355 results on '"Daniel Jun"'
Search Results
2. Effects of Green Coverage Ratio and Spaciousness on Self-Reported Recovery and Intellectual Concentration – a Pilot Study
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Kuniaki Mihara, Daniel Jun Chung Hii, Hiroyuki Takasuna, Katsuhiko Sakata, Mika Tatsuta, Kimi Ueda, and Hiroshi Shimoda
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- 2023
3. Highly Selective Butyrylcholinesterase Inhibitors Related to Amaryllidaceae Alkaloids - Design, Synthesis, and Biological Evaluation
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Filip Pidany, Jana Kroustkova, Abdullah Al Mamun, Daniela Suchankova, Xavier Brazzolotto, Florian Nachon, Fabien Chantegreil, Rafael Dolezal, Lenka Pulkrabkova, Lubica Muckova, Martina Hrabinova, Vladimir Finger, Martin Kufa, Ondrej Soukup, Daniel Jun, Jaroslav Jenco, Jiri Kunes, Lucie Novakova, Jan Korabecny, and Lucie Cahlikova
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Pharmacology ,Organic Chemistry ,Drug Discovery ,General Medicine - Published
- 2023
4. Development of a Graphene-Oxide-Deposited Carbon Electrode for the Rapid and Low-Level Detection of Fentanyl and Derivatives
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Daniel Jun, Glenn Sammis, Pouya Rezazadeh-Azar, Erwann Ginoux, and Dan Bizzotto
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Sucrose ,Illicit Drugs ,COVID-19 ,Oxides ,Carbon ,Analytical Chemistry ,Analgesics, Opioid ,Fentanyl ,Heroin ,Cocaine ,Caffeine ,Humans ,Graphite ,Electrodes ,Pandemics - Abstract
The opioid overdose crisis in North America worsened during the COVID-19 pandemic, with multiple jurisdictions reporting more deaths per day due to the fentanyl-contaminated drug supply than COVID-19. The rapid quantitative detection of fentanyl in the illicit opioid drug supply or in bodily fluids at biologically relevant concentrations (i.e.,80 nM) remains a significant challenge. Electroanalytical techniques are inexpensive and can be used to rapidly detect fentanyl, but detection limits need to be improved. Herein, we detail the development of an electrochemical-based fentanyl analytical detection strategy that used a glassy carbon electrode modified with electrochemically reduced graphene oxide (ERGO) via electrophoretic deposition. The resulting surface was further electrochemically reduced in the presence of fentanyl to enhance the sensitivity. Multiple ERGO thicknesses were prepared in order to prove the versatility and ability to fine-tune the layer to the desired response. Fentanyl was detected at10 ppb (30 nM) with a limit of detection of 2 ppb and a calibration curve that covered 4 orders of concentration (from 1 ppb to 10 ppm). This method was sensitive to fentanyl analogues such as carfentanil. Interference from the presence of 100-fold excess of other opioids (heroin, cocaine) or substances typically found in illicit drug samples (e.g. caffeine and sucrose) was not significant.
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- 2022
5. Design and synthesis of novel tacrine–indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease
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Vendula Hepnarova, Slavka Hamulakova, Jan Korabecny, Ondrej Soukup, Roman Mezencev, Ladislav Janovec, Martina Hrabinova, Veronika Ihnatova, Yury O. Chernoff, Zachery J. Deckner, Nikola Novakova, Zuzana Kudličková, Kamil Kuca, Petr Bzonek, Jana Janockova, and Daniel Jun
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Indoles ,Stereochemistry ,Drug Evaluation, Preclinical ,Molecular Dynamics Simulation ,Ligands ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Molecular Targeted Therapy ,7-methoxytacrine ,Biological evaluation ,Pharmacology ,Indole test ,Amyloid beta-Peptides ,Chemistry ,DNA ,In vitro ,Molecular Docking Simulation ,Neuroprotective Agents ,Blood-Brain Barrier ,Tacrine ,Acetylcholinesterase ,Molecular Medicine ,Cholinesterase Inhibitors ,Dimerization ,Protein Binding ,Research Article ,medicine.drug - Abstract
The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine–indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood–brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood–brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.
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- 2021
6. OPCW BIOMEDICAL PROFICIENCY TEST IN THE LABORATORY OF ANALYTICAL CHEMISTRY AT THE DEPARTMENT OF TOXICOLOGY AND MILITARY PHARMACY
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Rafael Doležal, David Herman, Petr Bzonek, Lukáš Prchal, Marie Vajrychová, Nela Váňová, Alžběta Dlabková, and Daniel Jun
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Emergency Medical Services ,Immunology and Microbiology (miscellaneous) ,Veterinary (miscellaneous) ,Public Health, Environmental and Occupational Health ,Emergency Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Abstract
S ohledem na udalosti poslednich let neni riziko vojenskeho ci teroristickeho zneužiti vysoce toxických latek vcetně zakazaných bojových otravných latek zanedbatelne. Katedra toxikologie a vojenske farmacie Fakulty vojenskeho zdravotnictvi Univerzity obrany tudiž zavedla analyticke metody a postupy uprav biologických vzorků (plasma, moc) pro stanoveni identifikacnich znaků (biomarkerů) vystaveni nervově paralytickým latkam (sarinu, cyklosarinu, somanu, tabunu a V-latkam) a yperitu, cimž přinasi do Armady Ceske republiky schopnost potvrdit jejich zneužiti vůci žive sile. Metody popsane v clanku jsou založeny na průkazu metabolitů (O-alkyl methylfosfonových kyselin pro nervově paralyticke latky a thiodiglykolu pro yperit) a produktů jejich reakci s přitomnými biomolekulami (tyrosinových aduktů nervově paralytických latek a peptidových aduktů sirneho yperitu) pomoci kapalinove a plynove chromatografie spojene s hmotnostni spektrometrii. Funkcnost těchto metod je ověřovana a diskutovana v ramci testu odborne způsobilosti pro biomedicinskou analýzu s mezinarodni ucasti, který každorocně pořada Organizace pro zakaz chemických zbrani. Katedra se těchto testů ucastni od roku 2016, kdy se konal prvni rocnik.
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- 2020
7. DEFINITION OF THE TARGET POPULATION FOR EXTERNAL PACEMAKER AS A KEY ASPECT IN SUCCESSFUL MEDICAL DEVICE HTA PROCESS
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Jan Honegr, Petra Maresova, Kamil Kuca, and Daniel Jun
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Emergency Medical Services ,Medical device ,Process management ,business.industry ,Process (engineering) ,Veterinary (miscellaneous) ,Public Health, Environmental and Occupational Health ,Target population ,Immunology and Microbiology (miscellaneous) ,Emergency Medicine ,Key (cryptography) ,Medicine ,business ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Published
- 2020
8. Introduction of the Menaquinone Biosynthetic Pathway into Rhodobacter sphaeroides and de Novo Synthesis of Menaquinone for Incorporation into Heterologously Expressed Integral Membrane Proteins
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Amita Mahey, Tomas Richardson-Sanchez, Rachel C. Fernandez, Daniel Jun, J. Thomas Beatty, and Michael E. P. Murphy
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0106 biological sciences ,Photosynthetic reaction centre ,0303 health sciences ,biology ,Operon ,Chemistry ,Chloroflexus aurantiacus ,Biomedical Engineering ,General Medicine ,biology.organism_classification ,medicine.disease_cause ,Photosynthesis ,7. Clean energy ,01 natural sciences ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Metabolic engineering ,03 medical and health sciences ,Rhodobacter sphaeroides ,Biochemistry ,010608 biotechnology ,medicine ,Escherichia coli ,Integral membrane protein ,030304 developmental biology - Abstract
Quinones are redox-active molecules that transport electrons and protons in organelles and cell membranes during respiration and photosynthesis. In addition to the fundamental importance of these processes in supporting life, there has been considerable interest in exploiting their mechanisms for diverse applications ranging from medical advances to innovative biotechnologies. Such applications include novel treatments to target pathogenic bacterial infections and fabricating biohybrid solar cells as an alternative renewable energy source. Ubiquinone (UQ) is the predominant charge-transfer mediator in both respiration and photosynthesis. Other quinones, such as menaquinone (MK), are additional or alternative redox mediators, for example in bacterial photosynthesis of species such as Thermochromatium tepidum and Chloroflexus aurantiacus. Rhodobacter sphaeroides has been used extensively to study electron transfer processes, and recently as a platform to produce integral membrane proteins from other species. To expand the diversity of redox mediators in R. sphaeroides, nine Escherichia coli genes encoding the synthesis of MK from chorismate and polyprenyl diphosphate were assembled into a synthetic operon in a newly designed expression plasmid. We show that the menFDHBCE, menI, menA, and ubiE genes are sufficient for MK synthesis when expressed in R. sphaeroides cells, on the basis of high performance liquid chromatography and mass spectrometry. The T. tepidum and C. aurantiacus photosynthetic reaction centers produced in R. sphaeroides were found to contain MK. We also measured in vitro charge recombination kinetics of the T. tepidum reaction center to demonstrate that the MK is redox-active and incorporated into the QA pocket of this heterologously expressed reaction center.
