Separatrix splitting at a Hamiltonian 02iω0^2 i\omega bifurcation

We discuss the splitting of a separatrix in a generic unfolding of a degenerate equilibrium in a Hamiltonian system with two degrees of freedom. We assume that the unperturbed fixed point has two purely imaginary eigenvalues and a double zero one. It is well known that an one-parametric unfolding of the corresponding Hamiltonian can be described by an integrable normal form. The normal form has a normally elliptic invariant manifold of dimension two. On this manifold, the truncated normal form has a separatrix loop. This loop shrinks to a point when the unfolding parameter vanishes. Unlike the normal form, in the original system the stable and unstable trajectories of the equilibrium do not coincide in general. The splitting of this loop is exponentially small compared to the small parameter. This phenomenon implies non-existence of single-round homoclinic orbits and divergence of series in the normal form theory. We derive an asymptotic expression for the separatrix splitting. We also discuss relations with behaviour of analytic continuation of the system in a complex neighbourhood of the equilibrium

Synthesis of Carbon Nanotubes and Nanofibers on Silica and Cement Matrix Materials

In order to create strong composite materials, a good dispersion of carbon nanotubes (CNTs) and nanofibers (CNFs) in a matrix material must be obtained. We proposed a simple method of growing the desirable carbon nanomaterial directly on the surface of matrix particles. CNTs and CNFs were synthesised on the surface of model object, silica fume particles impregnated by iron salt, and directly on pristine cement particles, naturally containing iron oxide. Acetylene was successfully utilised as a carbon source in the temperature range from 550 to 750 C. 5–10 walled CNTs with diameters of 10–15 nm at 600 C and 12–20 nm at 750 C were synthesised on silica particles. In case of cement particles, mainly CNFs with a diameter of around 30 nm were grown. It was shown that high temperatures caused chemical and physical transformation of cement particles.Peer reviewe

Cytogenomic Profile of Uterine Leiomyoma: In Vivo vs. In Vitro Comparison

We performed a comparative cytogenomic analysis of cultured and uncultured uterine leiomyoma (UL) samples. The experimental approach included karyotyping, aCGH, verification of the detected chromosomal abnormalities by metaphase and interphase FISH, MED12 mutation analysis and telomere measurement by Q-FISH. An abnormal karyotype was detected in 12 out of 32 cultured UL samples. In five karyotypically abnormal ULs, MED12 mutations were found. The chromosomal abnormalities in ULs were present mostly by complex rearrangements, including chromothripsis. In both karyotypically normal and abnormal ULs, telomeres were ~40% shorter than in the corresponding myometrium, being possibly prerequisite to chromosomal rearrangements. The uncultured samples of six karyotypically abnormal ULs were checked for the detected chromosomal abnormalities through interphase FISH with individually designed DNA probe sets. All chromosomal abnormalities detected in cultured ULs were found in corresponding uncultured samples. In all tumors, clonal spectra were present by the karyotypically abnormal cell clone/clones which coexisted with karyotypically normal ones, suggesting that chromosomal abnormalities acted as drivers, rather than triggers, of the neoplastic process. In vitro propagation did not cause any changes in the spectrum of the cell clones, but altered their ratio compared to uncultured sample. The alterations were unique for every UL. Compared to its uncultured counterpart, the frequency of chromosomally abnormal cells in the cultured sample was higher in some ULs and lower in others. To summarize, ULs are characterized by both inter- and intratumor genetic heterogeneity. Regardless of its MED12 status, a tumor may be comprised of clones with and without chromosomal abnormalities. In contrast to the clonal spectrum, which is unique and constant for each UL, the clonal frequency demonstrates up or down shifts under in vitro conditions, most probably determined by the unequal ability of cells with different genetic aberrations to exist outside the body

Предикторы отмены генно-инженерных биологических препаратов ввиду развития нежелательных явлений у пациентов с ревматоидным артритом

