Репозиторий Университета

© 2019 Elsevier Ltd Oxysterols are derivatives of cholesterol and biologically active molecules that are involved in a number of functions, including cholesterol homeostasis, immune response, embryogenic development and pathophysiology of neurodegenerative diseases. Enzymes catalyzing their synthesis and metabolism are of particular interest as potential or evaluated drug targets. Here we report for the first time biochemical analysis of purified human oxysterol 7α-hydroxylase selective for 24-hydroxycholesterol. Binding analyses indicated a tight binding of the oxysterols and estrone. Ligand screening revealed that CYP39A1 binds with high affinity antifungal drugs and prostate cancer drug galeterone (TOK-001). Site-directed mutagenesis of conserved Asn residue in the active site revealed its crucial role for protein folding and heme incorporation. Developed protocol for expression and purification enables further investigation of this hepatic enzyme as off-target in development of specific drugs targeting cytochrome P450 enzymes.

© 2019 WILEY-VCH Verlag GmbH  &  Co. KGaA, Weinheim Polydimethylsiloxane (PDMS) is a long-standing material of significant interest in microfluidics due to its unique features. As such, rapid prototyping of PDMS-based microchannels is of great interest. The most prevalent and conventional method for fabrication of PDMS-based microchips relies on softlithography, the main drawback of which is the preparation of a master mold, which is costly and time-consuming. To prevent the attachment of PDMS to the master mold, silanization is necessary, which can be detrimental for cellular studies. Additionally, using coating the mold with a cell-compatible surfactant adds extra preprocessing time. Recent advances in 3D printing have shown great promise in expediting microfabrication. Nevertheless, current 3D printing techniques are sub-optimal for PDMS softlithography. The feasibility of producing master molds suitable for rapid softlithography is demonstrated using a newly developed 3D-printing resin. Moreover, the utility of this technique is showcased for a number of widely used applications, such as concentration gradient generation, particle separation, cell culture (to show biocompatibility of the process), and fluid mixing. This can open new opportunities for biologists and scientists with minimum knowledge of microfabrication to build functional microfluidic devices for their basic and applied research.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. WWP2 is an E3 ubiquitin ligase that differentially regulates the contextual tumour suppressor/progressor TGFβ signalling pathway by alternate isoform expression. WWP2 isoforms select signal transducer Smad2/3 or inhibitor Smad7 substrates for degradation through different compositions of protein-protein interactionWWdomains. The WW4 domain-containing WWP2-C induces Smad7 turnover in vivo and positively regulates the metastatic epithelial-mesenchymal transition programme. This activity and the overexpression of these isoforms in human cancers make them candidates for therapeutic intervention. Here, we use NMR spectroscopy to solve the solution structure of the WWP2 WW4 domain and observe the binding characteristics of Smad7 substrate peptide. We also reveal that WW4 has an enhanced affinity for a Smad7 peptide phosphorylated at serine 206 adjacent to the PPxY motif. Using the same approach, we show that the WW3 domain also binds Smad7 and has significantly enhanced Smad7 binding affinity when expressed in tandem with the WW4 domain. Furthermore, and relevant to these biophysical findings, we present evidence for a novel WWP2 isoform (WWP2C-DHECT) comprising WW3-WW4 tandem domains and a truncated HECT domain that can inhibit TGFβ signalling pathway activity, providing a further layer of complexity and feedback to the WWP2 regulatory apparatus. Collectively, our data reveal a structural platform for Smad substrate selection by WWP2 isoform WW domains that may be significant in the context of WWP2 isoform switching linked to tumorigenesis.