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- 2020
9. Simple validated method of LC–MS/MS determination of BZ agent in rat plasma samples
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Jana Zdarova Karasova, Alzbeta Dlabkova, Daniel Jun, Lenka Cechova, Jan Misik, David Herman, and Nela Vanova
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Male ,Spectrometry, Mass, Electrospray Ionization ,3-Quinuclidinyl benzilate ,Electrospray ionization ,Pharmaceutical Science ,Mass spectrometry ,01 natural sciences ,High-performance liquid chromatography ,Cholinergic Antagonists ,Analytical Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Limit of Detection ,Tandem Mass Spectrometry ,Lc ms ms ,medicine ,Animals ,Environmental Chemistry ,Sample preparation ,030216 legal & forensic medicine ,Rats, Wistar ,Chromatography, High Pressure Liquid ,Spectroscopy ,Detection limit ,Chromatography ,Chemistry ,010401 analytical chemistry ,Extraction (chemistry) ,Rats ,0104 chemical sciences ,Quinuclidinyl Benzilate ,medicine.drug - Abstract
Agent BZ (3-quinuclidinyl benzilate) is a centrally acting synthetic anticholinergic agent, considered as a potential military incapacitating chemical warfare agent. Despite its significance as a model compound in pharmacological research and its potential misuse in chemical attacks, few modern analytical methods for BZ determination in biological samples have been published. The goal of the present work is to develop and validate a sensitive and rapid LC-MS/MS method for the determination of agent BZ in rat plasma. The sample preparation was based on solid-phase extraction on C-18 cartridges. The reversed-phase HPLC coupled with the mass spectrometer with electrospray ionization in the positive ion-selective reaction monitoring mode was employed in the BZ analysis. Atropine was used as an internal standard. The presented method is selective, accurate, precise, and linear (r2 = 0.9947) in a concentration range from 0.5 ng/mL to 1 000 ng/mL and sensitive enough (limit of detection 0.2 ng/mL; limit of quantification 0.5 ng/mL) to determine the BZ plasma levels in rats exposed to 2 mg/kg and 10 mg/kg of BZ. The highest level of BZ in plasma was observed 5 minutes after intramuscular administration (154.6 ± 22.3 ng/mL in rats exposed to 2 mg/kg of BZ and 1024 ± 269 ng/mL in rats exposed to 10 mg/kg). After 48 h, no BZ was observed at detectable levels. This new method allows the detection and quantification of BZ in biological samples after exposure of an observed organism and it will be further optimized for other tissues to observe the distribution of BZ in organs.
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- 2020
10. Design Methodology for Deep Out-of-Distribution Detectors in Real-Time Cyber-Physical Systems
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Michael Yuhas, Daniel Jun Xian Ng, and Arvind Easwaran
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FOS: Computer and information sciences ,Computer Science - Machine Learning ,Machine Learning (cs.LG) - Abstract
When machine learning (ML) models are supplied with data outside their training distribution, they are more likely to make inaccurate predictions; in a cyber-physical system (CPS), this could lead to catastrophic system failure. To mitigate this risk, an out-of-distribution (OOD) detector can run in parallel with an ML model and flag inputs that could lead to undesirable outcomes. Although OOD detectors have been well studied in terms of accuracy, there has been less focus on deployment to resource constrained CPSs. In this study, a design methodology is proposed to tune deep OOD detectors to meet the accuracy and response time requirements of embedded applications. The methodology uses genetic algorithms to optimize the detector's preprocessing pipeline and selects a quantization method that balances robustness and response time. It also identifies several candidate task graphs under the Robot Operating System (ROS) for deployment of the selected design. The methodology is demonstrated on two variational autoencoder based OOD detectors from the literature on two embedded platforms. Insights into the trade-offs that occur during the design process are provided, and it is shown that this design methodology can lead to a drastic reduction in response time in relation to an unoptimized OOD detector while maintaining comparable accuracy., Comment: 6 pages, 10 figures
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- 2022
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11. A Singular Value Approach to Robustify Deep Convolutional Neural Network
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Yeli Feng, Daniel Jun Xian Ng, and Arvind Easwaran
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- 2022
12. Non-covalent acetylcholinesterase inhibitors: In vitro screening and molecular modeling for novel selective insecticides
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Vendula Hepnarova, Martina Hrabinova, Lubica Muckova, Tomas Kucera, Monika Schmidt, Rafael Dolezal, Lukas Gorecki, Veronika Hrabcova, Jan Korabecny, Eva Mezeiova, Daniel Jun, and Jaroslav Pejchal
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Insecticides ,Mosquito Vectors ,General Medicine ,Toxicology ,Organophosphates ,Carbofuran ,Butyrylcholinesterase ,Anopheles ,Acetylcholinesterase ,Tacrine ,Animals ,Humans ,Cholinesterase Inhibitors ,Carbamates - Abstract
Insecticides represent the most crucial element in the integrated management approach to malaria and other vector-borne diseases. The evolution of insect resistance to long-used substances and the toxicity of organophosphates (OPs) and carbamates are the main factors contributing to the development of new, environmentally safe pesticides. In our work, fourteen compounds of 7-methoxytacrine-tacrine heterodimers were tested for their insecticidal effect. Compounds were evaluated in vitro on insect acetylcholinesterase from Anopheles gambiae (AgAChE) and Musca domestica (MdAChE). The evaluation was executed in parallel with testing on human erythrocyte acetylcholinesterase (HssAChE) and human butyrylcholinesterase (HssBChE) using a modified Ellman's method. Compound efficacy was determined as IC
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- 2022
13. Monoterpene indole alkaloids from Vinca minor L. (Apocynaceae): Identification of new structural scaffold for treatment of Alzheimer's disease
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Rudolf, Vrabec, Jana, Maříková, Miroslav, Ločárek, Jan, Korábečný, Daniela, Hulcová, Anna, Hošťálková, Jiří, Kuneš, Jakub, Chlebek, Tomáš, Kučera, Martina, Hrabinová, Daniel, Jun, Ondřej, Soukup, Vincenza, Andrisano, Jaroslav, Jenčo, Marcela, Šafratová, Lucie, Nováková, Lubomír, Opletal, and Lucie, Cahlíková
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Glycogen Synthase Kinase 3 beta ,Alzheimer Disease ,Butyrylcholinesterase ,Phytochemicals ,Acetylcholinesterase ,Monoterpenes ,Plant Components, Aerial ,Vinca ,Indole Alkaloids - Abstract
One undescribed indole alkaloid together with twenty-two known compounds have been isolated from aerial parts of Vinca minor L. (Apocynaceae). The chemical structures of the isolated alkaloids were determined by a combination of MS, HRMS, 1D, and 2D NMR techniques, and by comparison with literature data. The NMR data of several alkaloids have been revised, corrected, and missing data have been supplemented. Alkaloids isolated in sufficient quantity were screened for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7) and butyrylcholinesterase (BuChE; E.C. 3.1.1.8) inhibitory activity. Selected compounds were also evaluated for prolyl oligopeptidase (POP; E.C. 3.4.21.26), and glycogen synthase 3β-kinase (GSK-3β; E.C. 2.7.11.26) inhibition potential. Significant hBuChE inhibition activity has been shown by (-)-2-ethyl-3[2-(3-ethylpiperidinyl)-ethyl]-1H-indole with an IC
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- 2021
14. Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies
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Ondřej Soukup, Filip Pidaný, Rozálie Peřinová, Lubica Muckova, Jiří Kuneš, Tomas Kucera, Abdullah Al Mamun, Negar Maafi, Jan Korábečný, Rudolf Andrýs, Monika Schmidt, Jiří Janoušek, Martina Hrabinova, Jana Maříková, Lucie Cahlíková, Daniela Hulcová, Daniel Jun, Lucie Nováková, and Maria Carmen Catapano
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Pharmacology ,01 natural sciences ,chemistry.chemical_compound ,Neuroblastoma ,Tumor Cells, Cultured ,Biology (General) ,Spectroscopy ,Butyrylcholinesterase ,0303 health sciences ,biology ,Biological activity ,General Medicine ,Receptor antagonist ,Acetylcholinesterase ,Computer Science Applications ,Molecular Docking Simulation ,Chemistry ,Alzheimer’s disease ,medicine.drug_class ,QH301-705.5 ,Tyramine ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Structure-Activity Relationship ,medicine ,Humans ,Computer Simulation ,Physical and Theoretical Chemistry ,Amaryllidaceae Alkaloids ,norbelladine-type ,Molecular Biology ,IC50 ,QD1-999 ,amaryllidaceae alkaloid ,030304 developmental biology ,Cholinesterase ,Cell Proliferation ,010405 organic chemistry ,Organic Chemistry ,docking studies ,0104 chemical sciences ,chemistry ,Docking (molecular) ,biology.protein ,Cholinesterase Inhibitors - Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1–20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.