Currently, a large number of highly effective biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) are used for the treatment of rheumatoid arthritis (RA). However, in addition to effectiveness, it is necessary to evaluate the risk of adverse events (AEs) when using them.Objective: to determine the predictors of bDMARDs and tsDMARDs discontinuation due to AEs in patients with RA.Patients and methods. The study included 661 patients with RA who took bDMARDs and tsDMARDs. The search for predictors of targeted therapy discontinuation due to AEs was carried out in two stages. At the first stage, using the Kaplan-Meier method, we selected indicators that showed the greatest significant single-factor relationship with the duration of retention on therapy. At the second stage, significant independent indicators were obtained by iterative selection of variables within the multivariate proportional risk model according to Cox.Results and discussion. The presence of rheumatoid nodules (p<0.001), high doses of glucocorticoids (GC; p<0.001), low doses of methotrexate (MT; p=0.009) are significant independent factors for increasing the risk of drugs discontinuation due to the development of AEs. The type of bDMARDs/tsDMARD used also significantly correlated with the risk of discontinuation of therapy due to AEs. A relatively high risk of treatment discontinuation was observed with infliximab (IFN) and certolizumab pegol (CZP). Cancellation of IFN was associated with the occurrence of infusion reactions and infectious complications, and CZP was associated with infectious complications.Conclusion. An increase in the dose of MT and decrease in the use of GCs can help prevent the development of AEs leading to the abolition of biologics and tsDMARDs. Significant differences were found between bDMARDs in terms of the risk of their cancellation due to AEs.В настоящее время для лечения ревматоидного артрита (РА) используется большое число генно-инженерных биологических (ГИБП) и таргетных синтетических базисных противовоспалительных препаратов (тсБПВП), которые обладают высокой эффективностью. Однако, помимо эффективности, необходимо оценивать риск возникновения нежелательных явлений (НЯ) при их использовании.Цель исследования — определить предикторы отмены ГИБП и тсБПВП из-за НЯ у пациентов с РА.Пациенты и методы. В исследование включен 661 пациент с РА, принимавший ГИБП и тсБПВП. Поиск предикторов отмены таргетной терапии ввиду НЯ проводился в два этапа. На первом этапе с помощью метода Каплана—Майера были отобраны показатели, которые демонстрировали наибольшую значимую однофакторную связь с длительностью удержания на терапии. На втором этапе значимые независимые показатели были получены путем пошагового отбора переменных в рамках многофакторной модели пропорционального риска по Коксу.Результаты и обсуждение. Наличие ревматоидных узелков (p<0,001), высокие дозы глюкокортикоидов (ГК; p<0,001), низкие дозы метотрексата (МТ; p=0,009) являются значимыми независимыми факторами увеличения риска отмены препаратов из-за развития НЯ. Используемый ГИБП/тсБПВП также значимо коррелировал с риском отмены терапии из-за НЯ. Относительно высокий риск прекращения лечения был отмечен у инфликсимаба (ИНФ) и цертолизумаба пэгола (ЦЗП). Отмена ИНФ была связана с возникновением инфузионных реакций и инфекционных осложнений, а ЦЗП — с инфекционными осложнениями.Заключение. Увеличение дозы МТ, уменьшение использования ГКмогут способствовать предотвращению развития НЯ, приводящих к отмене ГИБП и тсБПВП. Выявлены существенные различия между ГИБП в отношении риска их отмены вследствие НЯ

Democracy, protest and public sphere in Russia after the 2011–2012 anti-government protests: digital media at stake

The 2011–2012 Russian protest mobilisations were largely enabled by the rise of social networks. Social and technological advancements paired to pave the way for the ‘biggest protests since the fall of USSR’. Ubiquitous and uncensored social media facilitated the networking and mobilisation for this protest activity: Liberal masses were able to share and discuss their grievances, unite and coordinate online for the offline protest. The digitally savvy protest public developed to confront the government, which appeared to be astonished by the scale of protest. Those mobilisations marked an important gap between the government’s conception of the society and the real state of resistance. This article studies three main hypotheses regarding the potential of the protest movement in Russia. The hypotheses were drawn from recent sociological, political and media studies on Russian resistance. Current research aims to contribute to the debate from the digital media perspective. It therefore evaluates three main assumptions: Digital media have the potential to empower, dependent upon the relevant political, social and economic factors; digital media isolates protest publics and therefore may be more useful for the government than the resistance; and recent censorship of digital media communication signals a tightening of both formal and informal restrictions against opposition and protest politics. This article uses theoretical and factual evidence on the limitations of democracy and the public sphere and conceptualises the government’s management of resistance in Russia during and after the 2011–2012 protests. It studies how the hybrid political regime in Russia balances restrictions on freedom of speech with strengthened state propaganda and how it mediates media oppression and invites self-censorship. Finally, it examines how the state communication watchdog has recently focused its attention at the digital realm. This move confirms the importance of the online protest communication for the Russian political environment. Yet the state’s acknowledgement of digital political resistance may lead to further oppression and curbing of this emerging component of Russian politics

Изучение влияния антител к боковым карбогидратным звеньям аллергенов на популяционный профиль сенсибилизации пациентов в Юго-западном регионе Украины

Были обследованы на наличие IgE антител к 28 аллергенам методом иммуноблоттинга производства компании Mediwiss (Германия) 500 пациентов Юго-Западного региона Украины с подозрением либо клинически установленным диагнозом аллергического ринита, конъюнктивита, бронхиальной астмы, поллиноза. У (21,1±2,00) % обследованных пациентов с наличием антител к различным аллергенам выявлялись антитела к ССD-маркеру, присутствовавшем на блоте. Такие пациенты значительно меняли эпидемиологическую картину сенсибилизации обследованной когорты за счет повышения процента положительных реакций на растительные, инсектные аллергены, а также на латекс. Использование ССD-блокера при повторном обследовании 84 пациентов с множественной сенсибилизацией достоверно снижало процент положительных реакций именно на вышеуказанные аллергены, содержащие боковые кроссреактивные карбогидратные цепочки. Это позволяет рекомендовать использование ССD-блокера для устранения перекрестных неспецифических реакций при рутинном обследовании пациентов с аллергическими заболеваниями. Следует учитывать также возможность неспецифических реакций при эпидемиологическом анализе серопозитивности к аллергенам в популяции.500 patients from the South-Western region of Ukraine with suspected or clinically confirmed diagnosis of allergic rhinitis, conjunctivitis, bronchial asthma, pollinosis were examined for the presence of IgE antibodies to 28 allergens by immunoblotting manufactured by Mediwiss (Germany). It was shown that (21.10±2.00)% of the examined patients with antibodies to various allergens have also antibodies to the CСD-marker present on the blot. Such patients significantly changed the epidemiological pattern of sensitization of the examined cohort due to increase of the percentage of positive reactions to plant, insect allergens, and also to latex. The use of CСD-blocker in the re-examination of 84 patients with multiple sensitization significantly reduced the percentage of positive reactions particularly to the allergens containing cross-reactive carbohydrate chains. This makes it possible to recommend the use of CCD-blocker for the elimination of cross-nonspecific reactions during the routine examination of patients with allergic diseases. The possibility of non-specific reactions in the epidemiological analysis of seropositivity to allergens in the population should also be taken into account

