Аналіз міграційних процесів в ЄС та теорія мультикультиралізму: сучасний стан та перспективи

The article deals with the problem of the migration crisis that has hit the EU. Since 2015, there has been a sharp increase in the number of refugees from the region, to which European countries were not ready. By the end of 2019, Europe has already exhausted its economic capacity to receive and accommodate refugees, but their flow is continuing. Over the last 5 years, more than 4 million refugees from the Middle East, North Africa and South Asia have come to Europe. In 2015, the flow of migrants was over 1.5 million people, in 2016 - 900 000, in 2017 - 650 000, in 2018 - 600 000, in 2019 - almost 550 000.The main causes of large-scale movement of migrants to Europe have been identified. Among them are wars and conflicts that destabilize the situation in their native countries; demographic outbreak in Africa and the Middle East, deteriorating funding for refugee camps in Turkey, Lebanon and Jordan, exacerbation of the 2018-2019 Syrian crisis; the availability of high social guarantees and diaspora relatives in many EU countries.The political, social, cultural consequences of the migration crisis for individual countries and the EU are analyzed. The increasing flow of refugees has exacerbated in European societies the problems of terrorism, the increase in crime rates, the poor cultural compatibility of the local population with refugees, the increased right-wing sentiment and the high social costs of migrant adaptation.The importance of the ideology of multiculturalism for the current migration crisis in the EU is substantiated. The phenomenon of multiculturalism is compared with the phenomena of globalization and shows the impact on the situation in society, which lead to conflict. Multiculturalism has recently been perceived as a means that can mitigate the negative (primarily for traditional cultures, ethnic and religious groups) consequences of globalization, but narrowing the philosophical view of the phenomenon of multiculturalism to the institutional level, modern representatives of the humanities and practices in Europe (political scientists, sociologists, politicians) faced with the fact that the interaction of cultures has not been adequately reflected in theory and held in practice.В статье освещено современное состояние миграционных проблем, с которыми столкнулись, начиная с 2015 г., страны-члены ЕС. С 2015 г. наблюдается резкий рост числа беженцев, к которым европейские страны были не готовы. К концу 2019 г. Европа уже исчерпала свои экономические возможности принимать и размещать беженцев, но их поток продолжается. За последние 5 лет в Европу прибыло более 4 млн беженцев с Ближнего Востока, Северной Африки и Южной Азии. В 2015 г. поток мигрантов составил более 1,5 млн человек, в 2016 г. – 900 000, в 2017 г. – 650 000, в 2018 г. – 600 000, в 2019 г. – почти 550 000.Определены основные причины масштабного перемещения мигрантов в Европу. Среди них войны и конфликты, которые дестабилизируют ситуацию в родных странах; демографические вспышки в Африке и на Ближнем Востоке; ухудшение финансирования лагерей для беженцев в Турции, Ливане и Иордании, обострение сирийского кризиса 2018–2019 гг.; наличие высоких социальных гарантий и родственников из диаспоры во многих странах ЕС.Проанализированы политические, социальные, культурные последствия миграционного кризиса для отдельных стран и ЕС. Растущий поток беженцев обострил в европейских обществах проблемы терроризма, рост уровня преступности, недостаточную культурную совместимость местного населения с беженцами, усиление правых настроений и высокие социальные расходы на адаптацию мигрантов.Обосновано значение идеологии мультикультурализма для современного миграционного кризиса в ЕС. Явление мультикультурализма сопоставляется с явлениями глобализации и демонстрируется влияние на ситуации в обществе, которые приводят к конфликту. Мультикультурализм недавно воспринимался как средство, которое способно смягчить негативные (прежде всего для традиционных культур, этнических и конфессиональных групп) последствия глобализации, но сужая философский взгляд на феномен мультикультурализма к институциональному уровню, современные представители гуманитарной науки и практики в Европе (политологи, социологи, политики) столкнулись с тем, что взаимодействие культур пока не находит должного отражения в теории и удерживается на практике.У статті висвітлено сучасний стан міграційних проблем, з якими зіштовхнулись, починаючи з 2015 р., країни-члени ЄС. З 2015 р. спостерігається різке зростання кількості біженців, до яких європейські країни були не готові. До кінця 2019 р. Європа вже вичерпала свої економічні можливості приймати та розміщувати біженців, але їх потік продовжується. За останні 5 років до Європи прибуло понад 4 млн біженців з Близького Сходу, Північної Африки та Південної Азії. У 2015 р. потік мігрантів становив понад 1,5 млн людей, у 2016 р. – 900 000, у 2017 р. – 650 000, у 2018 р. – 600 000, у 2019 р. – майже 550 000. Визначено основні причини масштабного переміщення мігрантів до Європи. Серед них війни та конфлікти, які дестабілізують ситуацію у рідних країнах; демографічні спалахи в Африці та на Близькому Сході; погіршення фінансування таборів для біженців у Туреччині, Лівані та Йорданії, загострення сирійської кризи 2018–2019 рр.; наявність високих соціальних гарантій та родичів з діаспори у багатьох країнах ЄС. Проаналізовано політичні, соціальні, культурні наслідки міграційної кризи для окремих країн та ЄС. Зростаючий потік біженців загострив у європейських суспільствах проблеми тероризму, зростання рівня злочинності, недостатню культурну сумісність місцевого населення з біженцями, посилення правих настроїв та високі соціальні витрати на адаптацію мігрантів. Обґрунтовано значення ідеології̈ мультикультуралізму для сучасної міграційної кризи в ЄС. Явище мультикультуралізму порівнюється з явищами глобалізації̈ та демонструється вплив на ситуації̈ в суспільстві, які призводять до конфлікту. Мультикультуралізм донедавна сприймався як засіб, який здатний пом’якшити негативні (насамперед для традиційних культур, етнічних та конфесійних груп) наслідки глобалізації, але звужуючи філософський погляд на феномен мультикультуралізму до інституційного рівня, сучасні представники гуманітарної̈ науки й практики в Європі (політологи, соціологи, політики) зіткнулися з тим, що взаємодія культур поки не знаходить належного зображення в теорії та стримується на практиці

