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Genomes exhibit large regions with segmental copy number variation, many of which include entire genes and are multiallelic. We have developed a computational method GeneToCN that counts the frequencies of gene-specific k-mers in FASTQ files and uses this information to infer copy number of the gene. We validated the copy number predictions for amylase genes (AMY1, AMY2A, AMY2B) using experimental data from digital droplet PCR (ddPCR) on 39 individuals and observed a strong correlation (R = 0.99) between GeneToCN predictions and experimentally determined copy numbers. An additional validation on FCGR3 genes showed a higher concordance for FCGR3A compared to two other methods, but reduced accuracy for FCGR3B. We further tested the method on three different genomic regions (SMN, NPY4R, and LPA Kringle IV-2 domain). Predicted copy number distributions of these genes in a set of 500 individuals from the Estonian Biobank were in good agreement with the previously published studies. In addition, we investigated the possibility to use GeneToCN on sequencing data generated by different technologies by comparing copy number predictions from Illumina, PacBio, and Oxford Nanopore data of the same sample. Despite the differences in variability of k-mer frequencies, all three sequencing technologies give similar predictions with GeneToCN. [ABSTRACT FROM AUTHOR]

Genomes exhibit large regions with segmental copy number variation, many of which include entire genes and are multiallelic. We have developed a computational method GeneToCN that counts the frequencies of gene-specific k-mers in FASTQ files and uses this information to infer copy number of the gene. We validated the copy number predictions for amylase genes (AMY1, AMY2A, AMY2B) using experimental data from digital droplet PCR (ddPCR) on 39 individuals and observed a strong correlation (R = 0.99) between GeneToCN predictions and experimentally determined copy numbers. An additional validation on FCGR3 genes showed a higher concordance for FCGR3A compared to two other methods, but reduced accuracy for FCGR3B. We further tested the method on three different genomic regions (SMN, NPY4R, and LPA Kringle IV-2 domain). Predicted copy number distributions of these genes in a set of 500 individuals from the Estonian Biobank were in good agreement with the previously published studies. In addition, we investigated the possibility to use GeneToCN on sequencing data generated by different technologies by comparing copy number predictions from Illumina, PacBio, and Oxford Nanopore data of the same sample. Despite the differences in variability of k-mer frequencies, all three sequencing technologies give similar predictions with GeneToCN. [ABSTRACT FROM AUTHOR]

In the present work, construction of double-charged cationic amphiphilic 1,1′-{[3,5-bis(dodecyl¬oxy-carbonyl)-4-(thiophen-3-yl)-1,4-dihydropyridine-2,6-diyl]bis-(methylene)}bis(pyridin-1-ium) dibromide (7) was performed in four steps. Dodecyl 3-oxobutanoate (1) was condensed with thiophene-3-carbaldehyde (2) which was necessary for Hantzsch cyclisation dodecyl (E/Z)-3-oxo-2-(thiophen-3-ylmethylene)butanoate (3). Two-component Hantzsch type cyclisation of dodecyl (E/Z)-3-aminobut-2-enoate (4) and dodecyl (E/Z)-3-oxo-2-(thiophen-3-ylmethylene)butanoate (3) gave 3,5-bis(dodecyloxycarbonyl)-2,6-dimethyl-4-(thiophen-3-yl)-1,4-dihydropyridine (5). Bromination of compound 5 followed by nucleophilic substitution of bromine with pyridine gave the desired cationic amphiphilic 1,4-dihydropyridine 7. The obtained target compound 7 and new intermediates 3, 5 and 6 were fully characterised by IR, UV, 1H NMR, 13C NMR, HRMS or microanalysis. Characterisation of nanoparticles formed by the cationic 1,4-dihydropyridine 7 in an aqueous solution was performed by DLS measurements. [ABSTRACT FROM AUTHOR]

This comparative study looks into the proposed "vaccine passport" initiative from various human rights aspects. It was undertaken by the Global Digital Human Rights Network, an action started under the EU's Cooperation in Science and Technology programme. The network currently unites more than 80 scholars and practitioners from 40 countries. The findings are based on responses to questions put to the network members by the authors of this study in February 2021. [ABSTRACT FROM AUTHOR]

Silicon nitride (Si3N4) in a form of single and multi-layer nanofilms is proposed to be used as a dielectric layer in nanocapacitors for operation in harsh environmental conditions. Characterization of surface morphology, roughness and chemical bonds of the Si3N4 coatings has an important role in production process as the surface morphology affects the contact surface with other components of the produced device. Si3N4 was synthesized by using low pressure chemical vapour deposition method and depositing single and multi-layer (3 - 5 layers) nanofilms on SiO2 and polycrystalline silicon (PolySi). The total thickness of the synthesized nanofilms was 20 - 60 nm. Surface morphology was investigated by means of scanning electron microscopy (SEM) and atomic force microscopy (AFM). Chemical bonds in the layers were identified by means of Fourier transform infrared spectrometry, attenuated total reflection (FTIR-ATR) method. (From the SEM and AFM images it was estimated that both single and multi-layer coatings are deposited homogenously. Si-N breathing and stretching modes are observed in FTIR spectra and the surface morphology is highly dependent on PolySi, therefore suggesting the decrease of the roughness of the bottom electrode for use in the nanocapacitors. [ABSTRACT FROM AUTHOR]

• Response tolerance to the high dose (500 kGy) irradiation in air and water of highly sulfonated SPEEK is demonstrated. • Thermal and mechanical properties for SPEEK with degree of sulfonation up to 70 % remain stable after high dose irradiation compared to nonirradiated SPEEK membranes. • Irradiation in water enhances reduction of molecular arrangement at the DS > 70 % causing membrane dissolution in water. • Improved molecular arrangement due to the physical interaction of sulfonated groups affects mechanical stiffness of SPEEK60-70 membranes after irradiation in water. Sulfonated poly(ether ether ketones) (SPEEK) have raised interest as a replacement of Nafion® proton exchange membranes (PEM) for the application in harsh environments involving material exposure to ionizing radiation, for example, radioactive hydrogen isotope separation from water. This study is dedicated to evaluate the effects of high dose (500 kGy) electron beam irradiation on the physico-chemical and thermomechanical properties of highly sulfonated (degree of sulfonation 60–90 %) SPEEK membranes irradiated in air and water. Spectrometric and thermogravimetric analysis indicated slight changes in the material properties after irradiation with increase of the degree of sulfonation (DS). Tensile tests and thermomechanical analysis of irradiated samples indicated notable deterioration of properties at higher DS values. Results demonstrate that SPEEK membranes with DS around 70 % could be a replacement of the traditional PEM for the applications where exposure to ionizing radiation occurs. [ABSTRACT FROM AUTHOR]