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- 2021
15. Embedded out-of-distribution detection on an autonomous robot platform
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Michael Yuhas, Arvind Easwaran, Daniel Jun Xian Ng, Yeli Feng, and Zahra Rahiminasab
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FOS: Computer and information sciences ,Computer Science - Robotics ,Resource (project management) ,Artificial neural network ,Computer science ,Middleware ,Detector ,Real-time computing ,Detection performance ,Autonomous robot ,Robotics (cs.RO) ,Test data ,Case analysis - Abstract
Machine learning (ML) is actively finding its way into modern cyber-physical systems (CPS), many of which are safety-critical real-time systems. It is well known that ML outputs are not reliable when testing data are novel with regards to model training and validation data, i.e., out-of-distribution (OOD) test data. We implement an unsupervised deep neural network-based OOD detector on a real-time embedded autonomous Duckiebot and evaluate detection performance. Our OOD detector produces a success rate of 87.5% for emergency stopping a Duckiebot on a braking test bed we designed. We also provide case analysis on computing resource challenges specific to the Robot Operating System (ROS) middleware on the Duckiebot., 6 pages, 8 figures
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- 2021
16. Population-level management of Type 1 diabetes via continuous glucose monitoring and algorithm-enabled patient prioritization: Precision health meets population health
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Brianna Leverenz, Ming Yeh Lee, David M. Maahs, Priya Prahalad, Jeannine Leverenz, Anastasiya Vitko, Esli Osmanlliu, David Scheinker, Dianelys P. Morales, Ramesh Johari, Christos Vasilakis, Angela Gu, Daniel Jun, Jacqueline Vallon, and Johannes O. Ferstad
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Research design ,Prioritization ,Type 1 diabetes ,Telemedicine ,medicine.medical_specialty ,Population level ,Continuous glucose monitoring ,business.industry ,Dashboard (business) ,Population health ,medicine.disease ,Emergency medicine ,medicine ,business - Abstract
ObjectiveTo develop and scale algorithm-enabled patient prioritization to improve population-level management of type 1 diabetes (T1D) in a pediatric clinic with fixed resources, using telemedicine and remote monitoring of patients via continuous glucose monitor (CGM) data review.Research Design and MethodsWe adapted consensus glucose targets for T1D patients using CGM to identify interpretable clinical criteria to prioritize patients for weekly provider review. The criteria were constructed to manage the number of patients reviewed weekly and identify patients who most needed provider contact. We developed an interactive dashboard to display CGM data relevant for the patients prioritized for review.ResultsThe introduction of the new criteria and interactive dashboard was associated with a 60% reduction in the mean time spent by diabetes team members who remotely and asynchronously reviewed patient data and contacted patients, from 3.2±0.20 to 1.3±0.24 minutes per patient per week. Given fixed resources for review, this corresponded to an estimated 147% increase in weekly clinic capacity. Patients who qualified for and received remote review (n=58) have associated 8.8 percentage points (pp) (95% CI = 0.6–16.9pp) greater time-in-range (70-180 mg/dL) glucoses compared to 25 control patients who did not qualify at twelve months after T1D onset.ConclusionsAn algorithm-enabled prioritization of T1D patients with CGM for asynchronous remote review reduced provider time spent per patient and was associated with improved time-in-range.
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- 2021
17. Highly Sensitive Method to Isolate Photocurrent Signals from Large Background Redox Currents on Protein‐Modified Electrodes
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Dan Bizzotto, J. Thomas Beatty, and Daniel Jun
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Photocurrent ,Photosynthetic reaction centre ,Electron transfer ,Chemistry ,Electrode ,Electrochemistry ,Photochemistry ,Redox ,Catalysis ,Highly sensitive - Published
- 2019
18. Photosynthetic Reaction Centres Assembled on a Gold Electrode and the Photocurrent - Potential Response
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Daniel Jun, Adrian Grzedowski, J. Thomas Beatty, and Dan Bizzotto
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The photosynthetic reaction centre (RC) from Rhodobacter sphaeroides has been studied for use in biohybrid solar cells. Much of the previous work has focussed on improving photocurrent generation by loading the electrode surface with many copies of the protein resulting in multilayers. The primary disadvantage with this approach is the random orientation of proteins, with some supposedly oriented properly. We used RCs with Cys for covalent attachment to a gold electrode and for proper orientation. Areas of bare electrode surface and RCs bound non-specifically (i.e. not bound via the Cys) were competitively displaced by an insulating, non-redox layer of mercaptohexanol (MCH). The adsorbed monolayer of RCs was imaged using atomic force microscopy to detail the distribution of RCs on the gold surface for surfaces prepared with different RC deposition concentrations. Photocurrents were measured for all RC modified surfaces using a LED modulation method which enabled measurement of photocurrent in the presence of large faradaic currents from the sacrificial reactant (hydroquinone) at a variety of applied potentials.[1] The photocurrents generated from a monolayer composed of RCs and MCH resulted in consistent photocurrent currents. which enabled modeling of the photocurrent generation using the Marcus-Hush-Chidsey theory to extract a reorganization energy for this process. Multilayers of adsorbed RCs were distinctly different and revealed that the local environment in which the RCs are embedded significantly influenced photocurrent generation. [1] Jun, D.; Beatty, J. T.; Bizzotto, D. Highly Sensitive Method to Isolate Photocurrent Signals From Large Background Redox Currents on Protein‐Modified Electrodes. ChemElectroChem 2019, 6 (11), 2870–2875.
- Published
- 2022
19. Contract-Based Hierarchical Resilience Management for Cyber-Physical Systems
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Karthikeyan Thangamariappan, Daniel Jun Xian Ng, Mohammad Shihabul Haque, Arvind Easwaran, and School of Computer Science and Engineering
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FOS: Computer and information sciences ,0209 industrial biotechnology ,General Computer Science ,Computer science ,Software Reliability ,media_common.quotation_subject ,02 engineering and technology ,User requirements document ,Fault detection and isolation ,Computer Science - Software Engineering ,D.2.4.g ,D.2.4.f ,020901 industrial engineering & automation ,Software ,D.2.15 ,Component (UML) ,0202 electrical engineering, electronic engineering, information engineering ,Resilience (network) ,media_common ,Flexibility (engineering) ,Resilience ,business.industry ,Cyber-physical system ,020202 computer hardware & architecture ,Software Engineering (cs.SE) ,Risk analysis (engineering) ,Computer science and engineering [Engineering] ,Psychological resilience ,business - Abstract
Orchestrated collaborative effort of physical and cyber components to satisfy given requirements is the central concept behind Cyber-Physical Systems (CPS). To duly ensure the performance of components, a software-based resilience manager is a flexible choice to detect and recover from faults quickly. However, a single resilience manager, placed at the centre of the system to deal with every fault, suffers from decision-making overburden; and therefore, is out of the question for distributed large-scale CPS. On the other hand, prompt detection of failures and efficient recovery from them are challenging for decentralised resilience managers. In this regard, we present a novel resilience management framework that utilises the concept of management hierarchy. System design contracts play a key role in this framework for prompt fault-detection and recovery. Besides the details of the framework, an Industry 4.0 related test case is presented in this article to provide further insights., Comment: \copyright 2018 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works
- Published
- 2018
20. Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells
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Daniel Jun, Monika Hudáčová, Juraj Ševc, Jana Vargová, Jana Janockova, Mária Kožurková, Veronika Ihnatova, Jan Korábečný, Petr Bzonek, Lucie Junova, Nikola Novakova, Eva Konkoľová, Kamil Kuca, Ondrej Soukup, Rastislav Jendželovský, Slávka Hamuľaková, Peter Fedoročko, and Tomas Kucera
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0301 basic medicine ,Models, Molecular ,Chemistry Techniques, Synthetic ,Pharmacology ,blood–brain barrier ,lcsh:Chemistry ,chemistry.chemical_compound ,0302 clinical medicine ,A549 ,Coumarins ,lcsh:QH301-705.5 ,Spectroscopy ,Butyrylcholinesterase ,Molecular Structure ,Cell Cycle ,General Medicine ,Cell cycle ,Acetylcholinesterase ,Computer Science Applications ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Alzheimer’s disease ,antiproliferative activity ,cholinesterase ,Cell Survival ,Antineoplastic Agents ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Structure-Activity Relationship ,Alzheimer Disease ,Humans ,MTT assay ,Physical and Theoretical Chemistry ,Molecular Biology ,A549 cell ,biscoumarin ,Dose-Response Relationship, Drug ,Cell growth ,Organic Chemistry ,In vitro ,Enzyme Activation ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,A549 Cells ,Cancer cell ,Cholinesterase Inhibitors - Abstract
A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.