© 2019 Elsevier B.V. This study demonstrates a hollow structure constructed by Au nanoparticles decorated on the surface of the In2O3 hollow nanospheres. This structure is prepared via calcination of solid organic precursors and in-situ reduction of Au nanoparticles on the metal oxide surface. The In2O3 hollow nanospheres are with the diameter of ˜200 nm and the shell thickness of 30 nm, while the Au nanoparticles on the surface of In2O3 hollow spheres are with the size of ˜10 nm. XPS indicates that the Au modification can increase the deficient oxygen vacancy ratio, and the presence of the positive Au ions (Auδ+) in the composites helps to trap the electrons and further improve the sensing performance. The gas sensing tests indicate that the Au decorated In2O3 hollow nanocomposites show excellent sensitivity (26.3 of 100 ppm) and selectivity toward 1-butylamine at the optimized temperature of 340 °C. The decoration of Au nanoparticles can lower the optimized working temperature and shorten the response/recovery times. The enhanced sensing mechanism can be attributed to electronic and chemical sensitization. The decoration of Au nanoparticles on the In2O3 surface can cause the Schottky barrier at the interface. The existence of positive Au ions can boost the barrier by trapping extra electrons. These results tender the promising hollow structure for sensing organic amine vapor in field-based use.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Vitamin D (25(OH)D) insufficiency and deficiency are highly prevalent in adult soccer players and can exceed 80% even in regions with high insolation; however, the treatment of this condition is often complicated. The aim of the present study was to examine the prevalence of vitamin D insufficiency and deficiency in youth Russian soccer players and the efficacy of its treatment. Participants were 131 young male football players (age 15.6 ± 2.4 years). Low vitamin D levels (below 30 ng/mL) were observed in 42.8% of the analyzed participants. These athletes were split in two groups composed of persons with vitamin D deficiency (serum vitamin D below 21 ng/mL) and insufficiency (serum vitamin D in range of 21-29 ng/mL). A dietary supplement of 5000 IU cholecalciferol per day was administered for two months. After the treatment, an average 92% increase in vitamin D concentration was observed (before treatment—19.7 ± 5.4 ng/mL, after treatment—34.7 ± 8.6 ng/mL, p < 0.001) and 74% of the post-treatment values were within the reference range (30-60 ng/mL). Serum concentration of vitamin D increased by 200% ± 98% (p < 0.001) during the first month of treatment with vitamin D deficiency and insufficiency being successfully treated in 83% of the football players. In summary, the prevalence of vitamin D insufficiency and deficiency was high in young Russian soccer players. Furthermore, it was indicated that the daily usage of cholecalciferol in a dose 5000 IU was an effective and well-tolerated treatment for vitamin D insufficiency. No linear dependency between the duration of treatment and increase in vitamin 25(OH) D concentration was observed.

© 2019 Elsevier Ltd Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum. Adgrl3 −/− mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3 +/− mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models. This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’.

© 2019, Pleiades Publishing, Inc. Abstract: Angiomyolipoma (AML) is one of the most frequent and, at the same time, AML molecular genetics is one of the least studied among benign tumors. We performed deep sequencing of 409 genes involved in oncogenesis in tumor samples and peripheral blood of patients with sporadic AML of the kidney. We recorded mutations in the TSC2 gene in 65% of samples, which is consistent with international results. As a result of our work, we uncovered mutations in the SETD2, PDGFRA, STK36, SYNE1, PIK3CD, NF1, TOP1, and ITGB3 genes in sporadic renal AML for the first time. In two samples, we were able to clarify the clinical and morphological diagnosis by finding mutations in the genes in tumors lacking TSC2 gene lesions. Mutations in MET and CDC73 are also causative for other types of renal tumors: papillary renal cell carcinoma and CDC73-related disorders, respectively. The latter disease is accompanied by kidney cysts and hamartomas. The obtained results demonstrate a promising potential of mutational profiling of sporadic renal angiomyolipoma (sAML). Genotyping of sAML is particularly important for clarification of the clinical diagnosis in ambiguous cases, as well as for a more in-depth understanding of AML molecular genetics and etiopathogenesis, and for the identification of new molecular targets for personalized AML therapies.