This microreview covers the general methods on the synthesis of mono-, bis-, and tristyrylpyridinium fluorophores described in the literature in recent years. A summary of the most common synthesis can be divided into four distinct methods: aldol condensation followed by N-alkylation of pyridine moiety, Knoevenagel condensation reaction of picolinium salt and aldehyde, Wittig reaction of triphenylphosphine salt and pyridine aldehyde followed by N-alkylation of pyridine moiety, and Horner reaction between bisphosphonate derivative and 4-pyridinecarboxaldehyde followed by N-alkylation of pyridine moiety. Metal-catalyzed reactions were not reviewed. The microreview primary focuses on the synthesis of styrylpyridinium salts having in their structures a 4-pyridinium moiety. [ABSTRACT FROM AUTHOR]

Beryllium pebble behaviour has been studied regarding the accidental operation conditions of tritium breeding blanket of fusion reactors. Structure evolution, oxidation and thermal properties have been compared for nonirradiated and neutron irradiated beryllium pebbles during thermal treatment in a temperature range from ambient temperature to 1600 K. For neutron irradiated pebbles tritium release process was studied. Methods of temperature programmed tritium desorption (TPD) in combination with thermogravimetry (TG) and temperature differential analysis (TDA), scanning electron microscopy (SEM) in combination with Energy Dispersive X-ray analysis (EDX) have been used. It was found that there are strong relation between tritium desorption spectra and structural evolution of neutron irradiated beryllium. The oxidation rate is also accelerated by the structure damages caused by neutrons. [ABSTRACT FROM AUTHOR]

Beryllium oxide nano-structures grown during high temperature oxidation of neutron irradiated beryllium have been investigated. Oxidation of non-irradiated and neutron irradiated (neutron fluence (3 - 4) x 1025 m-2) beryllium was performed in a differential thermal analyzer in an atmosphere of air and its mixture with helium at temperatures up to 1050 °C. Structure of beryllium and its oxide was studied by the means of scanning electron microscopy (SEM). The growth of beryllium oxide nano-structures - "labyrinth type" layers and nano-rods on the inner surfaces of neutron irradiated beryllium was observed by means of SEM. The size of the rods was 10 nm - 100 nm in diameter and up to few micrometers in length. There were no or few BeO nano-rods found on the surfaces of non-irradiated pebbles after similar treatment. This indicates that neutron induced irradiation damages, such as dislocation loops, are responsible for the growth of BeO nano-structures. [ABSTRACT FROM AUTHOR]

• Effects of electron beam radiation on the physico-chemical and mechanical properties of two types of proton exchange membranes - commercial NafionⓇ117 and sulfonated poly(ether-ether-ketone) (SPEEK) with high degree of sulfonation (DS = 0.75±0.5), has been estimated. • The advantages of SPEEK membrane materials for applications in ionizing radiation environments are demonstrated. • The ionising radiation modified NafionⓇ shows reduced thermal and mechanical stability compared toSPEEK membranes. Proton exchange membranes (PEM), which have been commonly used in fuel cells have raised interest for the application in harsh environments involving ionizing radiation. Therefore, radiation stability and ability to sustain their functionality under the radiation environment are of great interest. Within this study, electron beam irradiation in dose range from 50 to 500kGy was used to evaluate the effects of radiation on the physico-chemical and mechanical properties of two types of PEM: commercial Nafion®117 and sulfonated poly(ether-ether-ketone) (SPEEK) with high degree of sulfonation (DS = 0.75±0.5). SPEEK membrane presented higher mechanical and thermal stability compared to that of Nafion® at doses up to 250 kGy, which was evidenced by infrared and electron paramagnetic resonance spectroscopy, thermal analysis, ion chromatography methods. Tensile tests at room temperature and dynamical mechanical analysis of irradiated membranes revealed improved strength, storage modulus at room and elevated temperatures (80°C) for irradiated SPEEK as compared to pristine PEM. For comparison Nafion® exhibited notable deterioration of mechanical properties including elongation at break due to the predominant oxidation and chain scission already at doses exceeding 50 kGy. The study indicated that SPEEK could be perspective replacement of traditional PEM for application in fuel cells exposed to ionising radiation. [ABSTRACT FROM AUTHOR]

Seventeen 1,4-dihydropyridine (1,4-DHP) amphiphiles including differently substituted pyridinium, pyrazinium, N-methyl piperidinium or N-methyl morpholinium moieties as the cationic head-group of the molecule have been designed and synthesised. 1,4-DHP amphiphiles have been earlier proposed as a promising tool for plasmid DNA (pDNA) delivery in vitro. In this work the ability of the 1,4-DHP amphiphiles to self-assemble, to bind pDNA and to transfer it into the cells as well as the cytotoxicity of 1,4-DHP amphiphiles–pDNA complexes was studied. Furthermore, antiradical activity (ARA) of the 1,4-DHP derivatives was determined. We have revealed that all new 1,4-DHP amphiphiles possessed self-assembling properties and formed nanoparticles in an aqueous environment. The structure of the cationic head-group of 1,4-DHP amphiphiles influenced the size of nanoparticles. Additionally, we demonstrated for the first time that the electronic nature of the substituent of the pyridinium as the cationic head-group of the 1,4-DHP amphiphiles strongly affected the ability of these compounds to bind pDNA and transfer it into the cells. The amphiphiles with electron-donating properties possessing substituents at pyridinium moieties were able to bind pDNA and to deliver it more efficiently than amphiphiles containing electron-withdrawing properties possessing substituents at pyridinium moieties. Moreover, in this study we have established that the presence of the cationic part in the molecule was essential for the expression of ARA among tested 1,4-DHP amphiphiles. Cationic 1,4-DHP derivatives containing pyrazinium or N-methyl morpholinium substituents in the cationic head-group of the molecule displayed the highest ARA. [ABSTRACT FROM AUTHOR]

Abstract: Beryllium pebbles are foreseen as a neutron multiplier in the tritium breeding blanket of the future fusion devices. Tritium inventory in the beryllium as a result of neutron-induced transmutations is a significant safety and technological issue for the operation of the breeding blanket. In this study, beryllium pebbles from 3 different irradiation experiments: BERYLLIUM, EXOTIC 8/3-13 and PBA, performed at High Flux Reactor HFR have been investigated. The distribution of tritium in the bulk of the pebbles and the abundance ratios of chemical forms of tritium T0, T+ and T2 have been analysed before and after the different thermo-annealing experiments. In order to determine the abundance ratios of chemical forms, the method of chemical scavengers has been used. The structure analysis has been done by scanning electron microscopy. The main chemical form of the tritium localized in the irradiated beryllium pebbles is T2, especially in the pebbles from PBA experiment. As a result of thermo-annealing, the abundances of the T2 and T0 change, T+ stays unaffected up to relatively high temperatures. The distribution of the tritium in the bulk is uneven – it increases rapidly at the centre of the pebble. Changes of pebble structure as a result of thermal treatment have been observed. [Copyright &y& Elsevier]

