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Cytochrome P450 46A1 (CYP46A1) is the CNS-specific cholesterol 24-hydroxylase that controls cholesterol elimination and turnover in the brain. In mouse models, pharmacologic CYP46A1 activation with low-dose efavirenz or by gene therapy mitigates the manifestations of various brain disorders, neurologic, and nonneurologic, by affecting numerous, apparently unlinked biological processes. Accordingly, CYP46A1 is emerging as a promising therapeutic target; however, the mechanisms underlying the multiplicity of the brain CYP46A1 activity effects are currently not understood. We proposed the chain reaction hypothesis, according to which CYP46A1 is important for the three primary (unifying) processes in the brain (sterol flux through the plasma membranes, acetyl-CoA, and isoprenoid production), which in turn affect a variety of secondary processes. We already identified several processes secondary to changes in sterol flux and herein undertook a multiomics approach to compare the brain proteome, acetylproteome, and metabolome of 5XFAD mice (an Alzheimer’s disease model), control and treated with low-dose efavirenz. We found that the latter had increased production of phospholipids from the corresponding lysophospholipids and a globally increased protein acetylation (including histone acetylation). Apparently, these effects were secondary to increased acetyl-CoA production. Signaling of small GTPases due to their altered abundance or abundance of their regulators could be affected as well, potentially via isoprenoid biosynthesis. In addition, the omics data related differentially abundant molecules to other biological processes either reported previously or new. Thus, we obtained unbiased mechanistic insights and identified potential players mediating the multiplicity of the CYP46A1 brain effects and further detailed our chain reaction hypothesis.

O presente artigo visa, a partir do trabalho argumentativo de Cançado Trindade, em sede de votos individuais, em opiniões consultivas e em sentenças na Corte Interamericana de Direitos Humanos (CorteIDH) e na Corte Internacional de Justiça (CorteICJ), a destacar a sua contribuição para a inclusão do debate sobre a extensão do jus cogens nas questões analisadas pelas Cortes e, posteriormente, pelo posicionamento que vieram a desenvolver sobre esse tema em sua jurisprudência. A pergunta que norteia o artigo é: como o autor Cançado Trindade contribuiu para consolidar o novo jus gentium do Século XXI? A fim de alcançar esse desiderato, busca-se traçar um panorama acerca do direito internacional tradicional do Século XX, com o objetivo de traçar a sua evolução, para, em um segundo momento, enfrentar-se a ampliação do jus cogens pela Corte IDH e pela Corte CIJ, finalizando com a análise das contribuições mais relevantes do autor para que se alcance o novo jus gentium do Século XXI. A metodologia utilizada foi a da pesquisa empírica em ciências sociais para o estudo das informações necessárias sobre a utilização do jus cogens pela CorteIDH. Os recursos metodológicos utilizados para desen volver o método aplicado foram o da pesquisa documental e jurisprudencial em sentenças, votos dissidentes, votos separados e opiniões consultivas das cortes. Os resultados indicaram a expressiva contribuição do autor para a consolidação da visão universalista e humanista do Direito Internacional.

Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885.

Background Our goal is to evaluate whether the administration of thrombolytic treatment has varying effects on clinical and radiological outcomes in patients with large‐vessel occlusion stroke, based on the type of stroke center where the treatment was given (thrombectomy‐capable center versus local stroke center). Methods We included patients with an acute ischemic large‐vessel occlusion stroke who were directly admitted to thrombectomy‐capable centers and treated with endovascular thrombectomy, or were transferred from local stroke centers as thrombectomy candidates, in Catalonia, Spain, between 2017 and 2021. The primary outcome was the shift analysis on the modified Rankin scale score at 90 days. Secondary outcomes included death at 90 days and the rate of parenchymal hemorrhage and successful reperfusion. Inverse‐probability weighting clustered at the type of stroke center was used to estimate the effects. Results The analysis included 2268 patients directly admitted to thrombectomy‐capable centers, of whom 975 (49%) were treated with thrombolysis, and 938 patients transferred from local stroke centers, of whom 580 (66%) were treated with thrombolysis and 616 (67%) were treated with thrombectomy. Mean age was 72 (SD ±13) years, median National Institute of Health Stroke Scale score was 17 (interquartile range, 12–21), and 1363 patients were women (48%). Patients treated with intravenous thrombolysis were younger, had shorter time from onset to first image, higher Alberta Stroke Program Early Computed Tomography Score, and lower rates of wake‐up stroke, atrial fibrillation, and anticoagulation intake. Patients treated with thrombolysis had better functional outcome at 90 days, with no difference between patients directly admitted to thrombectomy‐capable centers (adjusted common odds ratio [acOR], 1.50 [95% CI, 1.24–1.81]) and patients transferred from local stroke centers (acOR, 1.44 [95% CI, 1.04–2.01]). Patients treated with intravenous thrombolysis had lower death rate, higher rate of parenchymal hematoma, and similar rate of successful reperfusion, with no difference according to type of center (Pinteraction>0.1). Conclusion Administration of intravenous thrombolysis in patients with a large‐vessel stroke with intention of thrombectomy was associated with lower degrees of disability, lower death rate, and higher rates of parenchymal hematoma both in thrombectomy‐capable centers and in local stroke centers.