© 2019 by the authors. Background: Vitamin D insuffciency is prevalent among athletes, and it can negatively affect physical performance. At the same time, most of the available data were obtained from untrained individuals of various ages, and published studies performed in athletes led to contradictory conclusions. Methods: This cohort prospective study examined the serum concentration of 25-hydroxycalciferol (25(OH)D) and its association with running speed and muscle power in 131 young football players (mean age 15.6 ± 2.4 years). Results: 25(OH)D levels were below reference in 42.8% (serum 25(OH)D <30 ng/mL) and above reference in 30.5% of the participants (serum 25(OH)D 61-130 ng/mL). A comparison of the results of 5, 15, and 30 m sprint tests and the standing long jump test found no statistically significant differences between the two groups. Athletes from the 25(OH)D-insuffcient group were treated with 5000 IU cholecalciferol supplement daily for 60 days. After the treatment, the 25(OH)D concentration increased by 79.2% and was within reference in 84% of the treated athletes (serum 25(OH)D 30-60 ng/mL). Testing was repeated after the end of treatment, and a statistically significant increase in the results of the 5, 15, and 30 m sprint tests was observed (Cohen’s d was 0.46, 0.33, and 0.34, respectively), while the results of the standing long jump test remained unchanged. Body height, body weight, and lean body mass of the football players also increased. Conclusions: These findings indicate that there is likely no correlation between serum levels of 25(OH)D, muscle power, and running speed in young professional football players, and the changes observed post-treatment might have been caused by changes in the anthropometric parameters. During the study, all the anthropometric parameters changed, but the amount of lean body mass only correlated with the results of the 5 m sprint.

© 2019, Springer Nature B.V. The objective of this study was to determine the impact of polymorphism of CYP3A subfamily isoenzymes (allelic variants of CYP3A4*22 and CYP3A5*3) on the efficacy clopidogrel in patients with an acute coronary syndrome (ACS), who have undergone percutaneous coronary intervention (PCI). Platelet activity was determined on a VerifyNow P2Y12 test system in 81 patients with ACS aged 37–91 who had PCI. The activity of CYP3A4/5 was expressed as the ratio of the concentrations of cortisol and 6β-hydroxycortisol was performed by using high performance liquid chromatography. Genotyping was performed by using real-time polymerase real-time chain reaction. The frequencies for the CYP3A5 gene, rs 776746, were identified as follows: 77 (95.1%)—CC, 4 (4.9%)—CT; the allele frequencies by loci for the CYP3A4, rs rs35599367, were as follows: 78 (96.3%)—GG, 3 (3.7%)—AG. There was no statistically significant genotype-dependent difference between the presence of a minor T and G alleles and the presence of clopidogrel resistance (OR 3.53; 95% CI 0.46–26.94; p = 0.233 and p = 0.443, respectively). The average level of the metabolic relationship (6β-hydroxycortisol/cortisol) between the clopidogrel-resistant group and the normal platelet reactivity group was not statistically significantly different: 3.3 ± 2.8 versus 3.2 ± 3.2; p = 0.947. So, the activity of CYP3A4/5 was not related to platelet aggregation rates in this model. Genotyping and phenotyping CYP3A4\CYP3A5 does not predict the antiplatelet effect of clopidogrel. More extensive research is required to establish their clinical relevance.

© 2019, Pleiades Publishing, Inc. Abstract: Genetic engineering is considered as background for crop protection against pest damage by adding new genes inside the grains. Rice, like other cereals is included in gene engineering experiments. The questions about possible gene transfer related to food safety appear. It is important to find any additional genes or fragments in animal tissues after consumption of genetically modified (GM) food. Therefore, in this study, the remaining of CryIA(b) gene and P35 were assessed in the liver of rats fed with GM rice. This work presents an experimental study with the intervention of GM rice feeding by Sprague Dawley rats. Overall, 20 male and 20 female SD rats were fed by pellets made by GM rice in 50% of needed carbohydrate for 90 days. Then, sampling was done from rats liver. DNA extraction was done based on the protocol. The quality and quantity of the extracted DNA was done by agarose gel electrophoresis and spectrophotometry, respectively. Detection of GM genes residues, including CryIA(b), P35, and T35 was done by Polymerase Chain Reaction using specific primer pairs. The results were analyzed by agarose gel electrophoresis alongside with 50 bp DNA ladder. The results were compared with the ones in control groups with feeding by standard pellet of non-modified rice. All amplification tests were done in triplicates. Analysis of the amplification of P35, CryIA(b) and T35 showed no residues inside the liver tissue. The results showed no significant difference in the presence of transgenic gene of cryIA(b), T35, and P35 in the liver tissue between the control and experiment groups. Therefore, this study rejects the possibility of gene settle of GM rice gene residues in liver tissue of the animal model studied.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature.  The polypeptide analgesic compounds APCH3 (a TRPV1 receptor inhibitor) and PT1 (a P 2 X 3 receptor inhibitor) were shown not to act on the cardiovascular system or respiratory system when given either as single or multiple doses in mice. The low molecular weight compound sevanol (an ASIC3 receptor inhibitor) had no effect on the cardiovascular system, but prolonged use for 14 days affected measures of the respiratory system, significantly increasing respiratory rate and peak expiratory flow rate.