The effect of the solvent nature and temperature on the quaternization of 3,5-diethoxycarbonyl-2,6-di- methyl-4-(3-pyridyl)-1,4-dihydropyridine by lipophilic alkyl bromides has been investigated. By comparison of the solvent effect (acetone, acetonitrile, and 2-butanone) on the alkylation of the pyridine fragment of 3,5-diethoxycarbonyl-2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine it was established that conducting the reaction in acetonitrile at 81 °C is the most optimal. [ABSTRACT FROM AUTHOR]

This microreview is devoted to the specific recent synthetic approaches toward 1,4-dihydropyridines which represent significant group of N-containing heterocycles due to the wide applications of their pharmacological activities. Mainly 1,4-dihydropyridines are synthesized in Hantzsch reaction and its modifications. Nowadays a number of strategies and various catalysts or catalytic systems have been developed to improve the yields of 1,4-dihydropyridines and to reduce chemical impact on environment. Here the contemporary synthetic aspects from last five years such as use of ionic liquids, metal oxide nanoparticles and some reports about enzymatic approaches are discussed. [ABSTRACT FROM AUTHOR]

Abstract: A new synthetic approach to cationic pyridine derivatives is described here. Two different strategies for the synthesis of 1,1′-{[3,5-bis(ethoxycarbonyl)-4-phenylpyridine-2,6-diyl]dimethylene}bispyridinium salts have been developed. The key step of the first strategy relies on electrochemical and chemical oxidation of cationic 1,4-dihydropyridines; the second one involves nucleophilic substitution of pyridine dibromo derivatives. [Copyright &y& Elsevier]

Abstract: Monthly and annual means of main anions (SO42-, NO3-, Cl-) and summed base cations (Ca2+, Mg2+, K+, Na+) in bulk precipitation were studied at 10 stations during an 8-year monitoring period. The data showed statistically significant decreasing trends in most cases. Average declines of mean annual volume-weighted concentrations for both anions and cations were about two-fold. Despite the decrease, the loads of S and cations are still relatively high in Estonia (about 4–14kgSha-1 and 0.6–1.2keqha-1, respectively) compared with the loads in Finland and Sweden. Estimated linear decline trends followed the same pattern as annually combusted oil shale from Estonian power plants and emissions of SO2 and fly ash. Recent trends in chemical composition of bulk precipitation at the monitoring stations reflected economic changes in Estonia as well as transboundary fluxes from neighbouring countries. [Copyright &y& Elsevier]

N mineralisation was investigated in the mor humus layer of a podzol at a forested catchment area of Saarejärve Lake in Eastern Estonia. The investigated areas were pine (Rhodococcum understorey) and spruce (Vaccinium understorey) stands, which are permanent sample plots of an integrated monitoring network. The seasonal pattern of net N mineralisation was studied by incubating undisturbed cores of mor humus (0–8 cm) in buried polyethylene bags in situ. Samples were collected and incubated between July 1996 and April 1998. The period of incubation was approximately 1 month, except for wintertime when incubation lasted till thawing of ground (∼5 months). The amounts of mineral nitrogen formed during monthly incubations in vegetation period vary considerably (0.4–8.7 kg ha-1). About 70% of the variation of net ammonification could be explained by environmental factors - temperature, initial moisture and pH. Ammonium was the dominant form of mineral nitrogen, which is typical for mor humus. The rate of nitrification was very low, and most of the annual net nitrification occurred during just one or two months (May–June, October) depending on site and year. Measured annual net N mineralisation was 29.2 kg ha-1 for the spruce stand and 23.6 kg ha-1 for the pine stand. These measures were found to be in good accordance with other N-fluxes in the ecosystem. [ABSTRACT FROM AUTHOR]

Background: In the field of medical and scientific research, radionuclides are used to investigate various physiological and pathological processes. PRISMAP - the European medical radionuclide programme was created to bring together production facilities including intense neutron sources, an isotope mass separation facility, high-power accelerators, biomedical research institutes, and hospitals to support medical research. The aim of this article is to introduce readers with the current status of innovative radionuclides in Europe. Main body: A survey was created targeting the latest trends mainly focused on the demand, the production and the distribution of non-routinely used medical radionuclides for use in research, and for pre-clinical and clinical trials. This survey has been disseminated through the PRISMAP community. 16 of 104 respondents were working in the field of radionuclide production. The data found common aspects from all producer-facility respondents: the biggest challenge for the producers is the availability of target materials, which goes hand-in-hand with their purity/enrichment grade. The results show that there are sufficient national or international distribution routes and methods established, although having reported challenges due to legislation constraints, especially for novel radionuclides. Conclusions: Thanks to a questionnaire distributed by the PRISMAP consortium, the current status in radionuclides production was identified. Understanding the current status of radionuclide production is essential for assessing the continent's capabilities and addressing the burgeoning demands for cutting-edge medical radionuclides. [ABSTRACT FROM AUTHOR]

A synthesis of a cationic moiety and fluorescent moieties containing amphiphilic 1,4-dihydropyridine (1,4-DHP) derivatives was performed starting with the Hantzsch-type cyclization of dodecyl acetoacetate, phenylaldehyde and ammonium acetate. Bromination of the 2,6-dimethyl groups of a parent 1,4-DHP compound, followed by nucleophilic substitution of bromine with 4-(anthracen-9-yl)pyridine, produced the desired 1,1′-{[3,5-bis((dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis[4-(anthracen-9-yl)pyridin-1-ium] dibromide. The obtained target compound was fully characterized by the IR, 1H NMR, 13C NMR and HRMS data. Studies of the self-assembling properties and characterization of the nanoparticles obtained by the ethanol injection method were performed using dynamic light scattering (DLS) measurements. DLS measurement data showed that 1,1′-{[3,5-bis((dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis[4-(anthracen-9-yl)pyridin-1-ium] dibromide produced liposomes that had average diameters of 200 nm when the samples were freshly prepared, and 140 nm after 7 days or 1 month storage. The PDI values of the samples were approximately 0.50 and their zeta-potential values were approximately 41 mV when the samples were freshly prepared, and 33 mV after storage. The obtained nanoparticles were stored at room temperature for one month and remained stable during that period. The mean molecular area of the cationic 1,4-DHP-anthracene hybrid 4 was 118 Å2, while the mean molecular area of the cationic 1,4-DHP 5 without anthracene substituents was only 83 Å2. The photoluminescence quantum yield (PLQY) value for the EtOH solution of the 1,4-DHP derivative 4 was 10.8%, but for the 1,4-DHP derivative 5 it was only 1.8%. These types of compounds could be used as synthetic lipids in the further development of prospective theranostic delivery systems. [ABSTRACT FROM AUTHOR]

