29 research outputs found
Data from: An Investigation of Machine Learning Methods in Delta-radiomics Feature Analysis
No full textThis dataset includes 12 patients with advanced brain glioma treated with combination of stereotactic radiosurgery (SRS) and bevacizumab. DICOM files of T1 MRI, T2 FLAIR MRI collected at pre-radiotherapy (RT), one-week post-RT, and two-month post-RT are provided. The post-RT images have been rigidly registered to the pre-RT MRI by experienced medical physicists. The RT structure sets from pre-RT MRI contoured by experienced physicians are provided. <br
Ligand-Dependent Dynamics of the Active-Site Lid in Bacterial Dimethylarginine Dimethylaminohydrolase
No full textThe dimethylarginine dimethylaminohydrolase
(DDAH) enzyme family
has been the subject of substantial investigation as a potential therapeutic
target for the regulation of vascular tension. DDAH enzymes catalyze
the conversion of asymmetric <i>N</i><sup>η</sup><i>,N</i><sup>η</sup>-dimethylarginine (ADMA) to l-citrulline. Here the influence of substrate and product binding
on the dynamic flexibility of DDAH from <i>Pseudomonas aeruginosa</i> (PaDDAH) has been assessed. A combination of heteronuclear NMR spectroscopy,
static and time-resolved fluorescence measurements, and atomistic
molecular dynamics simulations was employed. A monodisperse monomeric
variant of the wild-type enzyme binds the reaction product l-citrulline with a low millimolar dissociation constant. A second
variant, engineered to be catalytically inactive by substitution of
the nucleophilic Cys249 residue with serine, can still convert the
substrate ADMA to products very slowly. This PaDDAH variant also binds l-citrulline, but with a low micromolar dissociation constant.
NMR and molecular dynamics simulations indicate that the active site
“lid”, formed by residues Gly17-Asp27, exhibits a high
degree of internal motion on the picosecond-to-nanosecond time scale.
This suggests that the lid is open in the apo state and allows substrate
access to the active site that is otherwise buried. l-Citrulline
binding to both protein variants is accompanied by an ordering of
the lid. Modification of PaDDAH with a coumarin fluorescence reporter
allowed measurement of the kinetic mechanism of the PaDDAH reaction.
A combination of NMR and kinetic data shows that the catalytic turnover
of the enzyme is not limited by release of the l-citrulline
product. The potential to develop the coumarin–PaDDAH adduct
as an l-citrulline sensor is discussed
Loop Interactions and Dynamics Tune the Enzymatic Activity of the Human Histone Deacetylase 8
No full textThe human histone deacetylase 8 (HDAC8)
is a key hydrolase in gene
regulation and has been identified as a drug target for the treatment
of several cancers. Previously the HDAC8 enzyme has been extensively
studied using biochemical techniques, X-ray crystallography, and computational
methods. Those investigations have yielded detailed information about
the active site and have demonstrated that the substrate entrance
surface is highly dynamic. Yet it has remained unclear how the dynamics
of the entrance surface tune and influence the catalytic activity
of HDAC8. Using long time scale all atom molecular dynamics simulations
we have found a mechanism whereby the interactions and dynamics of
two loops tune the configuration of functionally important residues
of HDAC8 and could therefore influence the activity of the enzyme.
We subsequently investigated this hypothesis using a well-established
fluorescence activity assay and a noninvasive real-time progression
assay, where deacetylation of a p53 based peptide was observed by
nuclear magnetic resonance spectroscopy. Our work delivers detailed
insight into the dynamic loop network of HDAC8 and provides an explanation
for a number of experimental observations
Loop Interactions and Dynamics Tune the Enzymatic Activity of the Human Histone Deacetylase 8
No full textThe human histone deacetylase 8 (HDAC8)
is a key hydrolase in gene
regulation and has been identified as a drug target for the treatment
of several cancers. Previously the HDAC8 enzyme has been extensively
studied using biochemical techniques, X-ray crystallography, and computational
methods. Those investigations have yielded detailed information about
the active site and have demonstrated that the substrate entrance
surface is highly dynamic. Yet it has remained unclear how the dynamics
of the entrance surface tune and influence the catalytic activity
of HDAC8. Using long time scale all atom molecular dynamics simulations
we have found a mechanism whereby the interactions and dynamics of
two loops tune the configuration of functionally important residues
of HDAC8 and could therefore influence the activity of the enzyme.
We subsequently investigated this hypothesis using a well-established
fluorescence activity assay and a noninvasive real-time progression
assay, where deacetylation of a p53 based peptide was observed by
nuclear magnetic resonance spectroscopy. Our work delivers detailed
insight into the dynamic loop network of HDAC8 and provides an explanation
for a number of experimental observations
Antiviral effect of doxycycline, tetracycline and remdesivir.
No full textEffect of doxycycline and tetracycline compared to remdesivir on SARS-COV-2 infection of ACE-2-overexpressing lung-derived cell lines in vitro. (TIF)</p
Baseline characteristics and drug treatment during the study.
No full textBaseline characteristics and drug treatment during the study.</p
Enrollment into the trial from 1st November 2020 until 10th May 2021.
No full text(A) Enrollment over time. Cumulative number of enrolled patients shown on the y-axis. (B) Enrollment by week. Black columns represent one full week of enrollment.</p
