1,813 research outputs found
Sampling of conformational ensemble for virtual screening using molecular dynamics simulations and normal mode analysis
Aim: Molecular dynamics simulations and normal mode analysis are
well-established approaches to generate receptor conformational ensembles
(RCEs) for ligand docking and virtual screening. Here, we report new fast
molecular dynamics-based and normal mode analysis-based protocols combined with
conformational pocket classifications to efficiently generate RCEs. Materials
\& methods: We assessed our protocols on two well-characterized protein targets
showing local active site flexibility, dihydrofolate reductase and large
collective movements, CDK2. The performance of the RCEs was validated by
distinguishing known ligands of dihydrofolate reductase and CDK2 among a
dataset of diverse chemical decoys. Results \& discussion: Our results show
that different simulation protocols can be efficient for generation of RCEs
depending on different kind of protein flexibility
Closed form solution for a double quantum well using Gr\"obner basis
Analytical expressions for spectrum, eigenfunctions and dipole matrix
elements of a square double quantum well (DQW) are presented for a general case
when the potential in different regions of the DQW has different heights and
effective masses are different. This was achieved by Gr\"obner basis algorithm
which allows to disentangle the resulting coupled polynomials without
explicitly solving the transcendental eigenvalue equation.Comment: 4 figures, Mathematica full calculation noteboo
Off-Critical Logarithmic Minimal Models
We consider the integrable minimal models , corresponding
to the perturbation off-criticality, in the {\it logarithmic
limit\,} , where are coprime and the
limit is taken through coprime values of . We view these off-critical
minimal models as the continuum scaling limit of the
Forrester-Baxter Restricted Solid-On-Solid (RSOS) models on the square lattice.
Applying Corner Transfer Matrices to the Forrester-Baxter RSOS models in Regime
III, we argue that taking first the thermodynamic limit and second the {\it
logarithmic limit\,} yields off-critical logarithmic minimal models corresponding to the perturbation of the critical
logarithmic minimal models . Specifically, in accord with the
Kyoto correspondence principle, we show that the logarithmic limit of the
one-dimensional configurational sums yields finitized quasi-rational characters
of the Kac representations of the critical logarithmic minimal models . We also calculate the logarithmic limit of certain off-critical
observables related to One Point Functions and show that the
associated critical exponents
produce all conformal dimensions in the infinitely extended Kac table. The corresponding Kac labels
satisfy . The exponent is obtained from the logarithmic limit of the free energy giving the
conformal dimension for the perturbing field . As befits a non-unitary
theory, some observables diverge at criticality.Comment: 18 pages, 5 figures; version 3 contains amplifications and minor
typographical correction
Challenges in implementing routine cardiopulmonary exercise testing in cystic fibrosis clinical practice: a single centre review
This is the final version. Available on open access from Springer via the DOI in this recordCardiopulmonary exercise testing (CPET) is viewed by many as the gold standard for assessing
exercise capacity in CF, being recommended on an annual basis. However, not all patients
undergo CPET for varying reasons. This service evaluation retrospectively reviewed data from
179 (92 male) patients in a single CF centre in the UK to identify such reasons. 75/179 patients
underwent CPET, whilst 104/179 did not. Of these 104, 41 patients were ≤ 11 years of age. Of
the remaining 63 patients, 26 did not undergo CPET for clinical reasons including needing IV
antibiotics, musculoskeletal issues and obesity. 17 refused to undergo CPET because of reasons
such as an unwillingness to travel and dislike of CPET. 20 did not undergo CPET for
miscellaneous reasons including difficulty contacting patients. Individuals with FEV1
<40%predicted were 85.7% less likely to undertake a CPET than individuals with FEV1
≥70%predicted. Understanding these challenges will assist clinical teams with future
implementation of CPET into routine care, by identifying areas for improvement and
establishing strategies for enhancing future provision of the test
The Initial Mass Function in disc galaxies and in galaxy clusters: the chemo-photometric picture
The observed brightness of the Tully-Fisher relation suggests a low stellar
M/L ratio and a "bottom-light" IMF in disc galaxies, but the corresponding
efficiency of chemical enrichment tends to exceed the observational estimates.