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Abstract: Osteoarthritis (OA), the most common form of arthritis, is characterized by inflammation of joints and cartilage degradation leading to disability, discomfort, severe pain, inflammation, and stiffness of the joint. It has been shown that adenosine, a purine nucleoside composed of adenine attached to ribofuranose, is enzymatically produced by the human synovium. However, the functional significance of adenosine signaling in homeostasis and pathology of synovial joints remains unclear. Adenosine acts through four cell surface receptors, i.e., A1, A2A, A2B, and A3, and here, we have systematically analyzed mice with a deficiency for A3 receptor as well as pharmacological modulations of this receptor with specific analogs. The data show that adenosine receptor signaling plays an essential role in downregulating catabolic mechanisms resulting in prevention of cartilage degeneration. Ablation of A3 resulted in development of OA in aged mice. Mechanistically, A3 signaling inhibited cellular catabolic processes in chondrocytes including downregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII), an enzyme that promotes matrix degradation and inflammation, as well as Runt-related transcription factor 2 (RUNX2). Additionally, selective A3 agonists protected chondrocytes from cell apoptosis caused by pro-inflammatory cytokines or hypo-osmotic stress. These novel data illuminate the protective role of A3, which is mediated via inhibition of intracellular CaMKII kinase and RUNX2 transcription factor, the two major pro-catabolic regulators in articular cartilage. Key messages: Adenosine receptor A3 (A3) knockout results in progressive loss of articular cartilage in vivo.Ablation of A3 results in activation of matrix degradation and cartilage hypertrophy.A3 agonists downregulate RUNX2 and CaMKII expression in osteoarthritic human articular chondrocytes.A3 prevents articular cartilage matrix degradation induced by inflammation and osmotic fluctuations.A3 agonist inhibits proteolytic activity of cartilage-degrading enzymes.

© 2018, Mary Ann Liebert, Inc. Background: Laparoscopic D3 anterior posterior extended mesenterectomy (D3APEM) in right colectomy has received increased attention. The aim of this study is to prove feasibility, systemize technical accomplishment, and provide short-term outcomes data. Methods: From July 2013 to February 2017, 18 patients with adenocarcinoma in the right colon underwent right colectomy with laparoscopic D3APEM, including lymph nodes anterior and posterior to the superior mesenteric vessels. A reconstructed three-dimensional anatomy map derived from the staging computed tomography was used as a road map at surgery. The procedure was systematized into seven operative steps: Step 1, trocar placement and inspection; Step 2, release of the transverse colon; Step 3, identification of the terminal mesenteric vessels; Step 4, release of the anterior flap; Step 5, division of the transverse mesocolon; Step 6, release of the posterior flap; and Step 7, anastomosis and specimen removal. Patient disposition and variations regarding vascular anatomy and ability to expose consequentially may necessitate a variation in the sequence of the steps. Results: A total of 7 (39%) cases were converted, 3 due to bleeding and 4 due to challenging dissection. Median operative time and blood loss were 276 minutes (168-439 minutes) and 200 mL (< 50-1300 mL), respectively. Postoperative complications occurred in 6 (33%), including 2 (11%) major complication requiring reoperation. Median hospital stay was 5 days (3-13 days). R0 resection was achieved in all cases. Median number of the lymph nodes harvested was 40 (25-86), including 11.5 (4-35) in the D3 volume. Six patients (33%) had positive nodes, 3 of them affecting the D3 zone, including 1 case of a skip metastasis. There was no mortality, and at present all the patients are alive. One patient developed distant lymph node metastases. Conclusion: Laparoscopic right colectomy with D3APEM is feasible, associated with acceptable morbidity and fast recovery; now in readiness for introduction in specialized colorectal institutions.

