PURPOSE: Chronic obstructive pulmonary disease (COPD) is a prevalent and preventable condition that typically worsens over time. Acute exacerbations of COPD significantly impact disease progression, underscoring the importance of prevention efforts. This observational study aimed to achieve two main objectives: (1) identify patients at risk of exacerbations using an ensemble of clustering algorithms, and (2) classify patients into distinct clusters based on disease severity. METHODS: Data from portable medical devices were analyzed post-hoc using hyperparameter optimization with Self-Organizing Maps (SOM), Density-Based Spatial Clustering of Applications with Noise (DBSCAN), Isolation Forest, and Support Vector Machine (SVM) algorithms, to detect flare-ups. Principal Component Analysis (PCA) followed by KMeans clustering was applied to categorize patients by severity. RESULTS: 25 patients were included within the study population, data from 17 patients had the required reliability. Five patients were identified in the highest deterioration group, with one clinically confirmed exacerbation accurately detected by our ensemble algorithm. Then, PCA and KMeans clustering grouped patients into three clusters based on severity: Cluster 0 started with the least severe characteristics but experienced decline, Cluster 1 consistently showed the most severe characteristics, and Cluster 2 showed slight improvement. CONCLUSION: Our approach effectively identified patients at risk of exacerbations and classified them by disease severity. Although promising, the approach would need to be verified on a larger sample with a larger number of recorded clinically verified exacerbations.
- Publication type
- Journal Article MeSH
Tunnels and channels facilitate the transport of small molecules, ions and water solvent in a large variety of proteins. Characteristics of individual transport pathways, including their geometry, physico-chemical properties and dynamics are instrumental for understanding of structure-function relationships of these proteins, for the design of new inhibitors and construction of improved biocatalysts. CAVER is a software tool widely used for the identification and characterization of transport pathways in static macromolecular structures. Herein we present a new version of CAVER enabling automatic analysis of tunnels and channels in large ensembles of protein conformations. CAVER 3.0 implements new algorithms for the calculation and clustering of pathways. A trajectory from a molecular dynamics simulation serves as the typical input, while detailed characteristics and summary statistics of the time evolution of individual pathways are provided in the outputs. To illustrate the capabilities of CAVER 3.0, the tool was applied for the analysis of molecular dynamics simulation of the microbial enzyme haloalkane dehalogenase DhaA. CAVER 3.0 safely identified and reliably estimated the importance of all previously published DhaA tunnels, including the tunnels closed in DhaA crystal structures. Obtained results clearly demonstrate that analysis of molecular dynamics simulation is essential for the estimation of pathway characteristics and elucidation of the structural basis of the tunnel gating. CAVER 3.0 paves the way for the study of important biochemical phenomena in the area of molecular transport, molecular recognition and enzymatic catalysis. The software is freely available as a multiplatform command-line application at http://www.caver.cz.
- MeSH
- Algorithms * MeSH
- Hydrolases chemistry metabolism MeSH
- Protein Conformation * MeSH
- Crystallography MeSH
- Proteins chemistry metabolism MeSH
- Cluster Analysis MeSH
- Molecular Dynamics Simulation MeSH
- Software * MeSH
- Computational Biology methods MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
... CONTENTS -- Xi -- Components in the Genetic Regulatory Systems of Prokaryotes and Eukaryotes, 412 -- An Ensemble ... ... Differentiation, 454 The Conceptual Framework: Cell Differentiation in Boolean Networks, 462 -- Ensembles ...
1st ed. 709 s. : il.