Tritium accumulation in fusion reactor materials is considered a serious radiological issue, therefore a lot of effort has been concentrated on the development of radiometric techniques. A novel method, based on gradual dissolution, for the determination of the total tritium content and its depth profiles in metallic samples is demonstrated. This method allows for the measurement of tritium in metallic samples after their exposure to a hydrogen and tritium mixture, tritium containing plasma or after irradiation with neutrons resulting in tritium formation. In this method, successive layers of metal are removed using an appropriate etching agent in the controlled regime and the amount of evolved gases are measured by means of chromatography (gas composition and release rate) and a proportional gas flow detector (tritium). Results for the tritium profiles in neutron irradiated, plasma exposed and gas loaded beryllium are reported. [ABSTRACT FROM AUTHOR]

Background: In order to support the ongoing research across Europe to facilitate access to novel radionuclides, the PRISMAP consortium (European medical radionuclides programme) was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research. The aim of this article is to introduce readers with current status of novel radionuclides in Europe. Main body: A consortium questionnaire was disseminated through the PRISMAP consortium and user community, professional associations and preclinical/clinical end users in Europe and the current status of clinical end-users in nuclear medicine were identified. A total of 40 preclinical/clinical users institutions took part in the survey. Clinical end users currently use the following radionuclides in their studies: 177Lu, 68 Ga, 111In, 90Y, other alpha emitters, 225Ac, 64Cu and Terbium isotopes. Radionuclides that would be of interest for users within the next 2–5 years are 64Cu, Terbium radionuclide "family" and alpha emitters, such as 225Ac. Conclusions: Thanks to a questionnaire distributed by the PRISMAP consortium, the current status and needs of clinical end-users in nuclear medicine were identified. [ABSTRACT FROM AUTHOR]

Sulfonated poly(ether ether ketone) (SPEEK) materials are promising candidates for replacing Nafion™ in applications such as proton exchange membrane (PEM) and direct methanol fuel cells. SPEEK membranes have several advantages such as low cost, thermal and radiation stability and controllable physicochemical and mechanical properties, which depend on the degree of sulfonation (DS). Commercial PEEK was homogenously sulfonated up to a DS of 60–90% and the membranes were prepared using a solvent casting method. Part of the samples were irradiated with a 10 MeV electron beam up to a 500 kGy dose to assess the ionizing radiation-induced effects. Both non-irradiated and irradiated membranes were characterized by Fourier Transformation infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), proton nuclear magnetic resonance (1H-NMR) spectroscopy, electrochemical impedance analysis and, for the first time for non-irradiated membranes, by spectrophotometric analysis with Cr(III). The above-mentioned methods for application for DS assessment were compared. The aim of this study is to compare different methods used for the determination of the DS of SPEEK membranes before and after high-dose irradiation. It was observed that irradiated membranes presented a higher value of DS. The appearance of different new signals in 1H-NMR and FT-IR spectra of irradiated membranes indicated that the effects of radiation induced changes in the structure of SPEEK materials. The good correlation of Cr(III) absorption and SPEEK DS up to 80% indicates that the spectrophotometric method is a comparable tool for the characterization of SPEEK membranes. [ABSTRACT FROM AUTHOR]

A set of styrylpyridinium (SP) compounds was synthesised in order to study their spectroscopic and cell labelling properties. The compounds comprised different electron donating parts (julolidine, p-dimethylaminophenyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl), conjugated linkers (vinyl, divinyl), and an electron-withdrawing N-alkylpyridinium part. Geminal or bis-compounds incorporating two styrylpyridinium (bis-SP) moieties at the 1,3-trimethylene unit were synthesised. Compounds comprising a divinyl linker and powerful electron-donating julolidine donor parts possessed intensive fluorescence in the near-infrared region (maximum at ~760 nm). The compounds had rather high cytotoxicity towards the cancerous cell lines HT-1080 and MH-22A; at the same time, basal cytotoxicity towards the NIH3T3 fibroblast cell line ranged from toxic to harmful. SP compound 6e had IC50 values of 1.0 ± 0.03 µg/mL to the cell line HT-1080 and 0.4 µg/mL to MH-22A; however, the basal toxicity LD50 was 477 mg/kg (harmful). The compounds showed large Stokes' shifts, including 195 nm for 6a,b, 240 nm for 6e, and 325 and 352 nm for 6d and 6c, respectively. The highest photoluminescence quantum yield (PLQY) values were observed for 6a,b, which were 15.1 and 12.2%, respectively. The PLQY values for the SP derivatives 6d,e (those with a julolidinyl moiety) were 0.5 and 0.7%, respectively. Cell staining with compound 6e revealed a strong fluorescent signal localised in the cell cytoplasm, whereas the cell nuclei were not stained. SP compound 6e possessed self-assembling properties and formed liposomes with an average diameter of 118 nm. The obtained novel data on near-infrared fluorescent probes could be useful for the development of biocompatible dyes for biomedical applications. [ABSTRACT FROM AUTHOR]

Liposomes and other nanoparticles have been widely studied as innovative nanomaterials because of their unique properties. Pyridinium salts, on the basis of 1,4-dihydropyridine (1,4-DHP) core, have gained significant attention due to their self-assembling properties and DNA delivery activity. This study aimed to synthesize and characterize original N-benzyl substituted 1,4-dihydropyridines and evaluate the influence on structure modifications on compound physicochemical and self-assembling properties. Studies of monolayers composed of 1,4-DHP amphiphiles revealed that the mean molecular areas values were dependent on the compound structure. Therefore, the introduction of N-benzyl substituent to the 1,4-DHP ring enlarged the mean molecular area by almost half. All nanoparticle samples obtained by ethanol injection method possessed positive surface charge and average diameter of 395–2570 nm. The structure of the cationic head-group affects the size of the formed nanoparticles. The diameter of lipoplexes formed by 1,4-DHP amphiphiles and mRNA at nitrogen/phosphate (N/P) charge ratios of 1, 2, and 5 were in the range of 139–2959 nm and were related to the structure of compound and N/P charge ratio. The preliminary results indicated that more prospective combination are the lipoplexes formed by pyridinium moieties containing N-unsubstituted 1,4-DHP amphiphile 1 and pyridinium or substituted pyridinium moieties containing N-benzyl 1,4-DHP amphiphiles 5a–c at N/P charge ratio of 5, which would be good candidates for potential application in gene therapy. [ABSTRACT FROM AUTHOR]