The article presents the results of studying the pellets crumbliness index of a pilot batch of extruded compound feed for pike-perch. The regimes of extruded pellets fish compound feed production with minimal crumbling were defined using a mathematical model. A 3-factorial central composite design was implemented to obtain a mathematical model of the process of extrudate resulting in the second-degree polynomial. The process influencing factors include the feed mixture moisture W (%), extrusion temperature T (°C) and steam pressure P (MPa). Experimental studies were conducted according to the experimental plan. The experimental data obtained were entered into the planning matrix. Experimental data was processed in a program prepared in Microsoft Excel. As a result, an adequate second-order mathematical model describing the dependence of the crumbliness index on the feed mixture moisture before extrusion, extrusion temperature and steam pressure was obtained. The mathematical model adequacy was tested based on Fisher's variance ratio. The Fisher criterion is an important statistical tool for verifying the adequacy of the model and analyzing the variance. The analysis of the obtained model and its graphical interpretation are presented. A good extrusion process mathematical model was developed. The fundamental principles of feed mixture processing on a single-screw extruder and the choice of its rational parameters ensure the production of extruded compound feed pellets for pike-perch with minimal crumbling were studied. A minimal crumbling is provided at the following values of the factors - feed mixture moisture before extrusion is 32%, extrusion temperature is 132 °C, and pressure is 0.4 MPa. In the selected levels of factors, the calculated value of extruded pellets crumbling was 1.02%.

The retina and brain are separated from the systemic circulation by the anatomical barriers, which are permeable (the outer blood-retinal barrier) and impermeable (the blood-brain and inner blood-retina barriers) to cholesterol. Herein we investigated whether whole-body cholesterol maintenance affects cholesterol homeostasis in the retina and brain. We used hamsters, whose whole-body cholesterol handling is more similar to those in humans than in mice, and conducted separate administrations of deuterated water and deuterated cholesterol. We assessed the quantitative significance of the retinal and brain pathways of cholesterol input and compared the results with those from our previous studies in mice. The utility of the measurements in the plasma of deuterated 24-hydroxycholesterol, the major cholesterol elimination product from the brain, was investigated as well. We established that despite a sevenfold higher serum LDL to HDL ratio and other cholesterol-related differences, in situ biosynthesis remained the major source of cholesterol for hamster retina, although its quantitative significance was reduced to 53% as compared to 72%–78% in the mouse retina. In the brain, the principal pathway of cholesterol input was also the same, in situ biosynthesis, accounting for 94% of the total brain cholesterol input (96% in mice); the interspecies differences pertained to the absolute rates of the total cholesterol input and turnover. We documented the correlations between deuterium enrichments of the brain 24-hydroxycholesterol, brain cholesterol, and plasma 24-hydroxycholesterol, which suggested that deuterium enrichment of plasma 24-hydroxycholesteol could be an in vivo marker of cholesterol elimination and turnover in the brain.

Spinal muscular atrophy 5q (SMA) is one of the most common neuromuscular inherited diseases and is the most common genetic cause of infant mortality. SMA is associated with homozygous deletion of exon 7 in the SMN1 gene. Recently developed drugs can improve the motor functions of infants with SMA when they are treated in the pre-symptomatic stage. With aim of providing an early diagnosis, newborn screening (NBS) for SMA using a real-time PCR assay with dried blood spots (DBS) was performed from January 2022 through November 2022 in Saint Petersburg, which is a representative Russian megapolis. Here, 36,140 newborns were screened by the GenomeX real-time PCR-based screening test, and three genotypes were identified: homozygous deletion carriers (4 newborns), heterozygous carriers (772 newborns), and wild-type individuals (35,364 newborns). The disease status of all four newborns that screened positive for the homozygous SMN1 deletion was confirmed by alternate methods. Two of the newborns had two copies of SMN2, and two of the newborns had three copies. We determined the incidence of spinal muscular atrophy in Saint Petersburg to be 1 in 9035 and the SMA carrier frequency to be 1 in 47. In conclusion, providing timely information regarding SMN1, confirmation of disease status, and SMN2 copy number as part of the SMA newborn-screening algorithm can significantly improve clinical follow-up, testing of family members, and treatment of patients with SMA.

Liquidambar L. is a significant constituent of the Cenozoic flora in the Northern Hemisphere. Currently, this genus exhibits a discontinuous distribution across Asia and North America, with the center of diversity being in southeastern Asia. This study presents the first occurrence of Liquidambar in the Oligocene of South China. Fossil sweetgum infructescences, associated pollen, and leaves have been found in the Nanning Basin, Guangxi. A new species, Liquidambar nanningensis sp. nov., is described based on the morphological and anatomical characteristics of three-dimensionally preserved infructescences. The Liquidambar fossils from the Nanning Basin show a combination of features indicative of the former genera of Altingiaceae, Altingia, Liquidambar s. str., and Semiliquidambar. The new occurrence expands the taxonomic and morphological diversity of the Paleogene Liquidambar species in South China.

Resumo A produção de políticas públicas é um processo complexo que envolve um conjunto de estímulos e condicionantes. Compreender o que, de fato, tem informado os burocratas e as organizações públicas é um elemento essencial para caracterizar a produção de políticas públicas, assim como para a discussão das potencialidades e dos limites das Políticas Públicas Baseadas em Evidências (PPBE) no contexto brasileiro. Neste estudo, investigamos as diferentes fontes de informação disponíveis aos burocratas brasileiros; dentre as quais, não somente as científicas, mas também as experienciais, as internas e as externas ao Estado. Esta pesquisa traz resultados de um survey respondido por 2.180 servidores da Administração Federal Direta no final de 2019. Os resultados indicam que há variação na utilização de fontes de informação a serem mobilizadas pelos burocratas de acordo com o tipo de trabalho desempenhado e, também, com a área de política pública na qual atuam.

