Publications by authors named "Jan Svoboda"

76 Publications

Synthesis of ()-3-[amino(phenyl)methylidene]-1,3-dihydro-2-indol-2-ones using an Eschenmoser coupling reaction.

Beilstein J Org Chem 2021 23;17:527-539. Epub 2021 Feb 23.

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, CZ532 10 Pardubice, Czech Republic.

A highly modular method for the synthesis of ()-3-[amino(phenyl/methyl)methylidene]-1,3-dihydro-2-indol-2-ones starting from easily available 3-bromooxindoles or (2-oxoindolin-3-yl)triflate and thioacetamides or thiobenzamides is described. A series of 49 compounds, several of which have previously been shown to possess significant tyrosin kinase inhibiting activity, was prepared in yields varying mostly from 70 to 97% and always surpassing those obtained by other published methods. The method includes an Eschenmoser coupling reaction, which is very feasible (even without using a thiophile except tertiary amides) and scalable. The ()-configuration of all products was confirmed by NMR techniques.
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http://dx.doi.org/10.3762/bjoc.17.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934781PMC
February 2021

Turning preference in dogs: North attracts while south repels.

PLoS One 2021 28;16(1):e0245940. Epub 2021 Jan 28.

Faculty of Forestry and Wood Sciences, Department of Game Management and Wildlife Biology, Czech University of Life Sciences, Praha, Czech Republic.

It was shown earlier that dogs, when selecting between two dishes with snacks placed in front of them, left and right, prefer to turn either clockwise or counterclockwise or randomly in either direction. This preference (or non-preference) is individually consistent in all trials but it is biased in favor of north if they choose between dishes positioned north and east or north and west, a phenomenon denoted as "pull of the north". Here, we replicated these experiments indoors, in magnetic coils, under natural magnetic field and under magnetic field shifted 90° clockwise. We demonstrate that "pull of the north" was present also in an environment without any outdoor cues and that the magnetic (and not topographic) north exerted the effect. The detailed analysis shows that the phenomenon involves also "repulsion of the south". The clockwise turning preference in the right-preferring dogs is more pronounced in the S-W combination, while the counterclockwise turning preference in the left-preferring dogs is pronounced in the S-E combination. In this way, south-placed dishes are less frequently chosen than would be expected, while the north-placed dishes are apparently more preferred. Turning preference did not correlate with the motoric paw laterality (Kong test). Given that the choice of a dish is visually guided, we postulate that the turning preference was determined by the dominant eye, so that a dominant right eye resulted in clockwise, and a dominant left eye in counterclockwise turning. Assuming further that magnetoreception in canines is based on the radical-pair mechanism, a "conflict of interests" may be expected, if the dominant eye guides turning away from north, yet the contralateral eye "sees the north", which generally acts attractive, provoking body alignment along the north-south axis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842976PMC
January 2021

Plasticity-Related Activity in the Hippocampus, Anterior Cingulate, Orbitofrontal, and Prefrontal Cortex Following a Repeated Treatment with D/D Agonist Quinpirole.

Biomolecules 2021 Jan 11;11(1). Epub 2021 Jan 11.

Laboratory of the Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic.

Quinpirole (QNP) sensitization is a well-established model of stereotypical checking relevant to obsessive-compulsive disorder. Previously, we found that QNP-treated rats display deficits in hippocampus-dependent tasks. The present study explores the expression of immediate early genes (IEG) during QNP-induced stereotypical checking in the hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and medial prefrontal cortex (mPFC). Adult male rats were injected with QNP (0.5 mg/mL/kg; = 15) or saline ( = 14) daily for 10 days and exposed to an arena enriched with two objects. Visits to the objects and the corners of the arena were recorded. QNP-treated rats developed an idiosyncratic pattern of visits that persisted across experimental days. On day 11, rats were exposed to the arena twice for 5 min and sacrificed. The expression of IEGs and was determined using cellular compartment analysis of temporal activity by fluorescence in situ hybridization. IEG-positive nuclei were counted in the CA1 area of the hippocampus, ACC, OFC, and mPFC. We found significantly fewer IEG-positive nuclei in the CA1 in QNP-treated rats compared to controls. The overlap between IEG expressing neurons was comparable between the groups. We did not observe significant differences in IEG expression between QNP treated and control rats in ACC, OFC, and mPFC. In conclusion, treatment of rats with quinpirole decreases plasticity-related activity in the hippocampus during stereotypical checking.
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http://dx.doi.org/10.3390/biom11010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827652PMC
January 2021

Surface Design of Antifouling Vascular Constructs Bearing Biofunctional Peptides for Tissue Regeneration Applications.

Int J Mol Sci 2020 Sep 16;21(18). Epub 2020 Sep 16.

Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovsky sq. 2, 162 06 Prague, Czech Republic.