- Published
- 2021
21. (±)- BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease
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Vendula Hepnarova, Kamil Musilek, Aurélie Baguet, Daniel Jun, José Marco-Contelles, Lhassane Ismaili, Emmanuel Haffen, Tomas Kucera, Jan Korabecny, Jana Janockova, Angela De Simone, Eva M. García-Frutos, Vincenza Andrisano, Manuela Bartolini, B. Refouvelet, Lucía Viejo, Cristóbal de los Ríos, Adeline Etievant, Ondrej Soukup, Rudolf Andrys, Julie Monnin, Raquel L Arribas, Conseil régional of Franche-Comté, Czech Science Foundation, Ministry of Education, Youth and Sports (Czech Republic), Ismaili L., Monnin J., Etievant A., Arribas R.L., Viejo L., Refouvelet B., Soukup O., Janockova J., Hepnarova V., Korabecny J., Kucera T., Jun D., Andrys R., Musilek K., Baguet A., Garcia-Frutos E.M., De Simone A., Andrisano V., Bartolini M., De Los Rios C., Marco-Contelles J., and Haffen E.
- Subjects
cholinesterase ,Physiology ,Monoamine oxidase ,Cognitive Neuroscience ,Ligand ,Pharmacology ,Ligands ,Calcium Channel ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,In vivo ,GSK-3 ,Humans ,Cholinesterases ,Cholinesterase Inhibitor ,Biginelli reaction ,Alzheimer's disease ,calcium channel ,cholinesterases ,GSK 3β ,MAO ,Calcium Channel Blockers ,Calcium Channels ,Cholinesterase Inhibitors ,Glycogen Synthase Kinase 3 beta ,Monoamine Oxidase ,GSK3B ,030304 developmental biology ,Cholinesterase ,0303 health sciences ,Voltage-dependent calcium channel ,biology ,Chemistry ,Calcium channel ,Cell Biology ,General Medicine ,Calcium channel, GSK 3β, MAO ,biology.protein ,Monoamine oxidase A ,Calcium Channel Blocker ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Human - Abstract
Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits., L.I. thanks the Regional Council of Franche-Comté (2016YC- 04540 and 04560) for financial support, Mrs. M.-J. Henriot (PHV Pharma) for her support in the HPLC analyses, and Vincent Luzet for preliminary results in synthesis. O.S., J.J., and J.K. acknowledge the support from the grant by Czech Science Foundation no. 20-29633J. T.K., D.J., and V.H. acknowledge support from the Long-term Development Plan (Faculty of Military Health Sciences). R.A. and K.M. thank the Ministry of Education, Youth and Sports of the Czech Republic (ERDF no. CZ.02.1.01/0.0/0.0/16_025/0007444).
- Published
- 2021
22. Cooling the urban environment
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Steve Kardinal Jusuf, Tong Shanshan, Daniel Jun Chung Hii, Tan Puay Yok, Tan Chun Liang, and Wong Nyuk Hein
- Subjects
Environmental science ,Environmental planning ,Urban environment - Published
- 2020
23. Pursuing the Complexity of Alzheimer's Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and
- Author
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Jan, Konecny, Anna, Misiachna, Martina, Hrabinova, Lenka, Pulkrabkova, Marketa, Benkova, Lukas, Prchal, Tomas, Kucera, Tereza, Kobrlova, Vladimir, Finger, Marharyta, Kolcheva, Stepan, Kortus, Daniel, Jun, Marian, Valko, Martin, Horak, Ondrej, Soukup, and Jan, Korabecny
- Subjects
N-methyl-d-aspartate receptor ,Fluorenes ,multi-target directed ligands ,in vitro ,CHO Cells ,acetylcholinesterase ,Receptors, N-Methyl-D-Aspartate ,Article ,fluorene ,Cricetulus ,Alzheimer Disease ,Blood-Brain Barrier ,in silico ,Butyrylcholinesterase ,butyrylcholinesterase ,Animals ,Humans ,Computer Simulation ,Cholinesterase Inhibitors ,Enzyme Inhibitors ,Alzheimer’s disease - Abstract
Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
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- 2020
24. Achieving resilience for cyber-physical systems with 4DIAC IEC 61499 through parametric contracts
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Daniel Jun Xian Ng
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Risk analysis (engineering) ,Computer science ,Cyber-physical system ,Resilience (network) ,Parametric statistics - Published
- 2020
25. Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
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José A. Dias, Tereza Kobrlova, Vendula Hepnarova, Tomas Kucera, Daniel Jun, Lubica Muckova, Florian Nachon, David Malinak, Jan Korabecny, Kamil Musilek, Franz Worek, Martina Hrabinova, Lukas Gorecki, Ondrej Soukup, Charlotte Courageux, Jana Zdarova Karasova, and Lukas Prchal
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0301 basic medicine ,Male ,Cholinesterase Reactivators ,Health, Toxicology and Mutagenesis ,Antidotes ,010501 environmental sciences ,Pharmacology ,Molecular Dynamics Simulation ,Toxicology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Oximes ,medicine ,Animals ,Butyrylcholinesterase ,0105 earth and related environmental sciences ,Tabun ,Nerve agent ,Mice, Inbred BALB C ,General Medicine ,Acetylcholinesterase ,In vitro ,Acute toxicity ,030104 developmental biology ,chemistry ,Toxicity ,Female ,medicine.drug - Abstract
To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.
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- 2020
26. Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems
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Jana Janockova, Jana Kubackova, Karel Vales, Petr Jost, João Pina, Zuzana Bednarikova, Jan Korabecny, Katarina Motykova, Eugenie Nepovimova, Luísa Cortes, Zofia Chrienova, Kamil Musilek, Carlos Serpa, Rafael Dolezal, Lucie Svobodova, Lucie Junova, Laura Aitken, Vendula Hepnarova, Martin Vališ, Katarina Chalupova, Ondrej Soukup, Danijela Rostohar, Marketa Chvojkova, Daniel Jun, Lubica Muckova, Catarina S. H. Jesus, Zuzana Gazova, Kamil Kuca, Rebecca E. Hughes, and Tomas Kucera
- Subjects
Amyloid ,Cholinergic Agents ,Pharmacology ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Protein Aggregates ,Structure-Activity Relationship ,In vivo ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Benzothiazoles ,Enzyme Inhibitors ,Molecular Biology ,IC50 ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,3-Hydroxyacyl CoA Dehydrogenases ,Acetylcholinesterase ,In vitro ,0104 chemical sciences ,Mitochondria ,010404 medicinal & biomolecular chemistry ,Neuroprotective Agents ,Benzothiazole ,chemistry ,Tacrine ,Cholinergic ,medicine.drug - Abstract
A series of tacrine – benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 µM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound – 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
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- 2020
27. Introduction of the Menaquinone Biosynthetic Pathway into
- Author
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Daniel, Jun, Tomas, Richardson-Sanchez, Amita, Mahey, Michael E P, Murphy, Rachel C, Fernandez, and J Thomas, Beatty
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Electron Transport ,Kinetics ,Spectrometry, Mass, Electrospray Ionization ,Photobleaching ,Bacterial Proteins ,Metabolic Engineering ,Ubiquinone ,Photosynthetic Reaction Center Complex Proteins ,Membrane Proteins ,Vitamin K 2 ,Rhodobacter sphaeroides ,Chromatography, High Pressure Liquid ,Plasmids - Abstract
Quinones are redox-active molecules that transport electrons and protons in organelles and cell membranes during respiration and photosynthesis. In addition to the fundamental importance of these processes in supporting life, there has been considerable interest in exploiting their mechanisms for diverse applications ranging from medical advances to innovative biotechnologies. Such applications include novel treatments to target pathogenic bacterial infections and fabricating biohybrid solar cells as an alternative renewable energy source. Ubiquinone (UQ) is the predominant charge-transfer mediator in both respiration and photosynthesis. Other quinones, such as menaquinone (MK), are additional or alternative redox mediators, for example in bacterial photosynthesis of species such as
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- 2020
28. Is It the Twilight of BACE1 Inhibitors?
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Martina Hrabinova, Daniel Jun, Ondrej Soukup, Jaroslav Pejchal, Monika Schmidt, and Tomas Kucera
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Amyloid beta ,Skin rashes ,Disease ,Bioinformatics ,Placebo ,Weight loss ,Alzheimer Disease ,Aricle ,mental disorders ,inhibitors ,Medicine ,Aspartic Acid Endopeptidases ,Humans ,β-secretase ,Pharmacology (medical) ,Prospective Studies ,Adverse effect ,substrates ,Pharmacology ,clinical trials ,Amyloid beta-Peptides ,biology ,business.industry ,General Medicine ,Clinical trial ,amyloid beta ,Psychiatry and Mental health ,Neurology ,β secretase ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Amyloid Precursor Protein Secretases ,business ,Alzheimer’s disease - Abstract
β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.