Feeding and fasting controls liver expression of a regulator of G protein signaling (Rgs16) in periportal hepatocytes

BACKGROUND: Heterotrimeric G protein signaling in liver helps maintain carbohydrate and lipid homeostasis. G protein signaling is activated by binding of extracellular ligands to G protein coupled receptors and inhibited inside cells by regulators of G protein signaling (RGS) proteins. RGS proteins are GTPase activating proteins, and thereby regulate Gi and/or Gq class G proteins. RGS gene expression can be induced by the ligands they feedback regulate, and RGS gene expression can be used to mark tissues and cell-types when and where Gi/q signaling occurs. We characterized the expression of mouse RGS genes in liver during fasting and refeeding to identify novel signaling pathways controlling changes in liver metabolism. RESULTS: Rgs16 is the only RGS gene that is diurnally regulated in liver of ad libitum fed mice. Rgs16 transcription, mRNA and protein are up regulated during fasting and rapidly down regulated after refeeding. Rgs16 is expressed in periportal hepatocytes, the oxygen-rich zone of the liver where lipolysis and gluconeogenesis predominates. Restricting feeding to 4 hr of the light phase entrained Rgs16 expression in liver but did not affect circadian regulation of Rgs16 expression in the suprachiasmatic nuclei (SCN). CONCLUSION: Rgs16 is one of a subset of genes that is circadian regulated both in SCN and liver. Rgs16 mRNA expression in liver responds rapidly to changes in feeding schedule, coincident with key transcription factors controlling the circadian clock. Rgs16 expression can be used as a marker to identify and investigate novel G-protein mediated metabolic and circadian pathways, in specific zones within the liver

A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice withKIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling (warfarin and BGB324) have fewer tumor initiation sites and reduced tumor size compared with the standard-of-care treatment. Rgs16::GFP is therefore an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens such as Axl-targeted agents. This screening strategy can potentially be applied to identify improved therapeutics for other cancers

Modern Diagnostic Studies in Rhinology: Necessary and Sufficient

The article provides the overview of the most modern diagnostics methods for diseases of the nasal cavity, paranasal sinuses and nasopharynx. The advisability of additional examinations for various pathologies has been provided. Methods of laboratory diagnostics and methods of material sampling for microbiological verification of pathogens are discussed. Methods of functional diagnostics of nasal breathing disorders are described

New High-Affinity Thrombin Aptamers for Advancing Coagulation Therapy: Balancing Thrombin Inhibition for Clot Prevention and Effective Bleeding Management with Antidote

Thrombin is a key enzyme involved in blood clotting, and its dysregulation can lead to thrombotic diseases such as stroke, myocardial infarction, and deep vein thrombosis. Thrombin aptamers have the potential to be used as therapeutic agents to prevent or treat thrombotic diseases. Thrombin DNA aptamers developed in our laboratory exhibit high affinity and specificity to thrombin. In vitro assays have demonstrated their efficacy by significantly decreasing Factor II activity and increasing PT and APTT times in both plasma and whole blood. Aptamers AYA1809002 and AYA1809004, the two most potent aptamers, exhibit high affinity for their target, with affinity constants (Kd) of 10 nM and 13 nM, respectively. Furthermore, the in vitro activity of these aptamers displays dose-dependent behavior, highlighting their efficacy in a concentration-dependent manner. In vitro stability assessments reveal that the aptamers remain stable in plasma and whole blood for up to 24 h. This finding is crucial for their potential application in clinical settings. Importantly, the thrombin inhibitory activity of the aptamers can be reversed by employing reverse complement sequences, providing a mechanism to counteract their anticoagulant effects when necessary to avoid excessive bleeding. These thrombin aptamers have been determined to be safe, with no observed mutagenic or immunogenic effects. Overall, these findings highlight the promising characteristics of these newly developed thrombin DNA aptamers, emphasizing their potential for therapeutic applications in the field of anticoagulation therapy. Moreover, the inclusion of an antidote in the coagulation therapy regimen can improve patient safety, ensure greater therapeutic efficacy, and minimize risk during emergency situations