Antifouling polymer layers containing extracellular matrix-derived peptide motifs offer promising new options for biomimetic surface engineering. In this contribution, we report the design of antifouling vascular grafts bearing biofunctional peptide motifs for tissue regeneration applications based on hierarchical polymer brushes. Hierarchical diblock poly(methyl ether oligo(ethylene glycol) methacrylate--glycidyl methacrylate) brushes bearing azide groups (poly(MeOEGMA--GMA-N)) were grown by surface-initiated atom transfer radical polymerization (SI-ATRP) and functionalized with biomimetic RGD peptide sequences. Varying the conditions of copper-catalyzed alkyne-azide "click" reaction allowed for the immobilization of RGD peptides in a wide surface concentration range. The synthesized hierarchical polymer brushes bearing peptide motifs were characterized in detail using various surface sensitive physicochemical methods. The hierarchical brushes presenting the RGD sequences provided excellent cell adhesion properties and at the same time remained resistant to fouling from blood plasma. The synthesis of anti-fouling hierarchical brushes bearing 1.2 × 10 nmol/cm RGD biomimetic sequences has been adapted for the surface modification of commercially available grafts of woven polyethylene terephthalate (PET) fibers. The fiber mesh was endowed with polymerization initiator groups via aminolysis and acylation reactions optimized for the material. The obtained bioactive antifouling vascular grafts promoted the specific adhesion and growth of endothelial cells, thus providing a potential avenue for endothelialization of artificial conduits.
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http://dx.doi.org/10.3390/ijms21186800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554689PMC
September 2020

New psychoactive substances on dark web markets: From deal solicitation to forensic analysis of purchased substances.

Drug Test Anal 2021 Jan 7;13(1):156-168. Epub 2020 Aug 7.

Forensic Laboratory of Biologically Active Substances, University of Chemistry and Technology Prague, Technická 5, Prague, Czech Republic.

The dark web scene has been drawing the attention of law enforcement agencies and researchers alike. To date, most of the published works on the dark web are based on data gained by passive observation. To gain a more contextualized perspective, a study was conducted in which three vendors were selected on the "Dream Market" dark web marketplace, from whom subsequently several new psychoactive substances (NPS) were ordered. All transactions were documented from the initial drug deal solicitation to the final qualitative analysis of all received samples. From the selected vendors, a total of nine NPS samples was obtained, all of which were analyzed by NMR, HRMS, LC-UV, and two also by x-ray diffraction. According to our analyses, four of the five substances offered under already known NPS names contained a different NPS. The selected vendors therefore either did not know about their product, or deliberately deceived the buyers. Furthermore, two of three obtained samples of purportedly novel NPS were identified as already documented substances sold under a different name. However, the third characterized substance sold as "MPF-47700" was a novel, yet uncharacterized, NPS. Finally, we received a single undeclared substance, later identified as 5F-ADB. In addition to chemical analysis of the nine obtained NPS samples, the methodology used also yielded contextual information about the accessibility of NPS on the dark web, the associated purchase process, and the modus operandi of three NPS vendors. Direct participation in dark web marketplaces seems to provide additional layers of information useful for forensic studies.
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http://dx.doi.org/10.1002/dta.2901DOI Listing
January 2021

Magnetic alignment enhances homing efficiency of hunting dogs.

Elife 2020 06 16;9. Epub 2020 Jun 16.

Department of Game Management and Wildlife Biology, Faculty of Forestry and Wood Sciences, Czech University of Life Sciences, Praha, Czech Republic.

Despite anecdotal reports of the astonishing homing abilities in dogs, their homing strategies are not fully understood. We equipped 27 hunting dogs with GPS collars and action cams, let them freely roam in forested areas, and analyzed components of homing in over 600 trials. When returning to the owner (homewards), dogs either followed their outbound track ('tracking') or used a novel route ('scouting'). The inbound track during scouting started mostly with a short (about 20 m) run along the north-south geomagnetic axis, irrespective of the actual direction homewards. Performing such a 'compass run' significantly increased homing efficiency. We propose that this run is instrumental for bringing the mental map into register with the magnetic compass and to establish the heading of the animal.
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http://dx.doi.org/10.7554/eLife.55080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297537PMC
June 2020

Conformation in Ultrathin Polymer Brush Coatings Resolved by Infrared Nanoscopy.

Anal Chem 2020 04 10;92(7):4716-4720. Epub 2020 Mar 10.

Department of Chemistry and Physics of Surfaces and Biointerfaces, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovsky sq. 2, 162 06 Prague, Czech Republic.