The article deals with the professional career of the Russian psychologist Helena Antipoff (1892-1974) in the Soviet Russia, between 1917 and 1924, after returning from her educational stay in Paris and Geneva, and before migrating to Brazil in 1929. During the brief Soviet period, Helena was a witness and an active participant in the grandiose and dramatic changes of the country. Her work, as well as the work of other Russian scientists who migrated to other countries during the years of war and social revolution, is now being extensively studied, and new knowledge reverse some established perceptions and stereotypes about the history of psychology in Russia. Antipoff start-up in the Russian psychological and educational communities was linked to the intensive scientific and social activities of the St. Petersburg school of scientists and psychologists at this period – Vladimir M. Bekhterev (1857-1927), Alexander F. Lazursky (1874-1917), Alexander P. Nechaev (1870-1948), Mikhail Y. Basov (1892-1931), Adrian S. Griboedov (1875-1948) and others. Helena`s professional self-realization in this six-year Russian period was developed in real hot spots of practical psychological problems of that time for the country (study of children in conditions of devastation, hunger and orphanhood; testing of enhancement/reduction of child intelligence in conditions of social cataclysm and war; comparison of intellectual abilities of children of different social groups and in different countries; social and psychological diagnostics and distribution of “street children” to different types of care and educational institutions).

CYP46A1 is a CNS-specific enzyme, which eliminates cholesterol from the brain and retina by metabolism to 24-hydroxycholesterol, thus contributing to cholesterol homeostasis in both organs. 2-Hydroxypropyl-β-cyclodextrin (HPCD), a Food and Drug Administration-approved formulation vehicle, is currently being investigated off-label for treatment of various diseases, including retinal diseases. HPCD was shown to lower retinal cholesterol content in mice but had not yet been evaluated for its therapeutic benefits. Herein, we put Cyp46a1−/− mice on high fat cholesterol-enriched diet from 1 to 14 months of age (control group) and at 12 months of age, started to treat a group of these animals with HPCD until the age of 14 months. We found that as compared with mature and regular chow-fed Cyp46a1−/− mice, control group had about 6-fold increase in the retinal total cholesterol content, focal cholesterol and lipid deposition in the photoreceptor-Bruch’s membrane region, and retinal macrophage activation. In addition, aged animals had cholesterol crystals at the photoreceptor-retinal pigment epithelium interface and changes in the Bruch’s membrane ultrastructure. HPCD treatment mitigated all these manifestations of retinal cholesterol dyshomeostasis and altered the abundance of six groups of proteins (genetic information transfer, vesicular transport, and cytoskeletal organization, endocytosis and lysosomal processing, unfolded protein removal, lipid homeostasis, and Wnt signaling). Thus, aged Cyp46a1−/− mice on high fat cholesterol-enriched diet revealed pathological changes secondary to retinal cholesterol overload and supported further studies of HPCD as a potential therapeutic for age-related macular degeneration and diabetic retinopathy associated with retinal cholesterol dyshomeostasis.

In the 21st century, the European banking system is going through a period of fundamental structural changes caused by global challenges that will determine its future ability to serve the financial needs of the economy on digital platforms. The aim of this research is to study how electronic social media influence the effectiveness of e-banking in the context of banking sector instability. The empirical model for determining the impact of digital media was developed on the basis of theoretical concepts and tested on a sample of 307 respondents from banking institutions (UniCredit, Raiffeisen, PrivatGroup) and 2,800 consumers of banking services through quantitative methods, as well as economic and statistical calculation methods. The obtained results show that digital social media have a quite strong effect (r=0.788) on creating consumer loyalty and increasing indicators of digital trade in banking services. The theoretical significance of this study is the synthesis of scientific approaches to the creation of a conceptual method for determining the effectiveness of engaging digital media resources as a marketing tool for improving the effectiveness of digital trade in banking services. The key practical aspect is the combination of theoretical approaches and business experience in optimizing and improving the use of electronic social media in the trade in banking services in a difficult period of economic development.

It has been proved that in the era of globalization and the development of information technologies, the need to optimize the supply chain of services increases, since the integration of participants in this chain is performed without the use of modern management information systems. In the paper, with the help of logic-cognitive, structural-functional methods, structural-logical and imitation modelling, a management approach to simulation of business interaction in the integration of enterprises with elements of ERP-system and CBIP is developed and proposed, which allows you to create a flexible, adaptive and secure IT infrastructure , which increases the efficiency of the enterprise and allows you to optimize the management of relations with other participants in the service supply chain. As a result of this application of modern supply chain management systems, a synergistic effect is achieved that allows you to minimize the number of technological operations, shorten the production cycle and reduce the cost of services both for each individual enterprise and in the service supply chain as a whole.

The accuracy of radio radiation source (RRS) coordinates determination in MLAT systems is largely determined by the algorithm used. Traditionally, the MPS use one-step estimates of RRS coordinates obtained by the least squares method (LSM), where differences in measurements of RRS signal reception moments at different receiving stations (RS) are used as input data. This approach ignores some of the information contained in the observations the moments and period of radio signal emission from RRS. The algorithm of joint filtration of RRS coordinates and time of transmission (ToT) for sampling of sequential observations is presented. The results of modeling of different algorithms for determination of RRS coordinates are presented, and the advantages of the proposed algorithm in comparison with the traditional algorithm based on the TDoA method are shown. Estimation of ToT and its filtration at a known period allows you to get closer to the accuracy provided by Time of Flight (ToF) method, which can not be implemented directly for MLAT systems. This hypothesis was confirmed by modeling with the use of two types of trajectories - circular movement and straight-line movement.