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- 2020
29. List of contributors
- Author
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Arturo Anadón, Rudolf Andrys, Pavel Avdonin, Jiri Bajgar, Mahdi Balali-Mood, Frank Balszuweit, Atrayee Banerjee, Cheryl B. Bast, Daria Belinskaia, Vijay K. Bharti, Claire E. Bollinger, Robert P. Casillas, Ryan Clark, Edward D. Clarkson, Toby B. Cole, Rhian B. Cope, Robert W. Coppock, Lucio G. Costa, Wolf-D. Dettbarn, Alzbeta Dlabkova, Robin B. Doss, Margitta M. Dziwenka, Jorge Estevez, Tim J. Evans, John K. Fink, Swaran J.S. Flora, Clement E. Furlong, Josef Fusek, Jacqueline Garrick, Jeffery M. Gearhart, Donald R. Gerecke, Dana F. Glass-Mattie, Saryu Goel, Nikolay Goncharov, Richard K. Gordon, Joshua P. Gray, Zoran Grubic, Kavita Gulati, Ramesh C. Gupta, Sharon M. Gwaltney-Brant, Tracey A. Hamilton, Kenneth J. Harris, Darryl B. Hood, Edward M. Jakubowski, Richard Jenkins, David A. Jett, Yuqin Jiao, Harald John, Nathan H. Johnson, Milan Jokanović, Daniel Jun, Georgy Karakashev, Jiri Kassa, Maja Katalinic, Kai Kehe, Natalia Khlebnikova, Urmila P. Kodavanti, Ekaterina Korf, Nadezhda Koryagina, Bojan Kovač, Gopala Krishna, Mayur Krishna, Kamil Kuca, Dinesh Kumar, Yukio Kuroiwa, Sergey Kuznetsov, Kamil Kuča, Joseph C. Larsen, Mikhail Leninskiy, Jing Liu, Heather Lochotzki, Oksana Lockridge, Jordana Lockwich, Bommanna G. Loganathan, Dragana Lončar-Stojiljković, Sofya V. Lushchekina, Megan E. Lyman, Mark Maguire, Galina F. Makhaeva, Jitendra K. Malik, David Malinak, Tomaz Mars, Judit Marsillach, María-Rosa Martínez-Larrañaga, Patrick Masson, Shigeki Masunaga, Monique McCallister, Linda A. McCauley, Roger O. McClellan, Patrick M. McNutt, Edward C. Meek, Elaine Merrill, Sylvia Milanez, Igor Mindukshev, Katarina Mis, Jan Misik, Michael J. Murphy, Kamil Musilek, Tamie Nakajima, Marian R. Nelson, Eugenie Nepovimova, Tetsu Okumura, Jiri Patocka, Katarina Pegan, Jaroslav Pejchal, Sergej Pirkmajer, René Pita, Jason Pitt, Yiuka Pitt, Gennady E. Platoff, Carey N. Pope, Andrey Radilov, Anu Rahal, Aramandla Ramesh, Arunabha Ray, Vladimir Rembovskiy, Raina Rhoades, Rudy J. Richardson, Dragana Ristić, Peter J. Robinson, Alejandro Romero, Chris Ruark, Harry Salem, Natalia Samchenko, Tetsuo Satoh, Russell E. Savage, Elena Savelieva, Lawrence M. Schopfer, Alfred M. Sciuto, Yasuo Seto, Michael P. Shakarjian, Vladimir Shmurak, Adam Skarka, Ranko Škrbić, Miguel Sogorb, Shardell M. Spriggs, Sakshi Srivastava, Dirk Steinritz, Miloš P. Stojiljković, Neera Tewari-Singh, Horst Thiermann, Suresh Kumar Thokchom, Larry J. Thompson, Anton Ukolov, Luis G. Valerio, M.J. van der Schans, Daya R. Varma, Eugenio Vilanova, Annetta Watson, Sanjeeva J. Wijeyesakere, Tina Wismer, R. Mark Worden, Franz Worek, Linzzi K. Wright, Hidenori Yamasue, Takemi Yoshida, Toshiharu Yoshioka, Robert A. Young, Snjezana Zaja-Milatovic, Valeriy Zinchenko, and Csaba K. Zoltani
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- 2020
30. Pharmacological prophylaxis against nerve agent poisoning: experimental studies and practical implications
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Josef Fusek, Daniel Jun, Kamil Kuca, Jiri Bajgar, and Jiri Kassa
- Subjects
Benactyzine ,Chemistry ,medicine.medical_treatment ,Organophosphate ,Pharmacology ,Acetylcholinesterase ,chemistry.chemical_compound ,Pyridostigmine ,Detoxification ,medicine ,Antidote ,Butyrylcholinesterase ,medicine.drug ,Nerve agent - Abstract
Prophylaxis against intoxication with organophosphate (OP) nerve agents is based on various approaches. Protection of acetylcholinesterase (AChE), the target enzyme for toxic action of OP nerve agents, is a basic requirement for effective prophylaxis. This can be achieved by using reversible AChE inhibitors, preferably carbamates (CMs). AChE inhibited by CMs is resistant to the action of an OP nerve agent for a transient period. After spontaneous recovery of the activity, normal AChE serves as a source of the active enzyme. Detoxification is carried out by the administration of enzymes hydrolyzing the OPs or evaluating specific enzymes (cholinesterases). The OP nerve agent is bound to the exogenously administered enzyme, and thus the OP level in the organism is decreased (“scavenger” effect). The administration of enzymes, such as AChE and butyrylcholinesterase, as scavengers seems to be very promising, as the enzyme acts at the very beginning of the toxic action, and without interaction with target tissues and without side effects. The antidotes currently used for the treatment of OP poisoning can be tested as prophylactics. This principle can be considered as a treatment in advance. Standard antidotes were studied in this respect; that is, anticholinergics, enzyme reactivators, anticonvulsants, and others. The problem with their use is the timing, duration, and achievement of sufficient levels of these antidotes after administration. At present, pyridostigmine seems to be a common prophylactic antidote, while PANPAL (tablets with pyridostigmine, trihexyphenidyle, and benactyzine) and TRANSANT (a transdermal patch containing HI-6) are the prophylactics. Future drug development will be focused on scavengers (cholinesterases and other enzymes) acting prior to the binding of the nerve agent to the target sites, and to other drugs either reversible cholinesterase inhibitors (e.g., huperzine A, physostigmine, acridine derivatives, etc.) or other compounds.