© 2018, © 2018 Taylor  &  Francis. A library of 29 2-amino-6-sulfanylpyridine-3,5-dicarbonitriles functionalized with a pyridoxine moiety was synthesized using a three-component one-pot reaction of aldehyde derivative of pyridoxine, malononitrile, and thiophenol. The obtained bipyridine structures were converted into methylpyridinium salts. Several compounds demonstrated expressed antibacterial activity with MICs (minimum inhibitory concentrations) in the range of 0.5–4 µg/mL against the three studied Gram-positive strains and 8–64 µg/mL against the Gram-negative E. coli strain, which was comparable or better than the activity of the reference antimicrobial agents. At the same time, all the synthesized compounds were inactive against the Gram-negative P. aeruginosa. Several compounds also demonstrated high cytotoxic activity against the studied tumor cells, but without selectivity for the normal HSF (human foreskin fibroblast) cells. Despite the preliminary character of the performed biological studies, the obtained results make the obtained structural chemotype a promising starting point for the design of physiologically active compounds.

© 2018 Wolters Kluwer Health, Inc. All rights reserved. Objective An estimated 336 per 100 000 people in Russia are infected with hepatitis C virus, including up to 75% with genotype (GT) 1b. In the TURQUOISE-II/-III trials, a 12-week regimen of the direct-acting antiviral agents ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) in GT1b-infected patients with compensated cirrhosis resulted in 12-week sustained virologic response (SVR) rates of 100%. Patients and methods In TURQUOISE-IV, GT1b-infected patients (n=36) from Russia and Belarus with compensated cirrhosis, who were treatment naive or previously treated with pegylated interferon/ribavirin (RBV), received OBV/PTV/ritonavir+DSV+RBV for 12 weeks. The primary efficacy end point was SVR at 12 weeks. Safety assessments included adverse event (AE) monitoring and laboratory testing. Results At baseline, patients had Child-Pugh scores of 5 (92%) or 6 (8%). Overall, 69% were treatment experienced (44% prior null responders, 32% relapsers, and 16% partial responders). All patients achieved SVR at 12 weeks (36/36; 100%). No patient experienced a serious AE or discontinued treatment prematurely. Treatment-emergent AEs possibly related to study drugs occurring in greater than or equal to 10% of patients were asthenia (19%), anemia (14%), cough (14%), and headache (11%); most events were mild in severity. Clinically significant laboratory abnormalities were infrequent. Conclusion In Russian and Belarusian patients with hepatitis C GT1b infection and compensated cirrhosis, 100% achieved SVR at 12 weeks after 12 weeks' treatment with OBV/PTV/ritonavir+DSV+RBV. The treatment was well tolerated.

© 2018 Wolters Kluwer Health, Inc. All rights reserved. This work presents the results of in-vitro biological activity studies of three novel anticancer agents, phosphonium salts based on the 3-hydroxypyridine scaffold, including one derivative of 4-deoxypyridoxine. Proliferation and viability of cells treated with these compounds was assessed by the colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of the compounds on apoptosis and cell cycle were studied by flow cytometry using annexin V-FITC/propidium iodide and propidium iodide staining, respectively. The influence of the compounds on mitochondrial membrane potential and intracellular reactive oxygen species was evaluated using tetramethyl rhodamine ethyl and DCFHA staining. Western blot analysis was used to study the changes in the expression of Bcl-xL, Bax, and caspase-3 apoptotic proteins. The treatment of ovarian adenocarcinoma cells OVCAR-4 with the tested compounds inhibited the growth and induced cell cycle arrest in the G1 phase. 3-Hydroxypyridine derivatives induced apoptosis by hyperexpression of Bax and caspase-3, whereas 4-deoxypyridoxine derivative induced cell death partly by reactive oxygen species generation and caspase-3 hyperexpression. These results indicate that the quaternary phosphonium salts studied represent potential therapeutic agents for the treatment of ovarian cancer.

