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109 results on '"Mládek, Arnošt"'

3. Lumbar Infusion Test

Author

Skalický, Petr, Mládek, Arnošt, Bubeníková, Adéla, Vlasák, Aleš, Whitley, Helen, Bradáč, Ondřej, and Bradac, Ondrej, editor

Published
2023
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5. Molecular Biology of CCM

Author

Mládek, Arnošt, Skalický, Petr, Beneš, Vladimír, Bradáč, Ondřej, Bradáč, Ondřej, editor, and Beneš, Vladimír, editor

Published
2020
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12. Deriving predictive pathophysiological markers from ICP analysis

Author

Mládek, Arnošt, Bradáč, Ondřej, Haninec, Pavel, and Mraček, Jan

Subjects
normotenzní hydrocefalus, intracranial pressure, NPH, normal pressure hydrocephalus, strojové učení, lumbar infusion test, nitrolební tlak, machine learning, LIT, lumbální infuzní test, ICP
Abstract

Deriving predictive pathophysiological markers from ICP analysis RNDr. Arnošt Mládek, Ph.D. December 13, 2021 Abstract Intracranial pressure (ICP) is an irreplaceable neurointensive care parameter and is an area under intensive research. The great diagnostic importance of ICP is underlied by two factors: (1) the central nervous system (CNS) is placed in a rigid cranial vault and even small local expansive processes (e.g. tumors, abscesses, bleeding) may lead to intracranial hypertension; (2) a specific property of the CNS is a rather uniform response to various pathological events since many etiologically heterogeneous diffuse injuries of neural tissue lead to oedema elevating ICP. The complexity of ICP monitoring stems from the neurosurgical insertion of the pressure sensor into the intracranial space and the associated risks of bleeding, neuroinfection and brain tissue damage. Intracranial pressure is more than just a number on a bedside monitor, even though in clinical practice this simplification is rather common. Similarly to electrocardiogram (ECG) signals whose information content goes well beyond heart rate calculation, understanding of ICP dynamics can provide us with insight into the current clinical status as well as prediction of further evolution. The mainstay of the dissertation thesis are...

Published
2022

30. Computational Study of the TiO2-Catalyzed Synthesis of Acyclonucleosides from Formamide: Implications for the Origin of Life

Author

Mládek, Arnošt, Burda, Jaroslav, and Futera, Zdeněk

Subjects
Quantum chemistry, Vznik života, TiO2, Nucleic acids, DFT, Origin of Life, Kvantová chemie, Nukleové kyseliny, Acyklonukleosidy, Acyclonucleosides
Abstract

The TiO2-catalyzed synthesis of nucleosides in non-aqueous formamide environ- ment via so-called acyclonucleoside intermediates represents an alternative way for the emergence of nucleic acids monomeric units, which could address the the fundamental problem associated with the formation of a --glycosidic bond between a nucleobase and a sugar moiety. In this computational contribution we present a plausible reaction route for the prebiotic TiO2-catalyzed synthesis of purine C2- and C3-acyclonucleosides in formamide, which does not require photocatalytic or radical chain mechanisms. The maximum computed activation energy along the proposed reaction channel is ≥ 32 kcal·mol≠1 , which is clearly feasible under the experimental conditions of the Saladino synthesis. We show that the rate determining step of the entire reaction path is the deprotonation of the formaldehyde hydrate methylene carbon occurring likely on defective binding sites of an anatase surface. Our calculations thus support the view of Saladino et al. about the catalytic role of the TiO2 surface in the one-pot synthesis of purine acyclonucleosides in heat formamide solution.

Published
2015

49. Formamide-Based Prebiotic Synthesis of Nucleobases: A Kinetically Accessible Reaction Route.

Author

Šponer, Judit E., Mládek, Arnošt, Šponer, Jiří, and Fuentes-Cabrera, Miguel

Subjects
*PREBIOTICS, *CHEMICAL reactions, *FORMAMIDE, *IMIDAZOLES, *AMINOIMIDAZOLE ribonucleotide synthetase, *CARBONITRILES, *RING formation (Chemistry)
Abstract

Synthesis of nucleobases in nonaqueous environments is an alternative way for the emergence of terrestrial life, which could solve the fundamental problem connected to the hydrolytic instability of nucleic acid components in an aqueous environment. In this contribution, we present a plausible reaction route for the prebiotic synthesis of nucleobases in formamide, which does not require participation of the formamide trimer and aminoimidazole-carbonitrile intermediates. The computed activation energy of the proposed pathway is noticeably higher than that of the HCN-based synthetic route, but it is still feasible under the experimental conditions of the Saladino synthesis. We show that, albeit both the pyrimidine and purine ring formation utilizes the undissociated form of formamide, the dehydration product of formamide, HCN, may also play a key role in the mechanism. The rate-determining step of the entire reaction path is the cyclization of the diaza-pentanimine precursor. The subsequent formation of the imidazole ring proceeds with a moderate activation energy. Our calculations thus demonstrate that the experimentally suggested reaction path without the involvement of aminoimidazole-carbonitrile intermediates is also a viable alternative for the nonaqueous synthesis of nucleobases. [ABSTRACT FROM AUTHOR]

Published
2012
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50. Energies and 2′-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations

Author

Mládek, Arnošt, Banáš, Pavel, Jurečka, Petr, Otyepka, Michal, Zgarbová, Marie, and Šponer, Jiří

Abstract

Sugar–phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2′-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2′-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2′-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2′-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2′-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2′-hydroxyl group orientations can be attributed to clashes between occupied orbitals.

Published
2014
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