Dual Checkpoint Aptamer Immunotherapy: Unveiling Tailored Cancer Treatment Targeting CTLA-4 and NKG2A

Recent strides in immunotherapy have illuminated the crucial role of CTLA-4 and PD-1/PD-L1 pathways in contemporary oncology, presenting both promises and challenges in response rates and adverse effects. This study employs a computational biology tool (in silico approach) to craft aptamers capable of binding to dual receptors, namely, inhibitory CTLA4 and NKG2A, thereby unleashing both T and NK cells and enhancing CD8+ T and NK cell functions for tumor cell lysis. Computational analysis highlighted AYA22T-R2-13 with HADDOCK scores of −78.2 ± 10.2 (with CTLA4), −60.0 ± 4.2 (with NKG2A), and −77.5 ± 5.6 (with CD94/NKG2A). Confirmation of aptamer binding to targeted proteins was attained via ELISA and flow cytometry methods. In vitro biological functionality was assessed using lactate dehydrogenase (LDH) cytotoxicity assay. Direct and competitive assays using ELISA and flow cytometry demonstrated the selective binding of AYA22T-R2-13 to CTLA4 and NKG2A proteins, as well as to the cell surface receptors of IL-2-stimulated T cells and NK cells. This binding was inhibited in the presence of competition from CTLA4 or NKG2A proteins. Remarkably, the blockade of CTLA4 or NKG2A by AYA22T-R2-13 augmented human CD8 T cell- and NK cell-mediated tumor cell lysis in vitro. Our findings highlight the precise binding specificity of AYA22T-R2-13 for CTLA4-B7-1/B7-2 (CD80/CD86) or CD94/NKG2A-HLA-E interactions, positioning it as a valuable tool for immune checkpoint blockade aptamer research in murine tumor models. These in vitro studies establish a promising foundation for further enhancing binding capacity and establishing efficacy and safety in animal models. Consequently, our results underscore the potential of AYA22T-R2-13 in cancer immunotherapy, offering high specificity, low toxicity, and the potential for cost-effective production

Современные диагностические исследования в ринологии: необходимое и достаточное

The article provides the overview of the most modern diagnostics methods for diseases of the nasal cavity, paranasal sinuses and nasopharynx. The advisability of additional examinations for various pathologies has been provided. Methods of laboratory diagnostics and methods of material sampling for microbiological verification of pathogens are discussed. Methods of functional diagnostics of nasal breathing disorders are described.В статье представлен обзор наиболее современных методов диагностики заболеваний полости носа, околоносовых пазух и носоглотки; обоснована целесообразность назначения дополнительных обследований при различной патологии. Обсуждаются методы лабораторной диагностики и способы забора материала для микробиологической верификации возбудителей заболеваний. Описаны методы функциональной диагностики нарушений носового дыхания

Regulating the ARNT/TACC3 Axis: Multiple Approaches to Manipulating Protein/Protein Interactions with Small Molecules

For several well-documented reasons, it has been challenging to develop artificial small molecule inhibitors of protein/protein complexes. Such reagents are of particular interest for transcription factor complexes given links between their misregulation and disease. Here we report parallel approaches to identify regulators of a hypoxia signaling transcription factor complex, involving the ARNT subunit of the HIF (Hypoxia Inducible Factor) activator and the TACC3 (Transforming Acidic Coiled Coil Containing Protein 3) coactivator. In one route, we used <i>in vitro</i> NMR and biochemical screening to identify small molecules that selectively bind within the ARNT PAS (Per-ARNT-Sim) domain that recruits TACC3, identifying KG-548 as an ARNT/TACC3 disruptor. A parallel, cell-based screening approach previously implicated the small molecule KHS101 as an inhibitor of TACC3 signaling. Here, we show that KHS101 works indirectly on HIF complex formation by destabilizing both TACC3 and the HIF component HIF-1α. Overall, our data identify small molecule regulators for this important complex and highlight the utility of pursuing parallel strategies to develop protein/protein inhibitors

Regulating the ARNT/TACC3 Axis: Multiple Approaches to Manipulating Protein/Protein Interactions with Small Molecules

For several well-documented reasons, it has been challenging to develop artificial small molecule inhibitors of protein/protein complexes. Such reagents are of particular interest for transcription factor complexes given links between their misregulation and disease. Here we report parallel approaches to identify regulators of a hypoxia signaling transcription factor complex, involving the ARNT subunit of the HIF (Hypoxia Inducible Factor) activator and the TACC3 (Transforming Acidic Coiled Coil Containing Protein 3) coactivator. In one route, we used <i>in vitro</i> NMR and biochemical screening to identify small molecules that selectively bind within the ARNT PAS (Per-ARNT-Sim) domain that recruits TACC3, identifying KG-548 as an ARNT/TACC3 disruptor. A parallel, cell-based screening approach previously implicated the small molecule KHS101 as an inhibitor of TACC3 signaling. Here, we show that KHS101 works indirectly on HIF complex formation by destabilizing both TACC3 and the HIF component HIF-1α. Overall, our data identify small molecule regulators for this important complex and highlight the utility of pursuing parallel strategies to develop protein/protein inhibitors