A small dose of the anti-HIV drug efavirenz (EFV) was previously discovered to activate CYP46A1, a cholesterol-eliminating enzyme in the brain, and mitigate some of the manifestation of Alzheimer’s disease in 5XFAD mice. Herein, we investigated the retina of these animals, which were found to have genetically determined retinal vascular lesions associated with deposits within the retinal pigment epithelium and subretinal space. We established that EFV treatment activated CYP46A1 in the retina, enhanced retinal cholesterol turnover, and diminished the lesion frequency >5-fold. In addition, the treatment mitigated fluorescein leakage from the aberrant blood vessels, deposit size, activation of retinal macrophages/microglia, and focal accumulations of amyloid β plaques, unesterified cholesterol, and Oil Red O-positive lipids. Studies of retinal transcriptomics and proteomics identified biological processes enriched with differentially expressed genes and proteins. We discuss the mechanisms of the beneficial EFV effects on the retinal phenotype of 5XFAD mice. As EFV is an FDA-approved drug, and we already tested the safety of small-dose EFV in patients with Alzheimer’s disease, our data support further clinical investigation of this drug in subjects with retinal vascular lesions or neovascular age-related macular degeneration.

Text proposes to discuss the violation of the right of access to justice based on the analysis of the current wording of art. 790-B, 791-A and 844 of the Consolidation of Labor Laws (CLT), introduced in the Brazilian legal system by Law No. 13,467 / 17, known as the Labor Reform. Such provisions allow the beneficiary of free justice to be convicted in some situations in court costs. Through a theoretical-normative study, it is discussed, through the deductive method, the unconventionality of these new devices to the extent that they directly violate, not only the Federal Constitution, but also international human rights conventions.

Resumo Este artigo analisa a capacidade de integração de políticas públicas suportadas por um mesmo instrumento de implementação. Partindo da abordagem dos estudos de implementação de políticas públicas que compreendem os instrumentos como “o estado em ação”, isto é, ferramentas de ação pública por meio das quais a ação governamental se materializa e é operacionalizada (Lascoumes & Le Galès, 2007; Linder & Peters, 1990), examina-se o caso da Rede do Cadastro Único para Programas Sociais, formada pelo instrumento do Cadastro Único - composto por sua base de dados, normas, processos e estrutura municipal de cadastramento e coleta de dados - e pelos 20 programas sociais que se utilizam de suas informações cadastrais sobre 27 milhões de famílias, quase 80 milhões de pessoas de baixa renda, para seleção de beneficiários e gerenciamento de políticas voltadas ao combate das diferentes formas de vulnerabilidade social. Adotou-se a metodologia da análise de redes sociais para responder a duas perguntas principais: qual é a posição ocupada pelo Cadastro Único (CadÚnico) na rede de relações formada com as políticas sociais que o utilizam e quais são as condições e o nível de integração que o CadÚnico promove entre essas políticas usuárias? As métricas e os sociogramas de dois contextos temporais distintos, 2016 e 2018, demonstraram que, embora haja potencial para que promova maior integração entre as políticas, o CadÚnico ainda não se apresenta como instrumento potente de integração de políticas públicas.

The article emphasizes the revival of folk traditions of the Ukrainian Podunavija, focuses on the significant role of folk choreography in this process. The role of folk dance for the national education of youth is revealed, and their respect for folk traditions and customs is implanted. The author highlights the problematic aspects of teaching folk dance and suggests ways to solve them. It is emphasized that the means of folk choreography form the national consciousness and respect for Ukrainian national traditions and customs.

The article starts with literature review on secondary metabolites, namely the iridoids contained in Linaria species (Scrophulariaceae). It describes the biological activity of the iridoid glycosides; the importance and the benefits of the secondary metabolites and their eventual application in organic plant cultivation. Is further elucidated the profile of the biologically active substances predominant in the purified extract of Linaria genistifolia (L.) Mill., named by us genistifoliosides. Are investigated the biological activity and the stimulating effect of genistifolioside aqueous solution in concentration 0.01% on the tomato seed germination, plants’ productivity (which is 33.9% higher) and the biochemical characteristics of the tomato fruit. It was elucidated, for the first time, the inhibitory effect of genistifolioside on the development of Alternaria alternata pathogenic fungi, affecting the vegetable crops; the 0.1% aqueous solution of genistifoliosides has the diameter of the fungi zone of inhibition 5.8 times bigger in comparison to the control sample and 4 times bigger in comparison to the certificated biopreparation. The purified extract of genistifoliosides exhibits properties of plant growth regulator as well as fungicidal properties and can be used in ecological agriculture.

O sistema de controle concentrado de constitucionalidade italiano tem características que sugerem a importância da eficácia vinculante horizontal e vertical às decisões constitucionais, como uma das bases da figura do precedente. A partir de uma análise jurisprudencial da Corte Constitucional italiana identificam-se os elementos que, atendendo à igualdade formal, estruturam critérios objetivos e razoáveis para que seja atribuído o efeito vinculante às suas decisões.