Polymer brush coatings are effective in preventing blood coagulation or bacterial attachment, but their chain conformation, while vital for this effect, was never characterized in high spatial resolution. Here, we report mid-infrared spectroscopic nanoscopy studies of few-nanometer-thin poly(ethylene oxide) (PEO) films which reveal marked spectral variations along the surface at a length scale smaller than 100 nm and originating only from the physical conformation of the chains. The conformation and average orientation of the polymer chains in the layer is extracted from the spectra with the aid of theoretic modeling, confirming the spontaneous formation of a crystalline phase. This result suggests spectroscopic nanoscopy as a powerful new tool to characterize polymer brush coatings.
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http://dx.doi.org/10.1021/acs.analchem.9b05661DOI Listing
April 2020

How N-(pyridin-4-yl)pyridin-4-amine and its methyl and nitro derivatives are arranged in the interlayer space of zirconium sulfophenylphosphonate: a problem solved by experimental and calculation methods.

J Comput Aided Mol Des 2020 06 12;34(6):683-695. Epub 2020 Feb 12.

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10, Pardubice, Czech Republic.

Classical molecular simulation methods were used for a description of an arrangement of intercalated molecules N-(pyridin-4-yl)pyridin-4-amine (AH) and its derivatives, 3-methyl-N-(pyridin-4-yl)pyridin-4-amine (AMe), and 3-nitro-N-(pyridin-4-yl)pyridin-4-amine (ANO2) within a layered structure of zirconium 4-sulfophenylphosphonate. The intercalated molecules were placed between SOH groups of the host layers. Their mutual positions and orientations were solved by molecular simulation methods and compared with the presented experimental results. Final calculated data showed differences of partially disordered arrangement of the intercalated molecules between zirconium 4-sulfophenylphosphonate layers. The calculation results revealed a dense net of hydrogen bonds connecting water molecules and the guests in the interlayer space and the sulfo groups of the host layers. We calculated the dipole moments of the AH, AMe and ANO2 guests in the final models in order to illustrate potential use of these materials in non-linear optics.
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http://dx.doi.org/10.1007/s10822-020-00299-wDOI Listing
June 2020

Role of -Benzoquinone in the Synthesis of a Conducting Polymer, Polyaniline.

ACS Omega 2019 Apr 19;4(4):7128-7139. Epub 2019 Apr 19.

Institute of Macromolecular Chemistry, Czech Academy of Sciences, 162 06 Prague 6, Czech Republic.

Polyaniline (PANI) and 2,5-dianilino--benzoquinone both are formed by oxidation of aniline in an acidic aqueous environment. The aim of this study is to understand the impact of addition of -benzoquinone on the structure of PANI prepared by the oxidation of aniline hydrochloride with ammonium peroxydisulfate and to elucidate the formation of low-molecular-weight byproducts. An increasing yield and size-exclusion chromatography, Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy, and nuclear magnetic resonance analyses of the products show that -benzoquinone does not act as a terminating agent in the synthesis of PANI and the content of 2,5-dianilino--benzoquinone increases with the increasing molar concentration of -benzoquinone in the reaction mixture, [BzQ]. Regarding the structure of PANI, Raman and UV-visible spectra show that the doping level and the charge delocalization both decrease with the increase of [BzQ], and the FTIR spectra of the PANI bases indicate an increased concentration of benzenoid units at higher [BzQ]. We explain these observations by an increasing concentration of structural defects in PANI chains and propose a 2,5-dianilino--benzoquinone-like structure of these defects present as pendant groups. The bands typical of 2,5-dianilino--benzoquinone-like moiety are observed even in the vibrational spectra of the sample prepared without addition of -benzoquinone. This confirms in situ oxidation of aniline to -benzoquinone within the course of the oxidation of aniline hydrochloride to PANI.
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http://dx.doi.org/10.1021/acsomega.9b00542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648476PMC
April 2019

Poly(2-oxazoline)s One-Pot Polymerization and Surface Coating: From Synthesis to Antifouling Properties Out-Performing Poly(ethylene oxide).

Biomacromolecules 2019 09 5;20(9):3453-3463. Epub 2019 Aug 5.

Institute of Macromolecular Chemistry , Czech Academy of Sciences , Heyrovskeho nam. 2 , 162 06 Prague 6 , Czech Republic.

Poly(2-alkyl-2-oxazoline)s (PAOx) represent a class of emerging polymers that can substitute or even outperform poly(ethylene oxide) (PEO) standard in various applications. Despite the great advances in PAOx research, there is still a gap in the direct experimental comparison of antifouling properties between PAOx and the golden standard PEO when exposed to blood. Motivated by this, we developed a straightforward protocol for the one-pot PAOx polymerization and surface coating by a "grafting to-" approach. First, we synthesized a library of hydrophilic poly(2-methyl-2-oxazoline)s (PMeOx) and poly(2-ethyl-2-oxazoline)s (PEtOx) with molar mass ranging from 1.5 to 10 kg/mol (DP = 16-115). The PAOx living chains were directly terminated by amine and hydroxyl groups of polydopamine (PDA) anchor layer providing the highest so far reported grafting densities ranging from 0.2 to 2.1 chains/nm. In parallel, PEO chains providing the same degree of polymerization (molar mass from 1.2 to 5 kg/mol, DP = 28-116) bearing thiol groups were grafted to PDA. The thickness, surface-related parameters, covalent structure, and antifouling properties of the resulting polymer brushes were determined via various surface sensitive techniques. The comparison of the synthesized PAOx and PEO brushes led us to the conclusion that at the same surface-related parameters, PMeOx brushes show significantly better antifouling character when challenged against human blood plasma.
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http://dx.doi.org/10.1021/acs.biomac.9b00751DOI Listing
September 2019

A therapeutic dose of memantine improves the performance of rats in an active place avoidance task under the continuous dissociation of distal room and proximal arena cues.