© 2018 Elsevier Inc. Growing evidence demonstrates that the serotonin system influences punishment behavior in social decision-making and that individual differences in the propensity to punish are, at least in part, due to genetic variation. However, the specific genes and their mechanisms by which they influence punishment behavior are not yet fully characterized. Here, we examined whether serotonin system-related gene variation impacts on altruistic punishment in the ultimatum game by using a longitudinal approach with three time points, covering a time frame up to four months in young adults (N = 106). Specifically, we investigated additive effects of 5-HTTLPR and TPH2 G-703T genotypes by using a composite score. This composite score was significantly associated with altruistic punishment, with individuals carrying both the S-allele and the G-allele demonstrating less punishment behavior. The results suggest that serotonin system-related gene variation contributes to individual differences in altruistic punishment. Furthermore, comparably high test-retest correlations suggest that punishment behavior in the ultimatum game represents a relatively stable, trait-like behavior.

© 2018 IOP Publishing Ltd. Maintaining the epithelial status of cells in vitro and fabrication of a multilayered epithelial lining is one of the key problems in the therapy using cell technologies. When cultured in a monolayer, epithelial cells change their phenotype from epithelial to epithelial-mesenchymal or mesenchymal that makes it difficult to obtain a sufficient number of cells in a 2D culture and to use them in tissue engineering. Here, using buccal epithelial cells from the oral mucosa, we developed a novel approach to recover and maintain the stable cell phenotype and form a multilayered epithelial lining in vitro via the 2D/3D cell self-assembling. Transitioning the cells from the monolayer to non-adhesive 3D culture conditions led to formation of self-assembling spheroids, with restoration of their epithelial characteristics after epithelial-mesenchymal transition. In 7 days, the cells within spheroids restored the apical-basal polarity, and the formation of both tight (ZO1) and adherent (E-cadherin) intercellular junctions was shown. Thus, culturing buccal epithelial cells in a 3D system allowed us to recover and durably maintain the morphological and functional characteristics of epithelial cells. The multilayered epithelial lining formation was achieved after placing spheroids for 7 days onto a hybrid matrix, which consisted of collagen layers and reinforcing poly (lactide-co-glycolide) fibers and was proven promising for replacement of the urothelium. Thus, we offer an effective technique of forming multilayered epithelial linings on carrier-matrices using cell spheroids that was not previously described elsewhere and can find a wide range of applications in tissue engineering, replacement surgery, and regenerative medicine.

© 2017 Informa UK Limited, trading as Taylor  &  Francis Group. Sub-constructs of morning–evening preference might be differentially related to polymorphisms in circadian clock genes. We previously reported significant association between a single nucleotide polymorphism in PER3 (rs2640909) and Morning but not Evening Lateness scale of the Sleep–Wake Pattern Assessment Questionnaire. To further explore such a scale-specific relationship, seven single nucleotide polymorphisms in five circadian clock genes were studied using exploratory and confirmatory samples (in total, n = 698). The association of rs2640909 with Morning Lateness scale was not replicated in the confirmatory sample but remained significant in the merged sample. Moreover, we found and confirmed an association of this scale with rs1159814 in RORα. The results provided further evidence for differential relationship of polymorphisms in circadian clock genes with morning and evening components of morning–evening preference. We also suggested possibility to take into account the pattern of geographic variation in allele frequency for prioritization of circadian clock polymorphisms in candidate gene studies.

© 2018 Elsevier B.V. Development of efficient biodegradable, environmentally responsive, biocompatible and non-toxic delivery system is needed for efficient gene delivery. As well known, properties of the vehicle are determined by the structure of carrier components. The aim of the current study was to estimate in vitro transfection efficacy of aliphatic di-, tri- and tetrapeptide-based cationic lipoplexes loaded with siRNA in function of a number of cationic groups using 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Physicochemical properties and cytotoxicity of the liposomes were found to be dependent upon a number of amino acid derivatives in an amphiphilic polar head. Uptake of liposomes loaded with nucleic acid (lipoplexes) and their localization in HEK293T cells was studied by confocal microscopy. The liposomes based on lipotripeptides had the highest transfection efficiency which was 20-fold higher than those fabricated from lipotetrapeptides.