Abstract: In this study the tritium distribution and the effect of structural changes thereon have been analyzed in the bulk of the tile selected from the JET Mark II SRP divertor. Tritium content has been analyzed by the full combustion technique . The structure has been investigated by the method of Scanning Electron Microscopy. Tritium depth profiles have been measured at different poloidal positions. A high specific activity of tritium (up to 156MBqg−1) was found at the plasma-facing surface. At some tile positions up to 98–99% of the T can be in the surface slice of 1mm thickness, whereas in other poloidal positions there can be more T in the bulk than at the surface. The structural changes of the tile material both at the surfaces and in the bulk have been measured. [Copyright &y& Elsevier]

The design of nanoparticle delivery materials possessing biological activities is an attractive strategy for the development of various therapies. In this study, 11 cationic amphiphilic 4-(N-alkylpyridinium)-1,4-dihydropyridine (1,4-DHP) derivatives differing in alkyl chain length and propargyl moiety/ties number and position were selected for the study of their self-assembling properties, evaluation of their cytotoxicity in vitro and toxicity on microorganisms, and the characterisation of their interaction with phospholipids. These lipid-like 1,4-DHPs have been earlier proposed as promising nanocarriers for DNA delivery. We have revealed that the mean diameter of freshly prepared nanoparticles varied from 58 to 513 nm, depending upon the 4-(N-alkylpyridinium)-1,4-DHP structure. Additionally, we have confirmed that only nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3 and 6, and by 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 were stable after two weeks of storage. The nanoparticles of these compounds were found to be homogenous in size distribution, ranging from 124 to 221 nm. The polydispersity index (PDI) values of 1,4-DHPs samples 3, 6, 10, and 11 were in the range of 0.10 to 0.37. We also demonstrated that the nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3, 6, and 9, and 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 had zeta-potentials from +26.07 mV (compound 6) to +62.80 mV (compound 11), indicating a strongly positive surface charge and confirming the relative electrostatic stability of these nanoparticle solutions. Transmission electron microscopy (TEM) images of nanoaggregates formed by 1,4-DHPs 3 and 11 confirmed liposome-like structures with diameters around 70 to 170 nm. The critical aggregation concentration (CAC) value interval for 4-(N-alkylpyridinium)-1,4-DHP was from 7.6 µM (compound 11) to 43.3 µM (compound 6). The tested 4-(N-alkylpyridinium)-1,4-DHP derivatives were able to quench the fluorescence of the binary 1,6-diphenyl-1,3,5-hexatriene (DPH)—1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) system, demonstrating hydrophobic interactions of 1,4-DHPs with phospholipids. Thus, 4-(N-dodecylpyridinium)-1,4-DHP derivative 3 quenched the fluorescence of the DPH–DPPC system more efficiently than the other 4-(N-alkylpyridinium)-1,4-DHP derivatives. Likewise the compound 3, also 4-(N-dodecylpyridinium)-1,4-DHP derivative 9 interacted with the phospholipids. Moreover, we have established that increasing the length of the alkyl chain at the quaternised nitrogen of the 4-(N-alkylpyridinium)-1,4-DHP molecule or the introduction of propargyl moieties in the 1,4-DHP molecule significantly influences the cytotoxicity on HT-1080 (human fibrosarcoma) and MH-22A (mouse hepatocarcinoma) cell lines, as well as the estimated basal cytotoxicity. Additionally, it was demonstrated that the toxicity of the 4-(N-alkylpyridinium)-1,4-DHP derivatives on the Gram-positive and Gram-negative bacteria species and eukaryotic microorganism depended on the presence of the alkyl chain length at the N-alkyl pyridinium moiety, as well as the number of propargyl groups. These lipid-like compounds may be proposed for the further development of drug formulations to be used in cancer treatment. [ABSTRACT FROM AUTHOR]

[Figure not available: see fulltext.] This work demonstrates studies of ferromagnetic nanoparticle functionalization by a lipid-like compound, cationic pyridine amphiphile derived from 1,4-dihydropyridine, 1,1'-{[3,5-bis(dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]dimethanediyl}dipyridinium dibromide, and determination of optimal conditions for the production of magnetoliposomes. The following methodologies, such as sonication, spontaneous swelling, and reverse-phase evaporation, were used for the preparation of liposomes. Ferrofluid containing γ-FeO nanoparticles with a positively charged surface was used for the preparation of magnetoliposomes. The obtained soft matter objects were studied by optical microscopy, transmission electron microscopy, and dynamic light scattering techniques. The optimal conditions for the production of magnetoliposomes were found by spontaneous swelling and reverse-phase evaporation methods using ferrofluid with positively charged γ-FeO nanoparticles and cationic 1,4-dihydropyridine derivative. [ABSTRACT FROM AUTHOR]

A synthesis of 3-(3,5-difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodides with ethyl or nonyl ester groups at positions 3 and 5 was performed. Treatment of the corresponding 2',6'-dimethyl-1',4'-dihydro-[3,4'-bipyridine]-3',5'-dicarboxylates with Selectfluor® followed by quaternization of pyridine moiety in the obtained dialkyl 2,4-diacetyl-2,4-difluoro-3-(pyridin-3-yl)pentanedioates with methyl iodide gave the desired 3-(3,5-difluoro-3,5-bis((alkoxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodides. This type of compound would be useful as synthetic lipids for further development of the delivery systems. The obtained target compounds were fully characterized by 1H NMR, 19F NMR, 13C NMR, HRMS, IR and UV data. The estimation of self-assembling properties and characterization of the nanoparticles obtained by ethanol solution injection in an aqueous media were performed by dynamic light scattering (DLS) measurements. DLS measurement data showed that 3-(3,5-difluoro-3,5-bis((nonyloxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodide created liposomes with the average diameter of 300–400 nm and polydispersity index (PDI) value around 0.30–0.40, while 3-(3,5-difluoro-3,5-bis((ethyloxy)carbonyl)-2,6-dioxoheptan-4-yl)-1-methylpyridin-1-ium iodide formed a heterogeneous sample with PDI value 1, which was not prospective for delivery system development. [ABSTRACT FROM AUTHOR]