- Published
- 2020
31. Demo Abstract: Contract-based Hierarchical Resilience Framework for Cyber-Physical Systems
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Ng, Daniel Jun Xian, Easwaran, Arvind, and Andalam, Sidharta
- Subjects
Software Engineering (cs.SE) ,FOS: Computer and information sciences ,Computer Science - Software Engineering - Abstract
This demonstration presents a framework for building a resilient Cyber-Physical Systems (CPS) cyber-infrastructure through the use of hierarchical parametric assume-guarantee contracts. A Fischertechnik Sorting Line with Color Detection training model is used to showcase our framework., Comment: 2 pages, 5 figures, published in the Demo Session of IEEE International Conference on Cyber-Physical Systems 2019. Publication rights licensed to ACM
- Published
- 2020
- Full Text
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32. CLAIR: A Contract-based Framework for Developing Resilient CPS Architectures
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Arvind Easwaran, Sidharta Andalam, Daniel Jun Xian Ng, and Karthikeyan Thangamariappan
- Subjects
FOS: Computer and information sciences ,Computer science ,media_common.quotation_subject ,Multitier architecture ,Distributed computing ,020208 electrical & electronic engineering ,020207 software engineering ,02 engineering and technology ,Transparency (human–computer interaction) ,Decoupling (cosmology) ,Automaton ,Software Engineering (cs.SE) ,Computer Science - Software Engineering ,Multilayered architecture ,0202 electrical engineering, electronic engineering, information engineering ,Code (cryptography) ,Psychological resilience ,Code maintenance ,media_common - Abstract
Industrial cyber-infrastructure is normally a multilayered architecture. The purpose of the layered architecture is to hide complexity and allow independent evolution of the layers. In this paper, we argue that this traditional strict layering results in poor transparency across layers affecting the ability to significantly improve resiliency. We propose a contract-based methodology where components across and within the layers of the cyber-infrastructure are associated with contracts and a light-weight resilience manager. This allows the system to detect faults (contract violation monitored using observers) and react (change contracts dynamically) effectively. It results in (1) improving transparency across layers; helps resiliency, (2) decoupling fault-handling code from application code; helps code maintenance, (3) systematically generate error-free fault handling code; reduces development time. Using an industrial case study, we demonstrate the proposed methodology., Comment: \copyright 2018 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works
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- 2020
- Full Text
- View/download PDF
33. ATLAS: Software for analysing the relationship between urban microclimate and urban morphology in a tropical city
- Author
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Nyuk Hien Wong, Daniel Jun Chung Hii, Zhongqi Yu, Yang He, Shisheng Chen, Marcel Ignatius, and Wen Zhang
- Subjects
Environmental Engineering ,media_common.quotation_subject ,Geography, Planning and Development ,Microclimate ,Urban morphology ,Regression analysis ,Building and Construction ,Solar irradiance ,Atmospheric sciences ,Quartile ,Sky ,Principal component analysis ,Tropical climate ,Environmental science ,Civil and Structural Engineering ,media_common - Abstract
This research applied clustering to unsupervised learning of meteorological data and evaluated the impact of urban morphology on temperature in different weather. Air Temperature Learning Algorithms (ATLAS) was developed for the cluster analysis of urban meteorological data and regression analysis of urban morphology and outdoor air temperature. The case study experiment was conducted on the university campus. Based on principal component analysis (PCA) reduced K-means clustering, this study evaluated the characteristics of reference meteorological data, and local solar irradiance and air temperature. Three weather conditions were identified for the given reference meteorological data. Revised selection criteria for clear, hot, and calm weather in tropical climate were proposed. The mean R a i n t o t shall be less than 0.01 mm, with 25th, 50th and 75th quartile to be 0 mm, respectively. The mean W a v g and its quartiles shall be less than 3 m/s. The mean, 50th and 75th quartile of S t o t , S m a x , and S a v g shall be higher than 5000 Wh/m2, 800 W/m2 and 200 W/m2, respectively. The mean, 50th and 75th quartile of T a v g , T m a x and T m i n shall be higher than 29 °C , 32 °C and 26 °C , respectively. The hourly ground level air temperature models were established in different weather. The results indicate the ground level air temperature in rainy and cool weather conditions are more predictable than hot and dry weather conditions. The sky view factor, exterior wall area, and green plot ratio have a greater impact on air temperature in sunny days than rainy days.
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- 2022
34. Sustainable laboratory evaluations: Optimized fume-hood- intensive ventilation and energy efficiency without compromising occupational safety and comfort
- Author
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Yueyang He, Daniel Jun Chung Hii, Nyuk Hien Wong, and Thian-Guan Peck
- Subjects
Renewable Energy, Sustainability and the Environment ,Strategy and Management ,Building and Construction ,Industrial and Manufacturing Engineering ,General Environmental Science - Published
- 2022
35. Oxime K033-Reactivation Activity of Cholinesterases Inhibited by Various Nerve Agents and Organophosphorus Pesticides
- Author
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Kamil Musilek, Ondrej Krejcar, Ondrej Soukup, Qinghua Wu, Daniel Jun, Teodorico C. Ramalho, Raquel O. Lopes, Jaroslav Pejchal, Tanos C. C. França, Marek Penhaker, Eugenie Nepovimova, and Kamil Kuca
- Subjects
biology ,Chemistry ,medicine.medical_treatment ,010401 analytical chemistry ,Pharmaceutical Science ,04 agricultural and veterinary sciences ,Pharmacology ,Pesticide ,Oxime ,040401 food science ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,0404 agricultural biotechnology ,Drug Discovery ,medicine ,biology.protein ,Molecular Medicine ,Antidote ,Organophosphorus pesticides ,Nerve agent ,medicine.drug ,Cholinesterase - Published
- 2018
36. ANÁLISE DO METABOLISMO OXIDATIVOS E SUA CORRELAÇÃO COM O DESEMPENHO OCUPACIONAL DE PACIENTES COM DOENÇA DE PARKINSON SOB PARÂMETROS DA CLASSIFICAÇÃO INTERNACIONAL DE FUNCIONALIDADE, INCAPACIDADE E SAÚDE
- Author
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Esther Samara da Costa Santos, Daniel Jun Hayashi, and Guilherme Henrique Siqueira Oeiras
- Published
- 2019
37. Outcomes of underweight, overweight, and obese pediatric kidney transplant recipients
- Author
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Ernesto P. Molmenti, Lulette Infante, Elliot Grodstein, Christine B. Sethna, Rachel M. Frank, Laura Castellanos, Daniel Jun, Pamela Singer, Kiranjot Kaur, Lewis W. Teperman, and Ahmed Fahmy
- Subjects
Adult ,Graft Rejection ,Male ,Nephrology ,medicine.medical_specialty ,Adolescent ,030232 urology & nephrology ,Delayed Graft Function ,030204 cardiovascular system & hematology ,Overweight ,Lower risk ,Body Mass Index ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Thinness ,Risk Factors ,Internal medicine ,Humans ,Medicine ,Obesity ,Registries ,Risk factor ,Child ,Kidney transplantation ,Retrospective Studies ,business.industry ,Graft Survival ,Age Factors ,Length of Stay ,medicine.disease ,Kidney Transplantation ,Transplant Recipients ,Transplantation ,Child, Preschool ,Preoperative Period ,Pediatrics, Perinatology and Child Health ,Kidney Failure, Chronic ,Female ,medicine.symptom ,Underweight ,business ,Body mass index - Abstract
Obesity is a risk factor for poor transplant outcomes in the adult population. The effect of pre-transplant weight on pediatric kidney transplantation is conflicting in the existing literature. Data was collected from the Organ Procurement and Transplantation Network (OPTN) database on recipients aged 2–21 years who received a kidney-only transplant from 1987 to 2017. Recipients were categorized into underweight, normal, overweight, and obese cohorts. Using adjusted regression models, the relationship between recipient weight and various graft outcomes (delayed graft function [DGF], acute rejection, prolonged hospitalization, graft failure, mortality) was examined. 18,261 transplant recipients (mean age 14.1 ± 5.5 years) were included, of which 8.7% were underweight, 14.8% were overweight, and 15% were obese. Obesity was associated with greater odds of DGF (OR 1.3 95% CI 1.13–1.49, p
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- 2018
38. Oxime K074 – in vitro and in silico reactivation of acetylcholinesterase inhibited by nerve agents and pesticides
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Alexandre A. de Castro, Eugenie Nepovimova, Elaine F. F. da Cunha, Ondrej Krejcar, Kamil Kuca, Tanos C. C. França, Teodorico C. Ramalho, Ondrej Soukup, Jan Korabecny, Kamil Musilek, and Daniel Jun
- Subjects
021110 strategic, defence & security studies ,Aché ,medicine.medical_treatment ,In silico ,0211 other engineering and technologies ,02 engineering and technology ,010501 environmental sciences ,Pesticide ,Pharmacology ,Toxicology ,Oxime ,01 natural sciences ,Acetylcholinesterase ,language.human_language ,In vitro ,chemistry.chemical_compound ,chemistry ,medicine ,language ,Antidote ,0105 earth and related environmental sciences ,Nerve agent ,medicine.drug - Abstract
Oxime K074 was formerly considered to be a lead structure for design of novel oximes for reactivation of tabun-inhibited acetylcholinesterase (AChE). In this study, we are summarizing its reactivat...
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- 2018
39. Reactivation Potential of Novel More Lipophilic Pralidoxime Analogs
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Jan Misik, Daniel Jun, Martina Hrabinova, and Kamil Kuca
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Pralidoxime ,Chemistry ,Drug Discovery ,medicine ,Pharmaceutical Science ,Molecular Medicine ,Pharmacology ,medicine.drug - Published
- 2018
40. Vector Control and Insecticidal Resistance in the African Malaria Mosquito Anopheles gambiae
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Kamil Kuca, Kamil Musilek, Monika Schmidt, Veronika Hrabcova, and Daniel Jun
- Subjects
0301 basic medicine ,Insecticides ,Anopheles gambiae ,Mosquito Vectors ,Disease ,Toxicology ,Insecticide Resistance ,03 medical and health sciences ,Anopheles ,parasitic diseases ,medicine ,Animals ,Humans ,Vector control ,Resistance (ecology) ,biology ,business.industry ,Transmission (medicine) ,General Medicine ,medicine.disease ,biology.organism_classification ,Malaria ,Biotechnology ,Mosquito control ,030104 developmental biology ,Insecticide resistance ,Drug Design ,Acetylcholinesterase ,business - Abstract
Mosquito-borne diseases (including malaria) belong among the leading causes of death in humans. Vector control is a crucial part of the global strategy for management of mosquito-associated diseases, when insecticide use is the most important component in this effort. However, drug and insecticide resistance threaten the successes made with existing methods. Reduction or elimination of malaria is not possible without effective mosquito control. This article reviews current strategies of intervention in vector control to decrease transmission of disease and covers current relevant knowledge in molecular biology, biochemistry, and medicinal chemistry.
