600 research outputs found
Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking
Simulating drug binding and unbinding is a challenge, as the rugged energy
landscapes that separate bound and unbound states require extensive sampling
that consumes significant computational resources. Here, we describe the use of
interactive molecular dynamics in virtual reality (iMD-VR) as an accurate
low-cost strategy for flexible protein-ligand docking. We outline an
experimental protocol which enables expert iMD-VR users to guide ligands into
and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease,
and recreate their respective crystallographic protein-ligand binding poses
within 5 - 10 minutes. Following a brief training phase, our studies shown that
iMD-VR novices were able to generate unbinding and rebinding pathways on
similar timescales as iMD-VR experts, with the majority able to recover binding
poses within 2.15 Angstrom RMSD of the crystallographic binding pose. These
results indicate that iMD-VR affords sufficient control for users to carry out
the detailed atomic manipulations required to dock flexible ligands into
dynamic enzyme active sites and recover crystallographic poses, offering an
interesting new approach for simulating drug docking and generating binding
hypotheses.Comment: PLOS ON
Good practice in food-related neuroimaging
The use of neuroimaging tools, especially functional magnetic resonance imaging, in nutritional research has increased substantially over the past 2 decades. Neuroimaging is a research tool with great potential impact on the field of nutrition, but to achieve that potential, appropriate use of techniques and interpretation of neuroimaging results is necessary. In this article, we present guidelines for good methodological practice in functional magnetic resonance imaging studies and flag specific limitations in the hope of helping researchers to make the most of neuroimaging tools and avoid potential pitfalls. We highlight specific considerations for food-related studies, such as how to adjust statistically for common confounders, like, for example, hunger state, menstrual phase, and BMI, as well as how to optimally match different types of food stimuli. Finally, we summarize current research needs and future directions, such as the use of prospective designs and more realistic paradigms for studying eating behavior
Modality-Dependent Impact of Hallucinations on Low-Frequency Fluctuations in Schizophrenia
Prior resting-state functional magnetic resonance imaging (fMRI) analyses have identified patterns of functional connectivity associated with hallucinations in schizophrenia (Sz). In this study, we performed an analysis of the mean amplitude of low-frequency fluctuations (ALFF) to compare resting state spontaneous low-frequency fluctuations in patients with Sz who report experiencing hallucinations impacting different sensory modalities. By exploring dynamics across 2 low-frequency passbands (slow-4 and slow-5), we assessed the impact of hallucination modality and frequency range on spatial ALFF variation. Drawing from a sample of Sz and healthy controls studied as part of the Functional Imaging Biomedical Informatics Research Network (FBIRN), we replicated prior findings showing that patients with Sz have decreased ALFF in the posterior brain in comparison to controls. Remarkably, we found that patients that endorsed visual hallucinations did not show this pattern of reduced ALFF in the back of the brain. These patients also had elevated ALFF in the left hippocampus in comparison to patients that endorsed auditory (but not visual) hallucinations. Moreover, left hippocampal ALFF across all the cases was related to reported hallucination severity in both the auditory and visual domains, and not overall positive symptoms. This supports the hypothesis that dynamic changes in the ALFF in the hippocampus underlie severity of hallucinations that impact different sensory modalities
Measurement of the Lifetime Difference Between B_s Mass Eigenstates
We present measurements of the lifetimes and polarization amplitudes for B_s
--> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and
light (L) mass eigenstates in the B_s system are separately measured for the
first time by determining the relative contributions of amplitudes with
definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we
obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07
+{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s
and average Gamma_s, of the decay rates of the two eigenstates, the results are
DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47
+{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters
on 16 March 2005; revisions are for length and typesetting only, no changes
in results or conclusion
HIVToolbox, an Integrated Web Application for Investigating HIV
Many bioinformatic databases and applications focus on a limited domain of knowledge federating links to information in other databases. This segregated data structure likely limits our ability to investigate and understand complex biological systems. To facilitate research, therefore, we have built HIVToolbox, which integrates much of the knowledge about HIV proteins and allows virologists and structural biologists to access sequence, structure, and functional relationships in an intuitive web application. HIV-1 integrase protein was used as a case study to show the utility of this application. We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories. Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site. Weblink: [http://hivtoolbox.bio-toolkit.com
Tracking Cats: Problems with Placing Feline Carnivores on δ18O, δD Isoscapes
Several felids are endangered and threatened by the illegal wildlife trade. Establishing geographic origin of tissues of endangered species is thus crucial for wildlife crime investigations and effective conservation strategies. As shown in other species, stable isotope analysis of hydrogen and oxygen in hair (δD(h), δ(18)O(h)) can be used as a tool for provenance determination. However, reliably predicting the spatial distribution of δD(h) and δ(18)O(h) requires confirmation from animal tissues of known origin and a detailed understanding of the isotopic routing of dietary nutrients into felid hair.We used coupled δD(h) and δ(18)O(h) measurements from the North American bobcat (Lynx rufus) and puma (Puma concolor) with precipitation-based assignment isoscapes to test the feasibility of isotopic geo-location of felidae. Hairs of felid and rabbit museum specimens from 75 sites across the United States and Canada were analyzed. Bobcat and puma lacked a significant correlation between H/O isotopes in hair and local waters, and also exhibited an isotopic decoupling of δ(18)O(h) and δD(h). Conversely, strong δD and δ(18)O coupling was found for key prey, eastern cottontail rabbit (Sylvilagus floridanus; hair) and white-tailed deer (Odocoileus virginianus; collagen, bone phosphate).Puma and bobcat hairs do not adhere to expected pattern of H and O isotopic variation predicted by precipitation isoscapes for North America. Thus, using bulk hair, felids cannot be placed on δ(18)O and δD isoscapes for use in forensic investigations. The effective application of isotopes to trace the provenance of feline carnivores is likely compromised by major controls of their diet, physiology and metabolism on hair δ(18)O and δD related to body water budgets. Controlled feeding experiments, combined with single amino acid isotope analysis of diets and hair, are needed to reveal mechanisms and physiological traits explaining why felid hair does not follow isotopic patterns demonstrated in many other taxa
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