Synthesis of a double-charged cationic amphiphilic 1,4-dihydropyridine derivative with dodecyl ester groups at positions 3 and 5 of the 1,4-DHP ring was performed starting from Hantzsch type cyclization of dodecyl acetoacetate, 2-naphthaldehyde and ammonium acetate. Bromination of this compound followed by nucleophilic substitution of bromine with (E)-4-(2-(naphthalen-2-yl)vinyl)pyridine gave the desired cationic amphiphilic 1,1′-{[3,5-bis(dodecyloxycarbonyl)-4-(naphthalen-2-yl)-1,4-dihydropyridine-2,6-diyl]bis(methylene)}bis{4-[(E)-2-(naphthalen-2-yl)vinyl]pyridin-1-ium}dibromide. The obtained target compound was fully characterized by IR, UV, 1H-NMR, 13C-NMR, HRMS and microanalysis. The characterization of the cationic 1,4-DHP nanoparticles in an aqueous solution was performed by DLS measurements. The obtained results showed that the compound formed nanoparticles with an average diameter of around 300 nm, a PDI value of around 490 and a zeta-potential of around 20 mV for freshly prepared samples. However, after one week of storage at room temperature, an aggregation of nanoparticles was detected. [ABSTRACT FROM AUTHOR]

Scandium (Sc) has gained significant interest in nuclear medicine due to its 43Sc, 44g/mSc, and 47Sc radioactive isotopes being suitable for cancer diagnostics and therapy, offering a promising avenue for theranostics. Various production methods, including irradiation of enriched or naturally abundant calcium (Ca), titanium (Ti), and vanadium (V) materials with different particle beams, have been investigated to produce 43Sc, 44g/mSc, and 47Sc. However, challenges persist in achieving high molar activity and radiochemical purity for medical applications. The physical isotope mass separation technique presents an alternative, obviating the need for enriched target materials by inherently isolating Sc isotopes during the separation process. Despite recent advancements in Sc mass separation at different facilities, efficiency and yield remain sub-optimal for medical dose production. This study aims to systematically investigate the thermal release kinetics of Sc radionuclides from activated natural titanium foils in tantalum (Ta) environments of ISOL (Isotope Separation On-Line) target units. By elucidating the combination of target material structure and temperature conditions, enhanced release parameters were identified. Maximum Sc release from a non-embossed n a t Ti foil samples was achieved at 1200 °C, for embossed n a t Ti foil samples at 1450 °C and for n a t V foil samples at 1600 °C, within an hour of reaching the set temperature. These findings offer insights into optimizing the mass separation process to improve the efficiency in Sc radionuclide production for medical applications. [ABSTRACT FROM AUTHOR]

Capsid assembly modulators (CAMs) have emerged as a promising class of antiviral agents. We studied the effects of twenty-one newly designed and synthesized CAMs including heteroaryldihydropyrimidine compounds (HAPs), their analogs and standard compounds on hepatitis B virus (HBV) capsid assembly. Cytoplasmic expression of the HBV core (HBc) gene driven by the exogenously delivered recombinant alphavirus RNA replicon was used for high level production of the full-length HBc protein in mammalian cells. HBV capsid assembly was assessed by native agarose gel immunoblot analysis, electron microscopy and inhibition of virion secretion in HepG2.2.15 HBV producing cell line. Induced fit docking simulation was applied for modelling the structural relationships of the synthesized compounds and HBc. The most efficient were the HAP class compounds—dihydropyrimidine 5-carboxylic acid n-alkoxyalkyl esters, which induced the formation of incorrectly assembled capsid products and their accumulation within the cells. HBc product accumulation in the cells was not detected with the reference HAP compound Bay 41-4109, suggesting different modes of action. A significant antiviral effect and substantially reduced toxicity were revealed for two of the synthesized compounds. Two new HAP compounds revealed a significant antiviral effect and a favorable toxicity profile that allows these compounds to be considered promising leads and drug candidates for the treatment of HBV infection. The established alphavirus based HBc expression approach allows for the specific selection of capsid assembly modulators directly in the natural cell environment. [ABSTRACT FROM AUTHOR]

Abstract: The novel 1,4-dihydropyridine derivatives containing the cationic pyridine moiety at the position 4, and the N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle were designed, synthesised, and assessed in biological tests. Among all the novel compounds, the 4-(N-dodecyl) pyridinium group-containing compounds 11 (without the N-propargyl group) and 12 (with the N-propargyl group) demonstrated the highest calcium antagonistic properties against neuroblastoma SH-SY5Y (IC50 about 5–14μM) and the vascular smooth muscle A7r5 cell (IC50 – 0.6–0.7μM) lines, indicating that they predominantly target the L-type calcium channels. These compounds showed a slight total antioxidant activity. At concentrations close to those of L-type calcium channel blocking ones, compound 12 did not affect mitochondrial functioning; also, no toxicity was obtained in vivo. The N-propargyl group as a substituent at position 1 of the 1,4-DHP cycle did not essentially influence the compounds’ activity. The 4-(N-dodecyl) pyridinium moiety-containing compounds can be considered as prototype molecules for further chemical modifications and studies as cardioprotective/neuroprotective agents. [Copyright &y& Elsevier]

This study was focused on the estimation of the targeted modification of 1,4-DHP core with (1) different alkyl chain lengths at 3,5-ester moieties of 1,4-DHP (C12, C14 and C16); (2) N-substituent at position 1 of 1,4-DHP (N-H or N-CH3); (3) substituents of pyridinium moieties at positions 2 and 6 of 1,4-DHP (H, 4-CN and 3-Ph); (4) substituent at position 4 of 1,4-DHP (phenyl and napthyl) on physicochemical properties of the entire molecules and on the characteristics of the obtained magnetoliposomes formed by them. It was shown that thermal behavior of the tested 1,4-DHP amphiphiles was related to the alkyl chains length, the elongation of which decreased their transition temperatures. The properties of 1,4-DHP amphiphile monolayers and their polar head areas were determined. The packing parameters of amphiphiles were in the 0.43–0.55 range. It was demonstrated that the structure of 1,4-DHPs affected the physicochemical properties of compounds. "Empty" liposomes and magnetoliposomes were prepared from selected 1,4-DHP amphiphiles. It was shown that the variation of alkyl chains length or the change of substituents at positions 4 of 1,4-DHP did not show a significant influence on properties of liposomes. [ABSTRACT FROM AUTHOR]