- Keywords
- Biologie, Evoluce, Fylogeneze,
- MeSH
- Biological Evolution MeSH
- Biology MeSH
- Phylogeny MeSH
- Evolution, Molecular MeSH
- Origin of Life MeSH
- Conspectus
- Obecná genetika. Obecná cytogenetika. Evoluce
- NML Fields
- molekulární biologie, molekulární medicína
This work extends the multi-scale computational scheme for the quantum mechanics (QM) calculations of Nuclear Magnetic Resonance (NMR) chemical shifts (CSs) in proteins that lack a well-defined 3D structure. The scheme couples the sampling of an intrinsically disordered protein (IDP) by classical molecular dynamics (MD) with protein fragmentation using the adjustable density matrix assembler (ADMA) and density functional theory (DFT) calculations. In contrast to our early investigation on IDPs (Pavlíková Přecechtělová et al., J. Chem. Theory Comput., 2019, 15, 5642-5658) and the state-of-the art NMR calculations for structured proteins, a partial re-optimization was implemented on the raw MD geometries in vibrational normal mode coordinates to enhance the accuracy of the MD/ADMA/DFT computational scheme. In addition, machine-learning based cluster analysis was performed on the scheme to explore its potential in producing protein structure ensembles (CLUSTER ensembles) that yield accurate CSs at a reduced computational cost. The performance of the cluster-based calculations is validated against results obtained with conventional structural ensembles consisting of MD snapshots extracted from the MD trajectory at regular time intervals (REGULAR ensembles). CS calculations performed with the refined MD/ADMA/DFT framework employed the 6-311++G(d,p) basis set that outperformed IGLO-III calculations with the same density functional approximation (B3LYP) and both explicit and implicit solvation. The partial geometry optimization did not universally improve the agreement of computed CSs with the experiment but substantially decreased errors associated with the ensemble averaging. A CLUSTER ensemble with 50 structures yielded ensemble averages close to those obtained with a REGULAR ensemble consisting of 500 MD frames. The cluster based calculations thus required only a fraction of the computational time.
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world with a highly variable clinical course. Its striking genetic heterogeneity is not yet fully understood. Although the CLL genetic landscape has been well-described, patient stratification based on mutation profiles remains elusive mainly due to the heterogeneity of data. Here we attempted to decrease the heterogeneity of somatic mutation data by mapping mutated genes in the respective biological processes. From the sequencing data gathered by the International Cancer Genome Consortium for 506 CLL patients, we generated pathway mutation scores, applied ensemble clustering on them, and extracted abnormal molecular pathways with a machine learning approach. We identified four clusters differing in pathway mutational profiles and time to first treatment. Interestingly, common CLL drivers such as ATM or TP53 were associated with particular subtypes, while others like NOTCH1 or SF3B1 were not. This study provides an important step in understanding mutational patterns in CLL.
- Publication type
- Journal Article MeSH
A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 μM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 μM was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 μM. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.
Single nucleotide polymorphisms located in 5' untranslated regions (5'UTRs) can regulate gene expression and have clinical impact. Recognition of functionally significant sequences within 5'UTRs is crucial in next-generation sequencing applications. Furthermore, information about the behavior of 5'UTRs during gene evolution is scarce. Using the example of the ATP-binding cassette transporter A1 (
- MeSH
- 5' Untranslated Regions * genetics MeSH
- ATP Binding Cassette Transporter 1 chemistry genetics MeSH
- Molecular Sequence Annotation MeSH
- Phylogeny MeSH
- Introns MeSH
- Nucleic Acid Conformation MeSH
- Conserved Sequence genetics MeSH
- Humans MeSH
- RNA, Messenger genetics metabolism MeSH
- Nucleotide Motifs genetics MeSH
- Open Reading Frames genetics MeSH
- Mammals genetics MeSH
- Amino Acid Sequence MeSH
- Base Sequence MeSH
- RNA Splicing genetics MeSH
- Base Composition genetics MeSH
- Enhancer Elements, Genetic genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
... Limbs Is Conveyed to the Spinal Cord 338 -- The Primary Sensory Neurons of the Trunk and Limbs Are Clustered ... ... Information 635 -- Taste Stimuli Are Detected by Taste Cells in the Mouth 636 -- Taste Cells Are Clustered ... ... Brain Stem Deviates From the Organization of the Spinal Cord in Two Important Ways 885 -- Neuronal Ensembles ... ... Endocrine Functions With Behavior 974 -- The Hypothalamus Contains Specialized Groups of Neurons Clustered ...
4th ed. xxxiii, 1414 s. : il., tab., grafy ; 30 cm
- MeSH
- Behavior MeSH
- Molecular Biology MeSH
- Nervous System Diseases MeSH
- Nervous System MeSH
- Neurochemistry MeSH
- Neurophysiology MeSH
- Neurons MeSH
- Neurosciences MeSH
- Publication type
- Monograph MeSH
- Conspectus
- Fyziologie člověka a srovnávací fyziologie
- NML Fields
- neurovědy
- biologie