Apolipoprotein E (APOE) is a component of lipid-transporting particles and a recognition ligand for receptors, which bind these particles. The APOE isoform ε2 is a risk factor for age-related macular degeneration; nevertheless, APOE absence in humans and mice does not significantly affect the retina. We found that retinal cholesterol biosynthesis and the levels of retinal cholesterol were increased in Apoe−/− mice, whereas cholesterol elimination by metabolism was decreased. No focal cholesterol deposits were observed in the Apoe−/− retina. Retinal proteomics identified the most abundant cholesterol-related proteins in WT mice and revealed that, of these cholesterol-related proteins, only APOA4 had increased expression in the Apoe−/− retina. In addition, there were changes in retinal abundance of proteins involved in proinflammatory and antiinflammatory responses, cellular cytoskeleton maintenance, vesicular traffic, and retinal iron homeostasis. The data obtained indicate that when APOE is absent, particles containing APOA1, APOA4, and APOJ still transport cholesterol in the intraretinal space, but these particles are not taken up by retinal cells. Therefore, cholesterol biosynthesis inside retinal cells increase, whereas metabolism to oxysterols decreases to prevent cells from cholesterol depletion. These and other compensatory changes underlie only a minor retinal phenotype in Apoe−/− mice.

With the development of the information society, there has been rapidly growing number of international research on the role of various (information, innovation, intelligent) technologies as a catalyst to fight corruption. As you know, the problems posed by corruption are economic, social and political consequences. In recent years economists and various researchers have shown increasing interest in studying the phenomenon of corruption. Many researchers in the field of studying corruption phenomenon are of theoretical nature, which studied different behaviors without having developed effective methods and technologies to identify and prevent corruption in the various spheres of government. In this regard, there is a need to study the world experience of application of technologies in the prevention of corruption and anti-corruption platform in Ukraine. This will allow to adapt them to positive experience in the implementation of mechanisms to identify and prevent corruption in Ukraine. The authors believe that to obtain a more accurate picture of the corruption situations that provide characteristics and its quantitative description is possible only by means of modelling the corruption phenomenon. In this regard, the analysis of theoretical models of corruption was made: the modelling made by the mathematical notation of the models and conclusions on the effectiveness of their application in management. Using simulation, the authors came to the conclusion that the detection and prevention of corruption should be carried out with the use of technologies and the system approach: from the study of statistics and use of anti-corruption platforms, public registers and databases to logical and probabilistic (LP) risk models of corruption.

Cholesterol homeostasis in the retina, a sensory organ in the back of the eye, has been studied in mice but not hamsters, despite the latter being more similar to humans than mice with respect to their whole-body cholesterol maintenance. The goal of this study was to begin to assess hamster retina and conduct initial interspecies comparisons. First, young (3-month old) and mature (6-month old) Syrian (golden) hamsters were compared with 3- and 6-month old mice for ocular biometrics and retinal appearance on optical coherence tomography and fluorescein angiography. Of the 30 evaluated hamsters, seven had retinal structural abnormalities and all had increased permeability of retinal blood vessels. However, hamsters did not carry the mutations causing retinal degenerations 1 and 8, had normal blood glucose levels, and only slightly elevated hemoglobin A1c content. Cholesterol and six other sterols were quantified in hamster retina and compared with sterol profiles in mouse and human retina. These comparisons suggested that cholesterol turnover is much higher in younger than mature hamster retina, and that mature hamster and human retinas share similarities in the ratios of cholesterol metabolites to cholesterol. This study supports further investigations of cholesterol maintenance in hamster retina.

This article analyses the theoretical foundations of outsourcing and the focus of the outsourcing market in Ukraine. The criteria of assessment for the transfer of business functions to outsourcing are determined and EMEA evaluated according to these criteria. The aim of this work is to study the international outsourcing of services and the implementation of analysis of the characteristics of the process of selecting areas for the transfer of business functions to international outsourcing, and in this context to determine the prospects for Ukrainian companies in this market. Methodology. The study is based on the estimation of the states of the EMEA on the key criteria for transferring business functions to outsourcing. When assessing countries, factors are used, which are important indicators of the economic and political climate in the country, and you need to consider when choosing where to send the direction to outsourcing. The assessment of the countries is conducted on a number of criteria such as: labour cost in the country, the attitude to private property, foreign languages’ skills (in the language of the country of the customer), availability of developed infrastructure, government support, and implemented under this context measures of state regulation, etc. Results of the evaluation showed that over the past few years in many countries, there has been rather significant activity aimed at improving the country’s attractiveness as an international outsourcers, including in Ukraine, so Ukraine has all the prerequisites to occupy a worthy place in the market players of international outsourcing and thus get all the benefits of scientific and technical development and integration in the innovation sector of the world economy. Practical implications. The research is needed for the classification of countries according to their attractiveness because each customer has their own priorities when choosing a supplier and in order to highlight strengths and weaknesses inherent in a particular country. Also, the study is intended to help potential customers of outsourcing services to identify the most suitable locations for the transfer of business functions to international outsourcing. Value/originality. The findings of the study can provide a better understanding of such a category as international outsourcing and help customers of outsourcing services to conduct their own assessment of the transmission of their business functions to international outsourcers.

We study the zero-temperature quantum phase diagram for a two-component Bose-Einstein condensate in an optical cavity. The two atomic spin states are Raman coupled by two transverse orthogonally polarized, blue-detuned plane-wave lasers inducing a repulsive cavity potential. For a weak pump the lasers favor a state with homogeneous density and predefined uniform spin direction. When one pump laser is polarized parallel to the cavity mode polarization, the photons coherently scattered into the resonator induce a polarization gradient along the cavity axis, which mediates long-range density-density, spin-density, and spin-spin interactions. We show that the coupled atom-cavity system implements central aspects of the t-J-V-W model with a rich phase diagram. At the mean-field limit we identify at least four qualitatively distinct density- and spin-ordered phases including ferromagnetic and antiferromagnetic order along the cavity axis, which can be controlled via the pump strength and detuning. Real-time observation of amplitude and phase of the emitted fields bears strong signatures of the realized phase and allows for real-time determination of phase transition lines. Together with measurements of the population imbalance, most properties of the phase diagram can be reconstructed.