Single-layered and multi-layered 20–60 nm thick silicon nitride (Si 3 N 4) dielectric nanofilms were fabricated using a low-pressure chemical vapour deposition (LPCVD) method. The X-ray photoelectron spectroscopy (XPS) confirmed less oxygen content in the multi-layered nanofilms. The capacitors with Si 3 N 4 multilayer demonstrated a tendency to a higher breakdown voltage compared to the capacitors with Si 3 N 4 single layer. Si 3 N 4 nanofilms and capacitors with Si 3 N 4 dielectric were exposed to 1 kGy dose of gamma photons. Fourier transform infrared (FTIR) spectroscopy analysis showed that no modifications of the chemical bonds of Si 3 N 4 were present after irradiation. Also, gamma irradiation did not influence the breakdown voltage of the capacitors but decreased their capacitance measured at 1 MHz frequency. However, the multi-layered capacitors were not affected by radiation more than the single-layered capacitors. These findings suggest a promising process to fabricate nano-scaled multi-layered Si 3 N 4 capacitors with improved breakdown voltage characteristics and resistance to ionizing radiation. [ABSTRACT FROM AUTHOR]

Background: Recently, alignment-free sequence analysis methods have gained popularity in the field of personal genomics. These methods are based on counting frequencies of short k-mer sequences, thus allowing faster and more robust analysis compared to traditional alignment-based methods. Results: We have created a fast alignment-free method, AluMine, to analyze polymorphic insertions of Alu elements in the human genome. We tested the method on 2,241 individuals from the Estonian Genome Project and identified 28,962 potential polymorphic Alu element insertions. Each tested individual had on average 1,574 Alu element insertions that were different from those in the reference genome. In addition, we propose an alignment-free genotyping method that uses the frequency of insertion/deletion-specific 32-mer pairs to call the genotype directly from raw sequencing reads. Using this method, the concordance between the predicted and experimentally observed genotypes was 98.7%. The running time of the discovery pipeline is approximately 2 h per individual. The genotyping of potential polymorphic insertions takes between 0.4 and 4 h per individual, depending on the hardware configuration. Conclusions: AluMine provides tools that allow discovery of novel Alu element insertions and/or genotyping of known Alu element insertions from personal genomes within few hours. [ABSTRACT FROM AUTHOR]

• JET-C divertor samples from 200 to 2009 and JET-ILW 2010–2012 are compared. • JET-C sample had >20 times higher concentration of tritium than JET-ILW sample. • FTIR signals of EP in the 400–1000 cm−1 range could be due to the metal-oxygen bonds. • In Raman spectra of EP an increased luminescence background occurs. • In the ESR spectra of EP a signals with g = 2.002 and 2.12 are observed and analysed. One of main reasons of the Joint European torus (JET) transformation from the carbon (JET-C) to ITER-like (JET-ILW) wall was high tritium retention of carbon. In order to compare the tritium retention, samples of analogous positions of the plasma-facing side of vertical tiles No. 3 of two campaigns: JET-C (2008–2009) and JET-ILW (2011–2012) were cut out. Temperature-programmed tritium desorption spectrometry in He + 0.1% H 2 gas flow showed that JET-C sample without a tungsten coating had by a factor of >20 higher surface concentration of tritium than JET-ILW tungsten-coated sample: 4.9 × 1013 and 1.7–2.2 × 1012 T atoms/cm2 respectively. Installation of metallic plasma facing wall in the JET was a unique possibility to collect from the vacuum vessel the first wall erosion products (EP) – dust and flakes. Selected EP were investigated by means of energy dispersion X-ray (EDX), electron spin resonance (ESR), infrared and Raman spectrometry. EDX analysis shows presence of metallic impurities and carbon as a main component. Investigations with ESR spectrometry allows to estimate presence of two main paramagnetic centres – g = 2.002 and g = 2.12. Infrared spectra show presence of inorganic oxides. The obtained results supplement the information about composition of the EP from fusion devices. [ABSTRACT FROM AUTHOR]

New amphiphilic 1,4-DHP derivative C12-Man-Q with remoted cationic moieties at positions 2 and 6 was synthesised to study DNA delivery activity. The results were compared with data obtained for cationic 1,4-DHP derivative D19, which is known to be the most efficient one among the previously tested 1,4-DHP amphiphiles. We analysed the effects of C12-Man-Q concentration, complexation media, and complex/cell contact time on the gene delivery effectiveness and cell viability. Transmission electron microscopy data confirms that lipoplexes formed by the compound C12-Man-Q were quite uniform, vesicular-like structures with sizes of about 50 nm, and lipoplexes produced by compound D19 were of irregular shapes, varied in size in the range of 25–80 nm. Additionally, confocal microscopy results revealed that both amphiphiles effectively delivered green fluorescent protein expression plasmid into BHK-21 cells and produced a fluorescent signal with satisfactory efficiency, although compound C12-Man-Q was more cytotoxic to the BHK-21 cells with an increase of concentration. It can be concluded that optimal conditions for C12-Man-Q lipoplexes delivery in BHK-21 cells were the serum free media without 0.15 M NaCl, at an N/P ratio of 0.9. Compound D19 showed higher transfection efficiency to transfect BHK-21 and Cos-7 cell lines, when transfecting active proliferating cells. Although D19 was not able to transfect all studied cell lines we propose that it could be cell type specific. The compound C12-Man-Q showed modest delivery activity in all used cell lines, and higher activity was obtained in the case of H2-35 and B16 cells. The transfection efficiency in cell lines MCF-7, HeLa, and Huh-7 appears to be comparable to the reference compound D19 and minimal in the HepG2 cell line. [ABSTRACT FROM AUTHOR]

The synthesis of multisubstituted 4-nitrobuta-1,3-dien-1-amines (nitrodienamines) from 3-aminocrotonates and nitroacetaldehyde potassium salt, has been performed in 45–89% yields. This one-step protocol works efficiently with a broad range of N-H and N-substituted 3-aminocrotonates and delivers both primary and secondary nitrodienamines. In addition, the possible variations of the substituents at the positions 2 and 3 of 4-nitrobuta-1,3-dien-1-amine have been shown. Generally, the yields of secondary 4-nitrobuta-1,3-dien-1-amines were lower than those of primary ones. The synthetic usefulness of obtained 4-nitrobuta-1,3-dien-1-amines has also been demonstrated by achieving the synthesis of multisubstituted 5-nitro-1,6-dihydropyridines in two-component cyclocondensation reactions of 4-nitrobuta-1,3-dien-1-amines with aromatic or aliphatic aldehydes. Lastly, diverse N-H and N-substituted 5-nitro-1,6-dihydropyridines have been obtained in 35–87% yields. [ABSTRACT FROM AUTHOR]

The use of 1,4-dihydropyridine (DHP) vesicles as drug delivery agents can improve the diffusion of nucleoside and nucleotide prodrugs through the cellular membrane without degradation. Different NMR studies: spin–lattice relaxation in the rotating frame (T1ρ), saturation transfer double difference (STDD), 1H NMR chemical shift titration, as well as isothermal titration calorimetry (ITC) experiments, showed that mononucleotides bind to 1,4-DHP vesicles. The influence of the structure of the mononucleotides as well as that of the derivatives of 1,4-DHP on the complexation parameters was studied. [ABSTRACT FROM AUTHOR]