Neurobiol Learn Mem 2019 07 11;162:59-66. Epub 2019 May 11.

Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, Prague 4, Czech Republic.

Memory is related to the function of N-methyl-D-aspartate (NMDA) receptors. Depending on the dose, NMDA receptor antagonists (such as memantine or MK-801) can impair memory and/or cognitive as well as procedural functions, while they also can prevent the long-term toxic effects of over-excitation of these receptors in pathophysiological processes. There is an unresolved question of whether memantine at low doses could exert an acute pro-cognitive activity. A therapeutic dose of memantine was found to improve short-term spatial memory tested in the alternation version of active place avoidance in a Carousel Maze, whereas no data are available on long-term memory in various versions of place avoidance. In an effort to reconcile this issue, rats were administered memantine (5 mg/kg) 30 min before a training session and trained in two different versions of place avoidance. A control group received saline injections. In an active place avoidance task (hereby referred to as Room+Arena-), this place was fixed to distal room cues, whereas cues from the arena were misleading. Performance thus demanded the on-going segregation of information that engages cognitive coordination. Following the Room+Arena- training, rats were trained in another place avoidance task (hereby referred to as Arena+), which requires focusing on substratal and idiothetic cues from the arena. In this version, a to-be-avoided sector rotated along with the arena in darkness that hid the extramaze cues. The rats given memantine avoided better than the control rats in the Room+Arena- task. In the Arena+ task, both groups had problems with acquiring the task. Subsequently, memantine was withdrawn and both groups relearned Room+Arena- avoidance with a new sector position. In this task, no effect of groups was seen. In conclusion, memantine at a therapeutic dose improved performance in a task that required the segregation of spatial stimuli into coherent subsets.
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http://dx.doi.org/10.1016/j.nlm.2019.03.011DOI Listing
July 2019

Neural and neuronal discoordination in schizophrenia: From ensembles through networks to symptoms.

Acta Physiol (Oxf) 2019 08 22;226(4):e13282. Epub 2019 May 22.

Department of Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.

Despite the substantial knowledge accumulated by past research, the exact mechanisms of the pathogenesis of schizophrenia and causal treatments still remain unclear. Deficits of cognition and information processing in schizophrenia are today often viewed as the primary and core symptoms of this devastating disorder. These deficits likely result from disruptions in the coordination of neuronal and neural activity. The aim of this review is to bring together convergent evidence of discoordinated brain circuits in schizophrenia at multiple levels of resolution, ranging from principal cells and interneurons, neuronal ensembles and local circuits, to large-scale brain networks. We show how these aberrations could underlie deficits in cognitive control and other higher order cognitive-behavioural functions. Converging evidence from both animal models and patients with schizophrenia is presented in an effort to gain insight into common features of deficits in the brain information processing in this disorder, marked by disruption of several neurotransmitter and signalling systems and severe behavioural outcomes.
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http://dx.doi.org/10.1111/apha.13282DOI Listing
August 2019

No effect of riluzole and memantine on learning deficit following quinpirole sensitization - An animal model of obsessive-compulsive disorder.

Physiol Behav 2019 05 28;204:241-247. Epub 2019 Feb 28.

Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic. Electronic address:

Rationale: Chronic quinpirole (QNP) sensitization is an established animal model relevant to obsessive-compulsive disorder (OCD) that has been previously shown to induce several OCD-like behavioral patterns, such as compulsive-like checking and increased locomotion.

Objectives: In current study we explored the effect of antiglutamatergic drugs, memantine and riluzole, on cognitive and behavioral performance of QNP sensitized rats.

Methods: During habituation phase, the rats (N = 56) were injected with QNP (0.25 mg/kg) or saline solution (every other day up to 10 injections) and placed into rotating arena without foot shocks for 50-min exploration. Active place avoidance task in rotating arena with unmarked to-be-avoided shock sector was used during acquisition phase. Rats were injected with memantine (1 mg/kg or 5 mg/kg), riluzole (1 mg/kg or 5 mg/kg) or saline solution 30 min before the trial and with QNP (0.25 mg/kg) or saline right before they were placed inside the rotating arena with 60° unmarked shock sector. Locomotion and number of entrances into the shock sector were recorded.

Results: QNP sensitization led to a robust deficit in place learning. However, neither memantine nor riluzole did reverse or alleviate the deficit induced by QNP. Contrarily, memantine significantly aggravated QNP induced deficit.