The retina, a thin tissue in the back of the eye, has two apparent sources of cholesterol: in situ biosynthesis and cholesterol available from the systemic circulation. The quantitative contributions of these two cholesterol sources to the retinal cholesterol pool are unknown and have been determined in the present work. A new methodology was used. Mice were given separately deuterium-labeled drinking water and chow containing 0.3% deuterium-labeled cholesterol. In the retina, the rate of total cholesterol input was 21 ¼g of cholesterol/g retina • day, of which 15 ¼g of cholesterol/g retina • day was provided by local biosynthesis and 6 ¼g of cholesterol/g retina • day was uptaken from the systemic circulation. Thus, local cholesterol biosynthesis accounts for the majority (72%) of retinal cholesterol input. We also quantified cholesterol input to mouse brain, the organ sharing important similarities with the retina. The rate of total cerebral cholesterol input was 121 ¼g of cholesterol/g brain • day with local biosynthesis providing 97% of total cholesterol input. Our work addresses a long-standing question in eye research and adds new knowledge to the potential use of statins (drugs that inhibit cholesterol biosynthesis) as therapeutics for age-related macular degeneration, a common blinding disease.

N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is an experimental pharmaceutical and a steroidal liver X receptor (LXR) agonist, which does not induce undesired hepatic lipogenesis. Herein, DMHCA was evaluated for its retinal effects on normal C57BL/6J and Cyp27a1−/−Cyp46a1−/− mice; the latter having higher retinal total and esterified cholesterol in addition to retinal vascular abnormalities. Different doses and two formulations were used for DMHCA delivery either via drinking water (C57BL/6J mice) or by oral gavage (Cyp27a1−/−Cyp46a1−/− mice). The duration of treatment was 1 week for C57BL/6J mice and 2 or 4 weeks for Cyp27a1−/−Cyp46a1−/− mice. In both genotypes, the higher DMHCA doses (37–80 mg/kg of body weight/day) neither increased serum triglycerides nor serum cholesterol but altered the levels of retinal sterols. Total retinal cholesterol was decreased in the DMHCA-treated mice, mainly due to a decrease in retinal unesterified cholesterol. In addition, retinal levels of cholesterol precursors lanosterol, zymosterol, desmosterol, and lathosterol were changed in Cyp27a1−/−Cyp46a1−/− mice. In both genotypes, DMHCA effect on retinal expression of the LXR target genes was only moderate and gender-specific. Collectively, the data obtained provide evidence for a decrease in retinal cholesterol as a result of DMHCA acting in the retina as an enzyme inhibitor of cholesterol biosynthesis rather than a LXR transcriptional activator. Specifically, DMHCA appears to partially inhibit the cholesterol biosynthetic enzyme Δ24-dehydrocholesterol reductase rather than upregulate the expression of LXR target genes involved in reverse cholesterol transport. The identified DMHCA dosages, formulations, and routes of delivery as well as the observed effects on the retina should be considered in future studies using DMHCA as a potential therapeutic for age-related macular degeneration and diabetic retinopathy.

While studying a movie novel, one receives the opportunity of tracing the reverse process: the process of the “text on the screen” being turned into the “text on paper”. This seems to become even more interesting considering the fact that cinema is a synthetic art form, where the patterns which affect all the senses of perception are used to create the audio-visual image. When it comes to words, naturally, in the cinema one mostly hears them. The word is, of course, one of the most important means of transferring information, yet not the principal one. In this way literature is entirely different from cinema, as it uses only one way of transferring information (visual – if it is a paper-based book, and auditory – in case one is dealing with an audio-version). Consequently, the process of making a movie novel is connected with converting information from one form into the other. In addition, there is the question about the peculiarities of movie novel poetics considering the fact that the general contents are known to the recipient and, what is more, were perceived with the help of the other senses.

Sophisticated criminal situation with juvenile delinquency in Arkhangelsk region has prompted practitioners to find new ways to counteract. The basis for the acquisition of new knowledge in the field of prevention of juvenile delinquency was the phased introduction of social support for the pre-trial juvenile in conflict with the law. Based on the survey of investigators, investigators, judges and social workers involved in the experiment, the analysis of materials of criminal cases involving young offender’s conclusions about the positive results of the experiment revealed the difficulties and challenges faced by law enforcers. The article provides suggestions for optimizing the procedure of pre-trial support.

Biological activity of the iridoid glycosides extract from Linaria genistifolia (L.) Mill. has been investigated, namely its influence on the resistance of the winter wheat Odesschi 51 plant to the caused by the Fusarium oxysporum and Helminthosporium avenae pathogenic fungi root rot. Our results indicate that summary iridoid glycosides from this plant, containing four major known compounds: 5-O-allosylantirrinoside, antirrinoside, linarioside and 6-β-hidroxiantirride, can be successfully employed in biological control of the afore-mentioned wheat pathogens: it stimulates wheat grains germination and embryonic root growth in conditions of fungal infection. 1H and 13C NMR characteristics of 5-O-allosylantirrinoside in Py-d5 are for the first time presented. Structures of two conformers of 5-O-allosylantirrinoside in D2O and Py-d5 solutions are proposed, based on the experimental NMR evidence and molecular modelling studies.

