.
Methods:
Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form.
Results:
Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0–60) years and at last follow-up 14.0 (0.1–70) years. In adults, height was normal with a mean (standard deviation) score of −0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients.
Conclusion:
This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems
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