Modified lithium orthosilicate (Li 4 SiO 4 ) pebbles with additions of titanium dioxide (TiO 2 ) are suggested as an alternative tritium breeding ceramic for the European solid breeder test blanket module. The noble metals – platinum (Pt), gold (Au) and rhodium (Rh), can be introduced into the modified Li 4 SiO 4 pebbles during the melt-based process, due to the corrosion of Pt-Rh and Pt-Au alloy crucible components. In this study, the surface microstructure, chemical and phase composition of the modified Li 4 SiO 4 pebbles with different contents of the noble metals was analysed. The influence of the noble metals on the radiolysis was evaluated after irradiation with accelerated electrons (E = 5 MeV), up to 12 MGy absorbed dose at 300–345 K in a dry argon atmosphere. Using electron spin resonance (ESR) spectroscopy, it was determined that the noble metals (up to 300 ppm) do not significantly influence the formation and accumulation of radiation-induced defects (RD) in the modified Li 4 SiO 4 pebbles. [ABSTRACT FROM AUTHOR]

The prevalence of Alzheimer’s disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD. [ABSTRACT FROM AUTHOR]

The ethoxycarbonylmethyl esters of 1,4-dihydropyridines were directly converted into carbamoylmethyl esters in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) in good to excellent yields under mild conditions. The use of TBD is crucial for the successful aminolysis of ethoxycarbonylmethyl ester of 1,4-dihydropyridines with secondary amines as without it the reaction does not proceed at all. The aminolysis reaction proceeded regioselectively, as the alkyl ester conjugated with the 1,4-dihydropyridine cycle was not involved in the reaction. Screening of other N-containing bases, such as triethylamine (TEA), pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, tetramethyl guanidine (TMG) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) as catalysts revealed no activity in the studied reaction. [ABSTRACT FROM AUTHOR]

New amphiphilic pyridine derivatives containing dodecyloxycarbonyl substituents at positions 3 and 5 and cationic moieties at positions 2 and 6 have been designed and synthesised. Compounds of this type can be considered as synthetic lipids. The corresponding 1,4-dihydropyridine (1,4-DHP) derivatives have earlier been proposed as a promising tool for plasmid DNA (pDNA) delivery in vitro. In this work studies of the self-assembling properties of amphiphilic pyridine derivatives leading to the formation of liposomes, determination of particle size, zeta-potential and critical micelle concentration (CMC) with dynamic light scattering (DLS) measurements are described. Furthermore, thermal analysis of pyridine derivatives was performed using thermogravimetry analysis (TGA) and differential thermal analysis (DTA) as well as the ability to deliver the pEGFP-C1 plasmid DNA (that encodes GFP reporter) into the Baby hamster kidney-derived (BHK-21) cell line was used for evaluation of gene delivery properties. We have revealed that the new pyridine derivatives possessed self-assembling properties which were proved by formation of nanoparticles with the average size from 115 to 743 nm, the zeta-potentials in the range of 48–79 mV and CMC values in the range of 2–67 μM. DTA data showed that all processes were endothermic for all compounds. Additionally, we established that among the tested pyridines the representatives with N -methylpyrrolidinium or pyridinium moieties as cationic head-group at the positions 2 and 6 possessed higher pEGFP-C1 transfection activity into the BHK-21 cell line. Nevertheless, the obtained results indicated that correlation of the physicochemical, structural properties and gene delivery activities of the tested compounds were not completely elucidated yet. On the other hand, the synthesised pyridines as possible metabolites of promising delivery systems on the 1,4-DHP core possessed lower pDNA transfection activity than the corresponding 1,4-DHP amphiphiles. [ABSTRACT FROM AUTHOR]

Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer’s disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4-dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer’s disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability of AP-12 to cross the BBB, improve spatial learning and memory in both mice strains, induce anxiolytic action in transgenic mice, and increase expression of hippocampal and cortical proteins (GAD67, Homer-1) related to synaptic plasticity. The compound AP-12 can be seen as a prototype molecule for use in the design of novel drugs useful to halt progression of clinical symptoms (more specifically, anxiety and decline in memory) of neurodegenerative diseases, particularly Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

New bispyridinium dibromides based on the 1,4-dihydropyridine (1,4-DHP) cycle were synthesised in the reaction between 4-pyridyl-1,4-DHP derivatives and propargyl bromide. It has been shown that variation of the substituent position on the pyridine as well as small changes in the electronic nature of the 1,4-DHP cycle as a result of the substituent nature at the 3 and 5 positions do not affect the course of the reaction and in all cases the corresponding bispyridinium dibromides 4a-e were formed. The antiradical activity, using 1,1-diphenyl-2-picrylhydrazine as a free radical scavenger, and the reducing capacity using phosphomolybdenum complexes have been evaluated for the newly synthesised compounds 4a-e. It has been shown that all tested 1,4-DHP bispyridinium dibromides 4a-e possess reducing capacity and antiradical properties. Moreover, the reducing capacity results could be explained by the influence of the electronic nature of the substituent at the 3 and 5 positions of the 1,4-DHP cycle. [ABSTRACT FROM AUTHOR]

Novel pyridinium salts based on 4-(3-pyridyl)-3,5-dipropargylcarbonyl-1,4-dihydropyridine were obtained by quaternization of pyridine moiety with different alkyl halides. The reducing capacity of the synthesized compounds was evaluated using the phosphomolybdenum complex method. The obtained results confirmed that all tested compounds possessed reducing capacity. Ca channel antagonist and agonist activities of the compounds were additionaly assayed by changes in intracellular Ca ion concentration in H9C2 and A7R5 cell lines. The obtained data confirmed that all synthesized 1,4-dihydropyridine derivatives have smooth muscle selective antagonist activities, and in the case of 4-phenyl derivative the activity was 4.7 times higher than that of amlodipine. [ABSTRACT FROM AUTHOR]

Methylene bridged polycyclic diazocines 2a and 2b were obtained in reactions of 1,3-indanedione, or benzo[b]thiophen-3(2H)one-1,1-dioxide, or 2,2'-methylene derivatives 3a,b with paraformaldehyde and ammonia or hexamethylenetetramine in acidic medium. A structural revision of methylene bridged benzothieno-diazocine 2b based on results of X-ray diffraction analysis is presented. Internal rearrangement of methylene bridged polycyclic diazocines into spiroheterocycles 4a,b is also described. [ABSTRACT FROM AUTHOR]