Effects of serum cholesterol on cholesterol content in the retina are currently unknown. It is also unclear how cholesterol levels are controlled in the retina. High-cholesterol diet and oral administrations of simvastatin were used to modulate serum cholesterol in mice. These treatments only modestly affected cholesterol content in the retina and had no significant effect on retinal expression of the major cholesterol- and vision-related genes; the sterol-regulatory element binding protein pathway of transcriptional regulation does not seem to be operative in the retina under the experimental conditions used. Evidence is obtained that posttranslational mechanisms play a role in the control of retinal cholesterol. Retinal genes were only upregulated by oral administrations of TO901317 activating liver X receptors. Three of the upregulated genes could be of particular importance (apoD, Idol, and Rpe65) and have not yet been considered in the context of cholesterol homeostasis in the retina. Collectively, the data obtained identify specific features of retinal cholesterol maintenance and suggest additional therapies for age-related macular degeneration, a blinding disease characterized by cholesterol and lipid accumulations in chorioretinal tissues.

Alzheimer's disease has been shown to have a global reduction in gene expression, called an epigenetic blockade, which may be regulated by histone post‐translational modifications. Histone H3 has been shown to be highly regulated by phosphorylation. We, therefore, chose H3 for investigation of phosphorylation of the core sites serine‐57 (S57) and threonine‐58 (T58). Hemispheres of brains from a mouse model of rapid amyloid deposition (5XFAD) were used for measurement of S57 and T58 phosphorylation. Multiple reaction monitoring (MRM) was used to measure the level of phosphorylation, which was normalized to a non‐modified “housekeeping” peptide of H3. S57 phosphorylation was decreased by 40%, T58 phosphorylation was decreased by 45%, and doubly phosphorylated S57pT58p was decreased by 30% in 5XFAD brain in comparison to C57BL/6J age‐ and sex‐matched wild type controls. Amyloid‐β (Aβ) and amyloid precursor protein were also measured to confirm that 5XFAD mice produced high levels of Aβ. Decreased phosphorylation of these sites in close proximity to DNA may lead to stabilization of DNA–histone interactions and a condensed chromatin state, consistent with the epigenetic blockade associated with AD. Our findings of H3 sites S57 and T58 exhibiting lower levels of phosphorylation in 5XFAD model compared to wild type control implicate these sites in the epigenetic blockade in neurodegeneration pathology.

Cytochrome P450 46A1 (CYP46A1) converts cholesterol to 24-hydroxycholesterol and thereby controls the major pathways of cholesterol removal from the brain. Cyp46a1-/- mice have a reduction in the rate of cholesterol biosynthesis in the brain and significant impairments to memory and learning. To gain insights into the mechanisms underlying Cyp46a1-/- phenotype, we used Cyp46a1-/- mice and quantified their brain sterol levels and the expression of the genes pertinent to cholesterol homeostasis. We also compared the Cyp46a1-/- and wild type brains for protein phosphorylation and ubiquitination. The data obtained enable the following inferences. First, there seems to be a compensatory upregulation in the Cyp46a1-/- brain of the pathways of cholesterol storage and CYP46A1-independent removal. Second, transcriptional regulation of the brain cholesterol biosynthesis via sterol regulatory element binding transcription factors is not significantly activated in the Cyp46a1-/- brain to explain a compensatory decrease in cholesterol biosynthesis. Third, some of the liver X receptor target genes (Abca1) are paradoxically upregulated in the Cyp46a1-/- brain, possibly due to a reduced activation of the small GTPases RAB8, CDC42, and RAC as a result of a reduced phosphorylation of RAB3IP and PAK1. Fourth, the phosphorylation of many other proteins (a total of 146) is altered in the Cyp46a1-/- brain, including microtubule associated and neurofilament proteins (the MAP and NEF families) along with proteins related to synaptic vesicles and synaptic neurotransmission (e.g., SLCs, SHANKs, and BSN). Fifth, the extent of protein ubiquitination is increased in the Cyp46a1-/- brain, and the affected proteins pertain to ubiquitination (UBE2N), cognition (STX1B and ATP1A2), cytoskeleton function (TUBA1A and YWHAZ), and energy production (ATP1A2 and ALDOA). The present study demonstrates the diverse potential effects of CYP46A1 deficiency on brain functions and identifies important proteins that could be affected by this deficiency.

Of the different oxygenated cholesterol metabolites, 7-ketocholesterol (7KCh) is considered a noxious oxy­sterol implicated in the development of certain pathologies, including those found in the eye. Here we elucidated whether sterol 27-hydroxylase cytochrome P450 27A1 (CYP27A1) is involved in elimination of 7KCh from the posterior part of the eye: the neural retina and underlying retinal pigment epithelium (RPE). We first established that the affinities of purified recombinant CYP27A1 for 7KCh and its endogenous substrate cholesterol are similar, yet 7KCh is metabolized at a 4-fold higher rate than cholesterol in the reconstituted system in vitro. Lipid extracts from bovine neural retina and RPE were then analyzed by isotope dilution GC-MS for the presence of the 7KCh-derived oxysterols. Two metabolites, 3β,27-dihydroxy-5-cholesten-7-one (7KCh-27OH) and 3β-hydroxy-5-cholesten-7-one-26-oic acid (7KCh-27COOH), were detected in the RPE but not in the neural retina. 7KCh-27OH was also formed when RPE homogenates were supplemented with NADPH and the mitochondrial redox system. Quantifications in human RPE showed that CYP27A1 is indeed expressed in the RPE at 2-4-fold higher levels than in the neural retina. The data obtained represent evidence for the role of CYP27A1 in retinal metabolism of 7KCh and suggest that, in addition to cholesterol removal, the functions of this enzyme could also include elimination of toxic endogenous compounds.

