90 research outputs found
Identifying Ligand Binding Conformations of the Ξ²2-Adrenergic Receptor by Using Its Agonists as Computational Probes
Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, Ξ²2-adrenergic receptor (Ξ²2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of Ξ²2AR. We show that the select ligands bind preferentially to different predicted conformers of Ξ²2AR, and identify a role of Ξ²2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. Β© 2012 Isin et al
A Pilot Randomized Controlled Trial of Omega-3 Fatty Acids for Autism Spectrum Disorder
We conducted a pilot randomized controlled trial to determine the feasibility and initial safety and efficacy of omega-3 fatty acids (1.3Β g/day) for the treatment of hyperactivity in 27 children ages 3β8 with autism spectrum disorder (ASD). After 12Β weeks, hyperactivity, as measured by the Aberrant Behavior Checklist, improved 2.7 (Β±4.8) points in the omega-3 group compared to 0.3 (Β±7.2) points in the placebo group (pΒ =Β 0.40; effect sizeΒ =Β 0.38). Correlations were found between decreases in five fatty acid levels and decreases in hyperactivity, and the treatment was well tolerated. Although this pilot study did not find a statistically significant benefit from omega-3 fatty acids, the small sample size does not rule out small to moderate beneficial effects
Biochemical mutagens affect the preservation of fungi and biodiversity estimations
Many fungi have significant industrial applications
or biosafety concerns and maintaining the original
characteristics is essential. The preserved fungi have to
represent the situation in nature for posterity, biodiversity
estimations, and taxonomic research. However, spontaneous
fungal mutations and secondary metabolites affecting
producing fungi are well known. There is increasing
interest in the preservation of microbes in Biological
Resource Centers (BRC) to ensure that the organisms
remain viable and stable genetically. It would be anathema
if they contacted mutagens routinely. However, for
the purpose of this discussion, there are three potential
sources of biochemical mutagens when obtaining individual
fungi from the environment: (a) mixtures of microorganisms
are plated routinely onto growth media
containing mutagenic antibiotics to control overgrowth
by contaminants, (b) the microbial mixtures may contain
microorganisms capable of producing mutagenic secondary
metabolites, and (c) target fungi for isolation may
produce βselfβ mutagens in pure culture. The probability
that these compounds could interact with fungi undermines
confidence in the preservation process and the
potential effects of these biochemical mutagens are considered
for the first time on strains held in BRC in this
review
Differences in characteristics of pediatric patients undergoing computed tomography between hospitals and primary care settings: implications for assessing cancer follow-up studies
Nck adapter proteins: functional versatility in T cells
Nck is a ubiquitously expressed adapter protein that is almost exclusively built of one SH2 domain and three SH3 domains. The two isoproteins of Nck are functionally redundant in many aspects and differ in only few amino acids that are mostly located in the linker regions between the interaction modules. Nck proteins connect receptor and non-receptor tyrosine kinases to the machinery of actin reorganisation. Thereby, Nck regulates activation-dependent processes during cell polarisation and migration and plays a crucial role in the signal transduction of a variety of receptors including for instance PDGF-, HGF-, VEGF- and Ephrin receptors. In most cases, the SH2 domain mediates binding to the phosphorylated receptor or associated phosphoproteins, while SH3 domain interactions lead to the formation of larger protein complexes. In T lymphocytes, Nck plays a pivotal role in the T cell receptor (TCR)-induced reorganisation of the actin cytoskeleton and the formation of the immunological synapse. However, in this context, two different mechanisms and adapter complexes are discussed. In the first scenario, dependent on an activation-induced conformational change in the CD3Ξ΅ subunits, a direct binding of Nck to components of the TCR/CD3 complex was shown. In the second scenario, Nck is recruited to the TCR complex via phosphorylated Slp76, another central constituent of the membrane proximal activation complex. Over the past years, a large number of putative Nck interactors have been identified in different cellular systems that point to diverse additional functions of the adapter protein, e.g. in the control of gene expression and proliferation
Standardized Assessment of Automatic Segmentation of White Matter Hyperintensities; Results of the WMH Segmentation Challenge
Quantification of cerebral white matter hyperintensities (WMH) of presumed vascular origin is of key importance in many neurological research studies. Currently, measurements are often still obtained from manual segmentations on brain MR images, which is a laborious procedure. Automatic WMH segmentation methods exist, but a standardized comparison of the performance of such methods is lacking. We organized a scientific challenge, in which developers could evaluate their method on a standardized multi-center/-scanner image dataset, giving an objective comparison: the WMH Segmentation Challenge (https://wmh.isi.uu.nl/). Sixty T1+FLAIR images from three MR scanners were released with manual WMH segmentations for training. A test set of 110 images from five MR scanners was used for evaluation. Segmentation methods had to be containerized and submitted to the challenge organizers. Five evaluation metrics were used to rank the methods: (1) Dice similarity coefficient, (2) modified Hausdorff distance (95th percentile), (3) absolute log-transformed volume difference, (4) sensitivity for detecting individual lesions, and (5) F1-score for individual lesions. Additionally, methods were ranked on their inter-scanner robustness. Twenty participants submitted their method for evaluation. This paper provides a detailed analysis of the results. In brief, there is a cluster of four methods that rank significantly better than the other methods, with one clear winner. The inter-scanner robustness ranking shows that not all methods generalize to unseen scanners. The challenge remains open for future submissions and provides a public platform for method evaluation
Renal function is a determinant of subjective well-being in active seniors but not in patients with subjective memory complaints
Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications
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