Conclusions: The exacerbation of cognitive deficit following antiglutamatergic agents could be mediated by decreased glutamate concentration in nucleus accumbens and decreased hippocampal activation in the QNP sensitization model.
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http://dx.doi.org/10.1016/j.physbeh.2019.01.013DOI Listing
May 2019

Peroxidase-like activity of magnetic poly(glycidyl methacrylate-co-ethylene dimethacrylate) particles.

Sci Rep 2019 02 7;9(1):1543. Epub 2019 Feb 7.

Department of Nanobiotechnology, Biology Centre, ISB, Czech Academy of Sciences, Na Sádkách 7, 370 05, České Budějovice, Czech Republic.

Poly(glycidyl methacrylate) (PGMA) is prone to modifications with different functional groups, magnetic fluids or direct coupling with biological molecules. The purpose of this research was to synthesize new magnetically responsive particles with peroxidase-like activity. Poly(glycidyl methacrylate-co-ethylene dimethacrylate) [P(GMA-EDMA)] particles containing carboxyl groups were obtained by emulsifier-free emulsion polymerization and hydrolysis and oxidation of PGMA with KMnO, resulting in poly(carboxymethyl methacrylate-co-ethylene dimethacrylate) [P(CMMA-EDMA)] particles. Thionine (Th) was also attached to the particles [(P(CMMA-EDMA)-Th] via EDC/NHS chemistry to observe its effect on electron transfer during the oxidation reaction. Finally, the particles were coated with a nitric acid-stabilized ferrofluid in methanol. The resulting magnetic particles were characterized by several methods, including scanning and transmission electron microscopy, X-ray photoelectron spectroscopy, and vibrating sample magnetometry. The effect of EDMA on the P(CMMA-EDMA) particle size and size distribution was investigated; the particle size changed from 300 to 340 nm, and the particles were monodispersed with a saturation magnetization of 11 Am/kg. Finally, the effects of temperature and pH on the peroxidase-like activity of the magnetic P(CMMA-EDMA) and P(CMMA-EDMA)-Th particles were investigated. The particles, which exhibited a high activity at pH 4-6 and at ∼37 °C, represent a highly sensitive sensor component potentially useful in enzyme-based immunoassays.
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http://dx.doi.org/10.1038/s41598-018-38012-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367401PMC
February 2019

Mnemonic and behavioral effects of biperiden, an M1-selective antagonist, in the rat.

Psychopharmacology (Berl) 2018 07 21;235(7):2013-2025. Epub 2018 Apr 21.

Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague 4, Czech Republic.

Rationale: There is a persistent pressing need for valid animal models of cognitive and mnemonic disruptions (such as seen in Alzheimer's disease and other dementias) usable for preclinical research.

Objectives: We have set out to test the validity of administration of biperiden, an M1-acetylcholine receptor antagonist with central selectivity, as a potential tool for generating a fast screening model of cognitive impairment, in outbred Wistar rats.

Methods: We used several variants of the Morris water maze task: (1) reversal learning, to assess cognitive flexibility, with probe trials testing memory retention; (2) delayed matching to position (DMP), to evaluate working memory; and (3) "counter-balanced acquisition," to test for possible anomalies in acquisition learning. We also included a visible platform paradigm to reveal possible sensorimotor and motivational deficits.

Results: A significant effect of biperiden on memory acquisition and retention was found in the counter-balanced acquisition and probe trials of the counter-balanced acquisition and reversal tasks. Strikingly, a less pronounced deficit was observed in the DMP. No effects were revealed in the reversal learning task.

Conclusions: Based on our results, we do not recommend biperiden as a reliable tool for modeling cognitive impairment.
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http://dx.doi.org/10.1007/s00213-018-4899-3DOI Listing
July 2018

Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits.

Front Pharmacol 2018 12;9:42. Epub 2018 Feb 12.

Department of Neurophysiology of Memory, Institute of Physiology, Czech Academy of Sciences, Prague, Czechia.

The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.
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http://dx.doi.org/10.3389/fphar.2018.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816576PMC
February 2018

Alkaline-earth metal phenylphosphonates and their intercalation chemistry.

Dalton Trans 2018 Feb;47(9):2867-2880

Institute of Macromolecular Chemistry of Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic.

The intercalation chemistry of layered alkaline-earth metal phenylphosphonates with the general formula MeCHPO·2HO (Ca, Sr, Ba) is reviewed. The preparation of the host materials is described and their behavior in dependence on the relative humidity and pH of the reaction medium is discussed. Mutual relationships between MeCHPO·2HO and Me(CHPOH) were investigated using a method of computer-controlled addition of reagents. The MeCHPO·2HO compounds are able to intercalate species having a free electron pair through the so-called coordination intercalation. In this way, 1-alkylamines, 1-alkanols, 1,n-diols and 1,2-diols were intercalated. In the case of the ethanol and methanol intercalates of strontium phenylphosphonate we were able to determine the structure of the host part by single-crystal X-ray diffraction. By combination of the data obtained from the diffraction with molecular modeling we suggested the arrangement of the host molecules in the interlayer space of the host. The arrangement of the shorter diols in the interlayer space of strontium phenylphosphonate was also proposed on the basis of molecular modeling calculations. These models help us to understand the structure of the prepared intercalates.
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http://dx.doi.org/10.1039/c7dt03728gDOI Listing
February 2018

The Platonic Receptacle (Hypodoché), Whitehead's Philosophy, and Genome Evolution.