Cholesterol 24S-hydroxylase (CYP46A1) is of key importance for cholesterol homeostasis in the brain. This enzyme seems to be resistant toward most regulatory factors and at present no drug effects on its activity have been described. The crystal structures of the substrate-free and substrate-bound CYP46A1 were recently determined (Mast et al., Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl. Acad. Sci. USA. 2008. 105: 9546–9551). These structural studies suggested that ligands other than sterols can bind to CYP46A1. We show here that the antifungal drug voriconazole binds to the enzyme in vitro and inhibits CYP46A1-mediated cholesterol 24-hydroxylation with a Ki of 11 nM. Mice treated with daily intraperitoneal injections of voriconazole for 5 days had high levels of voriconazole in the brain and significantly reduced brain levels of 24S-hydroxycholesterol. The levels of squalene, lathosterol, and HMG-CoA reductase mRNA were reduced in the brain of the voriconazole-treated animals as well, indicating a reduced cholesterol synthesis. Most of this effect may be due to a reduced utilization of cholesterol by CYP46A1. One of the side-effects of voriconazole is visual disturbances. Because CYP46A1 is also expressed in the neural retina, we discuss the possibility that the inhibition of CYP46A1 by voriconazole contributes to these visual disturbances.

Three phenylethanoid glycosides (1, 2, 3) and one iridoid glycoside (4) were isolated from aerial parts of Veronica chamaedrys L. (Scrophulariaceae) for the first time. On the basis of spectral analysis, the structures of these compounds were determined to be acteoside (3,4-dihydroxy-β-phenylethoxy-O-α-L-rhamnopyranosyl-(1→3)-4-O-caffeoyl-β-D-glucopyranoside) (1), ehrenoside (3,4-dihydroxy-β-phenylethoxy-O-α-L-arabinopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→3)-4-O-caffeoyl-β-D-glucopyranoside) (2), chamaedroside (3,4-dihydroxy-β-phenylethoxy-O-α-L-rhamnopyranosyl-(1→3)-4-O-caffeoyl-α-L-arabinopyranoside) (3) and aucuboside (4).

Histone deacetylase (HDAC) inhibition has promise as a therapy for Alzheimer's disease (AD) and other neurodegenerative diseases. Currently, therapeutic HDAC inhibitors target many HDAC isoforms, a particularly detrimental approach when HDAC isoforms are known to have different and specialized functions. We have developed a multiple reaction monitoring (MRM) mass spectrometry assay using stable isotope-labeled QconCATs as internal standards to quantify HDAC isoforms. We further determined a quantitative pattern of specific HDACs expressed in various human and mouse neural tissues. In human AD frontal cortex, HDAC1,2 decreased 32%, HDAC5 increased 47%, and HDAC6 increased 31% in comparison to age-matched controls. Human neural retina concentrations of HDAC1, 2, HDAC5, HDAC6, and HDAC7 decreased in age-related macular degeneration (AMD)-affected donors and exhibited a greater decrease in AD-affected donors in comparison to age-matched control neural retinas. Additionally, HDAC concentrations were measured in whole hemisphere of brain of 5XFAD mice, a model of β-amyloid deposition, to assess similarity to AD in human frontal cortex. HDAC profiles of human frontal cortex and mouse hemisphere had noticeable differences and relatively high concentrations of HDAC3 and HDAC4 in mice, which were undetectable in humans. Our method for quantification of HDAC isoforms is a practical and efficient technique to quantify isoforms in various tissues and diseases. Changes in HDAC concentrations reported herein contribute to the understanding of the pathology of neurodegeneration.

The purpose of this study is to understand the impact of the new Brazilian legislation regulating partnerships between the State and Civil Society (Nonprofit) Organizations between 1999 and 2002. The passing of Law No. 9790/99 – known as the Nonprofit Law – created the legal concept of Organizações da Sociedade Civil de Interesse Público – OSCIPs (Public Interest Civil Society Organizations). Based on an exploratory survey, this study, using the Institutional Theory, allowed the analysis of how older organizations (NGOs and traditional social benefit organizations) resisted to the adoption of the OSCIP standard due to organizational inertia, while acceptance of the model was greater among younger organizations, in a clear coercive and normative isomorphic development.

Cholesterol plays an important role in cellular function and membrane compartmentalization and is involved in the interaction with more than a dozen of different proteins. Using three cholesterol-metabolizing cytochrome P450s (P450s 7A1, 46A1, and 11A1), we have developed a rapid and simple assay for measurements of nanomolar to micromolar cholesterol affinities. In this assay, the P450 is incubated with a fixed amount of radiolabeled cholesterol and varying concentrations of cold cholesterol followed by separation of free and protein-bound cholesterol via filtration through a membrane. Free cholesterol is found in the flow-through fraction, whereas P450 binds to the membrane. The radioactivity of the membranes is then measured, and a saturation curve is generated after correction for nonspecific binding of cholesterol to the filter. The validity of the filter assay was confirmed by spectral assay, a traditional method to evaluate the interaction of the P450 enzymes with their substrates. Two types of membranes, one binding positively charged proteins and another binding negatively charged proteins, were identified. These membranes were also found to hold proteins through hydrophobic interactions.Thus, the cholesterol binding properties of a wide variety of proteins could be characterized using this filter assay.

A new flavonol glycoside, 5,4′-dimethylkaempferol 3-O-β-D-(6′′-α-Lrhamnopyranosyl) -glucopyranoside, together with three known compounds were isolated from the n-butanolic soluble fraction of underground and aerial parts of Linaria vulgaris Mill, collected on the territory of Moldova. The characterisation of these compounds was achieved by various chromatographic and spectroscopic methods (IR, UV, 13C-NMR, 1H-NMR and MS).