- Published
- 2018
41. In vitro and in silico Evaluation of Non-Quaternary Reactivators of AChE as Antidotes of Organophosphorus Poisoning - a New Hope or a Blind Alley?
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Eugenie Nepovimova, Ondrej Soukup, Petr Pavek, Petr Jost, Miroslav Psotka, David Malinak, Jan Korabecny, Kamil Musilek, Rafael Dolezal, Ales Sorf, Daniel Jun, Thuy Duong Nguyen, Ngoc Lam Pham, Martina Hrabinova, Karl J. Box, Vendula Hepnarova, Lukas Gorecki, Tereza Kobrlova, Jana Jankockova, Martina Ceckova, Kamil Kuca, and Breeze Outhwaite
- Subjects
0301 basic medicine ,Blind alley ,Cholinesterase Reactivators ,Aché ,In silico ,Organophosphorus Poisoning ,Antidotes ,Paraoxon ,Mice ,03 medical and health sciences ,Organophosphate Poisoning ,Low affinity ,Oximes ,Drug Discovery ,Animals ,Computer Simulation ,Chemistry ,Sarin ,Combinatorial chemistry ,Organophosphates ,In vitro ,language.human_language ,Rats ,Lower affinity ,030104 developmental biology ,Blood-Brain Barrier ,Butyrylcholinesterase ,Lipophilicity ,language ,Cholinesterase Inhibitors - Abstract
BACKGROUND In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. OBJECTIVE In this study, we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. METHODS This time, we used only in silico prediction and in vitro approaches. RESULTS Our data showed that tested uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. CONCLUSION From the presented data, it seems that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.
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- 2018
42. The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease
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Eugenie Nepovimova, Ondřej Soukup, Tomas Kucera, Daniel Kaping, Ngoc Lam Pham, Katarina Spilovska, Daniel Jun, L. Matouskova, M. Kerhartova, Eva Mezeiova, Lubica Muckova, Petr Jost, Kamil Kuca, Vendula Hepnarova, Frantisek Staud, Martina Hrabinova, Jan Korabecny, Rafael Dolezal, and N. Vykoukalova
- Subjects
0301 basic medicine ,Stereochemistry ,Carboxylic acid ,Cell Line ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,0302 clinical medicine ,Alzheimer Disease ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Humans ,Moiety ,Butyrylcholinesterase ,Cholinesterase ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,General Medicine ,Acetylcholinesterase ,030104 developmental biology ,chemistry ,Docking (molecular) ,Tacrine ,Quinolines ,biology.protein ,Cholinesterase Inhibitors ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 μM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.
- Published
- 2018
43. In vivo assembly of a truncated H subunit mutant of the Rhodobacter sphaeroides photosynthetic reaction centre and direct electron transfer from the QA quinone to an electrode
- Author
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Harveer Singh Dhupar, Ali Mahmoudzadeh, Daniel Jun, J. T. Beatty, Franck Duong, and John D. W. Madden
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0301 basic medicine ,Photosynthetic reaction centre ,biology ,Hydroquinone ,Protein subunit ,Electron donor ,Cell Biology ,Plant Science ,General Medicine ,010402 general chemistry ,biology.organism_classification ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Quinone ,03 medical and health sciences ,chemistry.chemical_compound ,Electron transfer ,Rhodobacter sphaeroides ,Crystallography ,030104 developmental biology ,chemistry ,Bacteriochlorophyll - Abstract
We address a challenge in the engineering of proteins to redirect electron transfer pathways, using the bacterial photosynthetic reaction centre (RC) pigment–protein complex. Direct electron transfer is shown to occur from the QA quinone of the Rhodobacter sphaeroides RC containing a truncated H protein and bound on the quinone side to a gold electrode. In previous reports of binding to the quinone side of the RC, electron transfer has relied on the use of a soluble mediator between the RC and an electrode, in part because the probability of QB quinone reduction is much greater than that of direct electron transfer through the large cytoplasmic domain of the H subunit, presenting a ~ 25 A barrier. A series of C-terminal truncations of the H subunit were created to expose the quinone region of the RC L and M proteins, and all truncated RC H mutants assembled in vivo. The 45M mutant was designed to contain only the N-terminal 45 amino acid residues of the H subunit including the membrane-spanning α-helix; the mutant RC was stable when purified using the detergent N-dodecyl-β-d-maltoside, contained a near-native ratio of bacteriochlorophylls to bacteriopheophytins, and showed a charge-separated state of $${{\text{P}}^{\text{+}}}{{\text{Q}}_{\text{A}}^-}$$ . The 45M-M229 mutant RC had a Cys residue introduced in the vicinity of the QA quinone on the newly exposed protein surface for electrode attachment, decreasing the distance between the quinone and electrode to ~ 12 A. Steady-state photocurrents of up to around 200 nA/cm2 were generated in the presence of 20 mM hydroquinone as the electron donor to the RC. This novel configuration yielded photocurrents orders of magnitude greater than previous reports of electron transfer from the quinone region of RCs bound in this orientation to an electrode.
- Published
- 2018
44. Oxidative stress in organophosphate poisoning: role of standard antidotal therapy
- Author
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Jaroslav Pejchal, David Herman, Daniel Jun, Alzbeta Dlabkova, and Nela Vanova
- Subjects
0301 basic medicine ,business.industry ,medicine.drug_class ,Organophosphate ,Pharmacology ,Toxicology ,medicine.disease_cause ,medicine.disease ,Acetylcholinesterase ,Organophosphate poisoning ,03 medical and health sciences ,chemistry.chemical_compound ,Atropine ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Toxicity ,medicine ,Anticholinergic ,business ,030217 neurology & neurosurgery ,Oxidative stress ,Nerve agent ,medicine.drug - Abstract
Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration.
- Published
- 2018
45. Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings
- Author
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Eva Novotná, Martin Vališ, Kamil Kuca, Ondrej Soukup, Jaroslav Pejchal, Eva Vodakova, Kamil Musilek, Jana Zdarova Karasova, Daniel Jun, Vendula Sepsova, Jiri Kassa, Anna Horova, Martina Hrabinova, and Eugenie Nepovimova
- Subjects
Models, Molecular ,0301 basic medicine ,Cell Survival ,Pharmaceutical Science ,Pharmacology ,AChE inhibitors ,nerve agents ,Cell Line ,Small Molecule Libraries ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Drug Discovery ,Soman ,medicine ,Humans ,Original Research ,Nerve agent ,Cholinesterase ,Drug Design, Development and Therapy ,soman ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,toxicity ,pre-treatment ,Acetylcholinesterase ,Acute toxicity ,030104 developmental biology ,chemistry ,Pyridostigmine ,Toxicity ,biology.protein ,prophylaxis ,Cholinesterase Inhibitors ,030217 neurology & neurosurgery ,HeLa Cells ,medicine.drug - Abstract
Kamil Kuca,1,2 Jana Zdarova Karasova,2,3 Ondrej Soukup,2 Jiri Kassa,3 Eva Novotna,2 Vendula Sepsova,2,3 Anna Horova,2 Jaroslav Pejchal,3 Martina Hrabinova,2,3 Eva Vodakova,2 Daniel Jun,2,3 Eugenie Nepovimova,1,2 Martin Valis,4 Kamil Musilek1,2 1Department of Chemistry, Faculty of Science, University of Hradec Kralove, 2Biomedical Research Center, University Hospital Hradec Kralove, 3Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, 4Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic Background: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity. Keywords: AChE inhibitors, prophylaxis, pre-treatment, nerve agents, toxicity, soman
- Published
- 2018
46. Cytotoxicity of acetylcholinesterase reactivators evaluated in vitro and its relation to their structure
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David Herman, Lubica Muckova, Petr Jost, Jaroslav Pejchal, Daniel Jun, and Nela Vanova
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Obidoxime ,Cholinesterase Reactivators ,Pralidoxime ,Cell Survival ,Health, Toxicology and Mutagenesis ,Chemical structure ,Drug Evaluation, Preclinical ,010501 environmental sciences ,Animal Testing Alternatives ,Toxicology ,01 natural sciences ,Lethal Dose 50 ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oximes ,medicine ,Humans ,Trimedoxime ,Cytotoxicity ,0105 earth and related environmental sciences ,Pharmacology ,Chemical Health and Safety ,Molecular Structure ,Public Health, Environmental and Occupational Health ,Hep G2 Cells ,General Medicine ,Fibroblasts ,Oxime ,Acetylcholinesterase ,Combinatorial chemistry ,chemistry ,Toxicity ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The development of acetylcholinesterase reactivators, i.e., antidotes against organophosphorus poisoning, is an important goal of defense research. The aim of this study was to compare cytotoxicity and chemical structure of five currently available oximes (pralidoxime, trimedoxime, obidoxime, methoxime, and asoxime) together with four perspective oximes from K-series (K027, K074, K075, and K203). The cytotoxicity of tested substances was measured using two methods - colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay and impedance based real-time cytotoxicity assay - in three different cell lines (HepG2, ACHN, and NHLF). Toxicity was subsequently expressed as toxicological index IC50. The tested compounds showed different cytotoxicity ranging from 0.92 to 40.06 mM. In HepG2 cells, K027 was the least and asoxime was the most toxic reactivator. In ACHN and NHLF cell lines, trimedoxime was the compound with the lowest adverse effects, whereas the highest toxicity was found in methoxime-treated cells. The results show that at least five structural features affect the reactivators' toxicity such as the number of oxime groups in the molecule, their position on pyridinium ring, the length of carbon linker, and the oxygen substitution or insertion of the double bond into the connection chain. Newly synthetized oximes with IC50 ≥ 1 mM evaluated in this three cell lines model might appear suitable for further testing.