Viruses 2017 12 14;9(12). Epub 2017 Dec 14.

Czech Academy of Sciences, Institute of Philosophy, Jilska 1, CZ-11000 Prague 1, Czech Republic.

The discovery of a universal genetic code utilized by all existing organisms became the backbone of biology. The coding capacity underwent changes during evolution, but its main fluctuation results from its different reading and regulation. The genetic code thus represents a sort of receptacle of living organism evolution. In this article, we propose an analogy between the genetic code and a broader Platonic , a concept that Alfred North Whitehead used to explain various aspects of science.
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http://dx.doi.org/10.3390/v9120381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744155PMC
December 2017

Geometry optimization of zirconium sulfophenylphosphonate layers by molecular simulation methods.

J Mol Model 2017 Dec 12;24(1):10. Epub 2017 Dec 12.

Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06, Prague 6, Czech Republic.

Classical molecular simulation methods were used for a detailed structural description of zirconium 4-sulfophenylphosphonate and zirconium phenylphosphonate 4-sulfophenylphosphonates with general formula Zr(HOSCHPO) (CHPO) ·yHO (x = 0.7-2; y = 0 or 2). First, models describing the structure of zirconium 4-sulfophenylphosphonate (x = 2) were calculated for the hydrated (y = 2) and dehydrated (y = 0) compounds. Subsequently, models for two mixed zirconium phenylphosphonate 4-sulfophenylphosphonates (x = 1.3 and 0.7) were calculated. Optimized models suggest that the presence of water molecules between sulfo groups creates a water-sulfonate layer with a system of hydrogen bonds. We suppose that this arrangement is the reason for a higher proton conductivity of the hydrated samples compared to dehydrated samples. When the water molecules are removed, a small decrease in the basal spacing (around 0.06 Å) is observed. This behavior is confirmed by the simulated models, where no significant changes in the structure on dehydration were observed except the absence of the water molecules and a lower number of hydrogen bonds between two adjacent sulfonate sheets. Due to the good crystallinity of the samples and the presence of sharp non-basal peaks in their X-ray diffraction patterns, Miller indices of the non-basal peaks in the diffraction patterns calculated from the models can be compared with those found in the experimental data. This allowed us to precisely describe for example (15 5-2) planes, from which mutual distances of the phenyl rings were determined to be 2.62 Å. Graphical Abstract Detailed ball and stick view into the interlayer structure of ZrSPhP1.3.
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http://dx.doi.org/10.1007/s00894-017-3549-8DOI Listing
December 2017

Drugs Interfering with Muscarinic Acetylcholine Receptors and Their Effects on Place Navigation.

Front Psychiatry 2017 9;8:215. Epub 2017 Nov 9.

Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia.

Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cognition is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knock-outs do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.
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http://dx.doi.org/10.3389/fpsyt.2017.00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684124PMC
November 2017

Simplified stratum corneum model membranes for studying the effects of permeation enhancers.

Int J Pharm 2017 Dec 20;534(1-2):287-296. Epub 2017 Oct 20.

University of Chemistry and Technology Prague, Faculty of Chemical Technology, Technická 5, 166 28, Prague, Czech Republic; Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address:

The activity of transdermal permeation enhancers is usually evaluated in vitro on human or animal skin, but skin samples can be hard to source and highly variable. To provide a more consistent basis for evaluating the activity of permeation enhancers, we prepared relatively simple and inexpensive artificial membranes that imitate the stratum corneum (SC) lipid matrix. Our membranes were composed of stearic acid, cholesterol, cholesterol sulfate and a ceramide (CER) component consisting of N-2-hydroxystearoyl phytosphingosine (CER[AP]) and/or N-stearoyl phytosphingosine (CER[NP]). First, the permeation of theophylline (TH) and indomethacin (IND) through these membranes was compared with their permeation through porcine skin. Because the mixed CER[AP]/[NP] membrane gave the closest results to skin, this membrane was then used to test the effects of two permeation enhancers: N-dodecyl azepan-2-one (Azone) and (S)-N-acetylproline dodecyl ester (L-Pro2). Both enhancers significantly increased the flux of TH and IND through the skin and, even more markedly, through the lipid membrane, L-Pro2 having a stronger effect than Azone. Thus, our simplified model of the SC lipid membrane based on phytosphingosine CERs appears to be suitable for mimicking skin permeation.
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http://dx.doi.org/10.1016/j.ijpharm.2017.10.038DOI Listing
December 2017

Directional preference in dogs: Laterality and "pull of the north".