Either suitable tuning of the IMF slope and mass limits or metal outflows from
disc galaxies must then be invoked.
A standard Solar Neighbourhood IMF cannot explain the high metallicity of the
hot intra-cluster medium: a different IMF must be at work in clusters of
galaxies. Alternatively, if the IMF is universal and chemical enrichment is
everywhere as efficient as observed in clusters, substantial loss of metals
must occur from the Solar Neighbourhood and from disc galaxies in general; a
"non-standard" scenario challenging our understanding of disc galaxy formation.Comment: 6 pages, 4 figures; in Proceedings of IMF@50: the Initial Mass
Function 50 years later; Corbelli, Palla and Zinnecker (eds.
Evolutionary Multi-Objective Design of SARS-CoV-2 Protease Inhibitor Candidates
Computational drug design based on artificial intelligence is an emerging
research area. At the time of writing this paper, the world suffers from an
outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus
replication is via protease inhibition. We propose an evolutionary
multi-objective algorithm (EMOA) to design potential protease inhibitors for
SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA
maximizes the binding of candidate ligands to the protein using the docking
tool QuickVina 2, while at the same time taking into account further objectives
like drug-likeliness or the fulfillment of filter constraints. The experimental
part analyzes the evolutionary process and discusses the inhibitor candidates.Comment: 15 pages, 7 figures, submitted to PPSN 202
Treatment of trigeminal ganglion neurons in vitro with NGF, GDNF or BDNF: effects on neuronal survival, neurochemical properties and TRPV1-mediated neuropeptide secretion
BACKGROUND: Nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) all play important roles in the development of the peripheral sensory nervous system. Additionally, these growth factors are proposed to modulate the properties of the sensory system in the adult under pathological conditions brought about by nerve injury or inflammation. We have examined the effects of NGF, GDNF and BDNF on adult rat trigeminal ganglion (TG) neurons in culture to gain a better understanding of how these growth factors alter the cytochemical and functional phenotype of these neurons, with special attention to properties associated with nociception. RESULTS: Compared with no growth factor controls, GDNF, at 1 and 100 ng/ml, significantly increased by nearly 100% the number of neurons in culture at 5 days post-plating. A significant, positive, linear trend of increasing neuron number as a function of BDNF concentration was observed, also peaking at nearly 100%. NGF treatment was without effect. Chronic treatment with NGF and GDNF significantly and concentration-dependently increased 100 nM capsaicin (CAP)-evoked calcitonin gene-related peptide (CGRP) release, reaching approximately 300% at the highest concentration tested (100 ng/ml). Also, NGF and GDNF each augmented anandamide (AEA)- and arachidonyl-2-chloroethylamide (ACEA)-evoked CGRP release, while BDNF was without effect. Utilizing immunohistochemistry to account for the proportions of TRPV1- or CGRP-positive neurons under each growth factor treatment condition and then standardizing evoked CGRP release to these proportions, we observed that NGF was much more effective in enhancing CAP- and 50 mM K(+)-evoked CGRP release than was GDNF. Furthermore, NGF and GDNF each altered the concentration-response function for CAP- and AEA-evoked CGRP release, increasing the E(max )without altering the EC(50 )for either compound. CONCLUSIONS: Taken together, our results illustrate that NGF, GDNF and BDNF differentially alter TG sensory neuron survival, neurochemical properties and TRPV1-mediated neuropeptide release in culture. In particular, our findings suggest that GDNF and NGF differentially modulate TRPV1-mediated neuropeptide secretion sensitivity, with NGF having a much greater effect on a per neuron basis than GDNF. These findings are discussed in relation to possible therapeutic roles for growth factors or their modulators in pathological pain states, especially as these relate to the trigeminal system
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