- Published
- 2018
47. The influence of modulators of acetylcholinesterase on the resistance of mice against soman and on the effectiveness of antidotal treatment of soman poisoning in mice
- Author
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Daniel Jun, Jiri Kassa, Eugenie Nepovimova, and Jan Korabecny
- Subjects
0301 basic medicine ,Health, Toxicology and Mutagenesis ,Biomedical Engineering ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Artificial Intelligence ,6-chlorotacrine ,Soman ,medicine ,Potency ,General Pharmacology, Toxicology and Pharmaceutics ,General Immunology and Microbiology ,General Neuroscience ,General Medicine ,Oxime ,Acetylcholinesterase ,Acute toxicity ,Atropine ,030104 developmental biology ,chemistry ,General Agricultural and Biological Sciences ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The potency of one reversible inhibitor of acetylcholinesterase (6-chlorotacrine), one reactivator of acetycholinesterase (K027) and their combination to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. While 6-chlorotacrine was able to markedly protect mice against acute toxicity of soman and the pharmacological pretreatment with 6-chlorotacrine increased the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice more than two times, the bispyridinium oxime K027 did not protect mice from acute toxicity of soman, however, the pharmacological pretreatment with this compound was able to markedly increase the efficacy of antidotal treatment of soman-poisoned mice. On the other hand, the combination of both modulators of acetylcholinesterase did not increase the prophylactic efficacy of 6-chlorotacrine alone. These findings demonstrate that pharmacological pretreatment of soman-poisoned mice can be promising and useful in the case of administration of 6-chlorotacrine while the administration of the oxime K027 did not bring any additional benefit when combined with 6-chlorotacrine.
- Published
- 2018
48. Synthesis, Biological Assessment and Molecular Modeling of Racemic QuinoPyranoTacrines for Alzheimer's Disease Therapy
- Author
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Jana Janockova, Ondrej Soukup, Daniel Jun, Mourad Chioua, José Marco-Contelles, Ignacio Moraleda, Lhassane Ismaili, Vendula Sepsova, Fakher Chabchoub, Isabel Iriepa, Hélène Martin, Youssef Dgachi, and Estefanía Serrano
- Subjects
0301 basic medicine ,Molecular Modeling ,General Chemistry ,Management ,Synthesis ,03 medical and health sciences ,Disease therapy ,030104 developmental biology ,0302 clinical medicine ,Political science ,QuinoPyranoTacrines ,Military health ,Cost action ,Biological Evaluation ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Biological evaluation - Abstract
In this report we describe the synthesis, biological evaluation and molecular modeling of new tacrine analogues such as QuinoPyranTacrines (QPTs), designed by juxtaposition of 1,4- naphthoquinone and tacrine. From these results we have identified QPT16 as a permeable, selective human acetylcholinesterase inhibitor [IC50= 1.1 0.15 mM], 3.5-fold less-hepatotoxic than tacrine at 1000 mM concentration, and consequently, a potential new hit-compound for further investigation targeted to find a new agent for AD therapy., LI thanks the Regional Council of Franche-Comte (2016YC-04540 and 04560) for financial support. OS thanks Faculty of Military Health Sciences, University of Defence, MH CZ – DRO (UHHK, 00179906) and by Long Term Development Plan – 1011 for support. JMC thank MINECO (Spain) for grant SAF2015-65586-R, and EU (COST Action CA15135: “Multi-target paradigm for innovative ligand identification in the drug discovery process”) for support.
- Published
- 2018
49. Profiling donepezil template into multipotent hybrids with antioxidant properties
- Author
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Jana Janockova, Ondrej Soukup, Katarina Spilovska, Eugenie Nepovimova, Eva Mezeiova, Jan Korabecny, Rafael Dolezal, Kamil Kuca, David Malinak, Daniel Jun, and Lukas Gorecki
- Subjects
0301 basic medicine ,Antioxidant ,medicine.medical_treatment ,multi-target directed ligands ,Review Article ,Pharmacology ,medicine.disease_cause ,Antioxidants ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Piperidines ,Alzheimer Disease ,mental disorders ,Drug Discovery ,medicine ,Humans ,oxidative stress ,Donepezil ,Rivastigmine ,Molecular Structure ,business.industry ,lcsh:RM1-950 ,General Medicine ,Acetylcholinesterase ,donepezil ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,Indans ,Cholinesterase Inhibitors ,business ,Alzheimer’s disease ,Oxidative stress ,medicine.drug - Abstract
Alzheimer’s disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer’s disease.
- Published
- 2018
50. Alkaloids from Narcissus poeticus cv. Pink Parasol of various structural types and their biological activity
- Author
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Daniel Jun, Marcela Šafratová, Martina Hrabinova, Jakub Chlebek, Lucie Nováková, Martina Seifrtova, Radim Havelek, Lucie Cahlíková, Daniela Hulcová, Jiří Kuneš, Anna Hošťálková, Veronika Hrabcova, Kateřina Breiterová, Lubomír Opletal, Miguel Prudêncio, Diana Fontinha, and Marta Machado
- Subjects
medicine.drug_class ,Narcissus poeticus ,Oligopeptidase ,Plant Roots ,01 natural sciences ,Jurkat Cells ,Mice ,Alkaloids ,Drug Discovery ,medicine ,Animals ,Humans ,Amaryllidaceae Alkaloids ,Butyrylcholinesterase ,biology ,010405 organic chemistry ,Chemistry ,Alkaloid ,Organic Chemistry ,Narcissus ,Biological activity ,Amaryllidaceae ,biology.organism_classification ,Growth Inhibitors ,0104 chemical sciences ,3. Good health ,010404 medicinal & biomolecular chemistry ,Biochemistry ,A549 Cells ,MCF-7 Cells ,Antiprotozoal ,Molecular Medicine ,Cholinesterase Inhibitors ,HT29 Cells ,HeLa Cells - Abstract
Fifteen Amaryllidaceae alkaloids (1–15) of various structural types were isolated by standard chromatographic methods from fresh bulbs of Narcissus poeticus cv. Pink Parasol. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic analyses, and by comparison with literature data. Narcipavline (5) and narcikachnine (6) are reported here for the first time. In their structure are combined two basic structural types of Amaryllidaceae alkaloids (galanthamine- and galanthindole-structural types), which represent a new structural type of these compounds. Alkaloids isolated in sufficient amounts were evaluated for their human erythrocytic acetylcholinesterase, and human serum butyrylcholinesterase (HuBuChE) inhibition activity using Ellman’s method. Z-Gly-Pro-p-nitroanilide was used as substrate in the prolyl oligopeptidase (POP) assay. Untested alkaloids were also screened for their cytotoxic activity against a small panel of human cancer cells, which spanned cell lines from different tissue types. In parallel, MRC-5 human fibroblasts were employed to determine overall toxicity against noncancerous cells. Some compounds were evaluated for their antiprotozoal activity. The newly isolated alkaloid narcipavline (5) showed interesting HuBuChE inhibition activity (IC50 = 24.4 ± 1.2 µM), and norlycoramine (11) demonstrated promising POP inhibition (IC50 = 0.21 ± 0.01 mM).
- Published
- 2017
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