PLoS One 2017 25;12(9):e0185243. Epub 2017 Sep 25.

Department of Game Management and Wildlife Biology, Faculty of Forestry and Wood Sciences, Czech University of Life Sciences, Kamýcká 129, Praha 6, Czech Republic.

Laterality is a well described phenomenon in domestic dogs. It was shown that dogs, under calm Earth's magnetic field conditions, when marking their home ranges, tend to head about north- or southwards and display thus magnetic alignment. The question arises whether magnetic alignment might be affected or even compromised by laterality and vice versa. We tested the preference of dogs to choose between two dishes with snacks that were placed left and right, in different compass directions (north and east, east and south, south and west or west and north) in front of them. Some dogs were right-lateral, some left-lateral but most of them were ambilateral. There was a preference for the dish placed north compared to the one placed east of the dog ("pull of the north"). This effect was highly significant in small and medium-sized breeds but not in larger breeds, highly significant in females, in older dogs, in lateralized dogs but less significant or not significant in males, younger dogs, or ambilateral dogs. Laterality and "pull of the north" are phenomena which should be considered in diverse tasks and behavioral tests with which dogs or other animals might be confronted. The interaction and possible conflict between lateralization and "pull of the north" might be also considered as a reason for shifted magnetic alignment observed in different animal species in different contexts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185243PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612717PMC
October 2017

Retroviral host range extension is coupled with Env-activating mutations resulting in receptor-independent entry.

Proc Natl Acad Sci U S A 2017 06 12;114(26):E5148-E5157. Epub 2017 Jun 12.

Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics, The Czech Academy of Sciences, Prague 14220, Czech Republic.

The extent of virus transmission among individuals and species is generally determined by the presence of specific membrane-embedded virus receptors required for virus entry. Interaction of the viral envelope glycoprotein (Env) with a specific cellular receptor is the first and crucial step in determining host specificity. Using a well-established retroviral model-avian Rous sarcoma virus (RSV)-we analyzed changes in an RSV variant that had repeatedly been able to infect rodents. By envelope gene () sequencing, we identified eight mutations that do not match the already described mutations influencing the host range. Two of these mutations-one at the beginning (D32G) of the surface Env subunit (SU) and the other at the end of the fusion peptide region (L378S)-were found to be of critical importance, ensuring transmission to rodent, human, and chicken cells lacking the appropriate receptor. Furthermore, we carried out assays to examine the virus entry mechanism and concluded that these two mutations cause conformational changes in the Env variant and that these changes lead to an activated, or primed, state of Env (normally induced after Env interaction with the receptor). In summary, our results indicate that retroviral host range extension is caused by spontaneous Env activation, which circumvents the need for original cell receptor. This activation is, in turn, caused by mutations in various regions.
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http://dx.doi.org/10.1073/pnas.1704750114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495266PMC
June 2017

Recent Advances in C-C and C-N Bond Forming Reactions Catalysed by Polystyrene-Supported Copper Complexes.

Molecules 2017 May 24;22(6). Epub 2017 May 24.

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic.

This present mini-review covers recently published results on Cu(I) and Cu(II) complexes immobilized on polystyrene carriers, which are used as heterogeneous, eco-friendly reusable catalysts applied for carbon-carbon and carbon-nitrogen forming reactions. Recent advances and trends in this area are demonstrated in the examples of oxidative homocoupling of terminal alkynes, the synthesis of propargylamines, nitroaldolization reactions, azide alkyne cycloaddition, -arylation of nitrogen containing compounds, aza-Michael additions, asymmetric Friedel-Crafts reactions, asymmetric Mukaiyama aldol reactions, and asymmetric 1,3-dipolar cycloaddition of azomethine ylides. The type of polystyrene matrix used for the immobilization of complexes is discussed in this paper, and particularly, the efficiency of the catalysts from the point of view of the overall reaction yield, and possible enantioselectivity and potential reusing, is reviewed.
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http://dx.doi.org/10.3390/molecules22060865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152779PMC
May 2017

Synthesis and characterization of new barium methylphosphonates.

Dalton Trans 2017 Apr;46(16):5363-5372

Institute of Macromolecular Chemistry of Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic.

Eight new barium methylphosphonates were prepared and described. In dependence on pH, either barium hydrogen methylphosphonates or barium methylphosphonates can be formed. In the case of barium methylphosphonates, BaCHPO·3HO crystallizes from the solution at room temperature and BaCHPO·HO at a temperature above 65 °C. On heating, these hydrates form two anhydrous barium methylphosphonates (α-BaCHPO and β-BaCHPO) with the same composition but with a different structure. In a basic environment, barium hydrogen methylphosphonate monohydrate, Ba(CHPOH)·HO, transforms to BaCHPO·3HO through an intermediate with the formula Ba(CHPOH)(CHPO)·4HO. The reverse reaction, that is the reaction of BaCHPO·3HO with methylphosphonic acid, proceeds to the intermediate only and hydrogen methylphosphonate is not formed. Acidic Ba(CHPOH)·HO is able to interact with basic amines and form stable intercalates with them. Structures of β-BaCHPO (P2/c, a = 8.4501(6) Å, b = 7.2555(7) Å, c = 7.4604(8) Å, β = 99.837(8)°, Z = 4) and BaCHPO·HO (P2/c, a = 20.5077(5) Å, b = 7.2175(2) Å, c = 7.4909(3) Å, β = 95.522(3)°, Z = 8) were solved from powder X-ray diffraction data. Both compounds are layered, and the layers are formed of two sheets of Ba atoms connected through oxygen atoms of the phosphonate groups. The methyl groups point towards the interlayer space. In the case of BaCHPO·HO, the molecules of water are coordinated to the Ba atoms and are placed in the interlayer space among the methyl groups.
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http://dx.doi.org/10.1039/c7dt00492cDOI Listing
April 2017

Adult neurogenesis reduction by a cytostatic treatment improves spatial reversal learning in rats.

Neurobiol Learn Mem 2017 May 27;141:93-100. Epub 2017 Mar 27.

Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. Electronic address:

Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hippocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromodeoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60° sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus.
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http://dx.doi.org/10.1016/j.nlm.2017.03.018DOI Listing
May 2017

Transient inactivation of the anterior cingulate cortex in rats disrupts avoidance of a dynamic object.

Neurobiol Learn Mem 2017 Mar 6;139:144-148. Epub 2017 Jan 6.

Department of Neurophysiology of Memory, Institute of Physiology CAS, Prague, Czech Republic. Electronic address:

Although animals often learn and monitor the spatial properties of relevant moving objects such as conspecifics and predators to properly organize their own spatial behavior, the underlying brain substrate has received little attention and hence remains elusive. Because the anterior cingulate cortex (ACC) participates in conflict monitoring and effort-based decision making, and ACC neurons respond to objects in the environment, it may also play a role in the monitoring of moving cues and exerting the appropriate spatial response. We used a robot avoidance task in which a rat had to maintain at least a 25cm distance from a small programmable robot to avoid a foot shock. In successive sessions, we trained ten Long Evans male rats to avoid a fast-moving robot (4cm/s), a stationary robot, and a slow-moving robot (1cm/s). In each condition, the ACC was transiently inactivated by bilateral injections of muscimol in the penultimate session and a control saline injection was given in the last session. Compared to the corresponding saline session, ACC-inactivated rats received more shocks when tested in the fast-moving condition, but not in the stationary or slow robot conditions. Furthermore, ACC-inactivated rats less frequently responded to an approaching robot with appropriate escape responses although their response to shock stimuli remained preserved. Since we observed no effect on slow or stationary robot avoidance, we conclude that the ACC may exert cognitive efforts for monitoring dynamic updating of the position of an object, a role complementary to the dorsal hippocampus.
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http://dx.doi.org/10.1016/j.nlm.2017.01.003DOI Listing
March 2017

Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans.

Psychopharmacology (Berl) 2017 Feb 24;234(4):535-547. Epub 2016 Nov 24.

Department of Neurophysiology of Memory, Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic.

Rationale: Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research.

Objectives: We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols.

Methods: We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats.

Results: Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil.

Conclusions: In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.
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http://dx.doi.org/10.1007/s00213-016-4488-2DOI Listing
February 2017

Validity of Quinpirole Sensitization Rat Model of OCD: Linking Evidence from Animal and Clinical Studies.

Front Behav Neurosci 2016 26;10:209. Epub 2016 Oct 26.

National Institute of Mental Health Klecany, Czech Republic.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with 1-3% prevalence. OCD is characterized by recurrent thoughts (obsessions) and repetitive behaviors (compulsions). The pathophysiology of OCD remains unclear, stressing the importance of pre-clinical studies. The aim of this article is to critically review a proposed animal model of OCD that is characterized by the induction of compulsive checking and behavioral sensitization to the D2/D3 dopamine agonist quinpirole. Changes in this model have been reported at the level of brain structures, neurotransmitter systems and other neurophysiological aspects. In this review, we consider these alterations in relation to the clinical manifestations in OCD, with the aim to discuss and evaluate axes of validity of this model. Our analysis shows that some axes of validity of quinpirole sensitization model (QSM) are strongly supported by clinical findings, such as behavioral phenomenology or roles of brain structures. Evidence on predictive validity is contradictory and ambiguous. It is concluded that this model is useful in the context of searching for the underlying pathophysiological basis of the disorder because of the relatively strong biological similarities with OCD.
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http://dx.doi.org/10.3389/fnbeh.2016.00209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080285PMC
October 2016