Эффективность использования CCD-блокера у пациентов с множественной сенсибилизацией

Мета роботи – вивчити ефективність використання CCD-блокера в пацієнтів із множинною сенсибілізацією (позитивні реакції на 10 та більше алергенів) для оптимізації алгоритму обстеження. Матеріал і методи. Обстежені 2197 пацієнтів у Південному регіоні України із клінічними проявами респіраторної алергії за допомогою тест-систем AllergyScreen Panel на 44 алергени. 84 пацієнти з множинними реакціями на алергени обстежені повторно після абсорбції сироватки крові комерційним CCD-блокером виробництва компанії MediWiss Analytic GmdH. Результати. У 85,4±0,75% пацієнтів реєструвались позитивні результати хоча б до одного з алергенів, 17,8±1,71% з них демонстрували антитіла до перехресних карбогідратних ланцюгів (CCD), які можуть спричиняти неспецифічні реакції. Встановлено вплив антитіл щодо CCD на кількість позитивних маркерів на блоті (критерій Манна-Уітні, p<0,001). Відсоток виявлення антитіл до CCD достовірно збільшувався в пацієнтів з 5 та більше маркерами на одному блоті (p<0,05) і становив від 22,72±6,31% у пацієнтів з 5 маркерами до 54,83±0,06% при визначенні 10 і більше. Характер змін після використання CCD-блокера відрізнявся для кожного пацієнта та залежав від індивідуальної сенсибілізації: 1) повне зникнення позитивних маркерів ймовірно при сенсибілізації лише до карбогідратних ланцюгів, 2) незмінні результати ймовірно лише до протеїнових епітопів, 3) сенсибілізація до обох складових одночасно може зумовлювати часткове зниження кількості та класу позитивних реакцій. Найбільший відсоток блокування в розрізі груп алергенів за походженням посідали рослинні алергени (близько 63%) та алергени інсектного походження та латекс (близько 28%). Висновок. Показана доцільність використання CCD-блокера в пацієнтів із полісенсибилізацією переважно до рослинних та інсектних алергенів.Objective: to study the effectiveness of CCD blocker use in patients with multiple sensitization (positive reactions to 10 and more allergens) in order to optimize the examination algorithm for such patients. Material and methods. 2197 patients were examined in the Southern region of Ukraine with clinical manifestations of respiratory allergy using the AllergyScreen Panel test systems for 44 allergens. 84 patients with multiple allergen reactions were re-examined after absorption of serum with a commercial CCD blocker, manufactured by MediWiss Analytic GmdH. Results. 85.4 ± 0.75% of patients had a positive reaction to at least one of the allergens. 17.8 ± 1.71% of patients had antibodies to сross-reactive carbohydrate determinants (CCDs) that may cause nonspecifc reactions. The effect of antibodies to CCD on the number of positive blot markers (Mann-Whitney, p <0.001) was determined. The percentage of antibody detection to the CCD signifcantly increased in patients with 5 or more markers per blot (p <0.05) and ranged from 22.72 ± 6.31% in patients with 5 markers to 54.83 ± 0.06% in 10 or more markers per blot. The nature of the changes after using the CCD blocker differed for each patient and depended on individual sensitization: 1) the complete disappearance of positive markers is probably due to sensitization only to the carbohydrate chains, 2) the unchanged results are probably due to sensitization to protein epitopes, and 3) sensitization to both components can simultaneously lead to partial reduction of the number and class of positive reactions. The highest percentage of blockage in the context of allergen origin groups was determined to plant (about 63%), insect and latex (about 28%) allergens. Conclusion. The expediency of CCD blocker using in patients with polysensitization predominantly to plant and insect allergens was shown.Цель работы – изучить эффективность использования CCD-блокера у пациентов с множественной сенсибилизацией (положительные реакции на 10 и более аллергенов) для оптимизации алгоритма обследования. Материал и методы. Обследованы 2197 пациентов в Южном регионе Украины с клиническими проявлениями респираторной аллергии с помощью тест-систем AllergyScreen Panel на 44 аллергена. 84 пациента с множественными реакциями обследованы повторно после абсорбции сыворотки крови CCD-блокером производства компании MediWiss Analytic GmdH. Результаты. У 85,4 ± 0,75% пациентов регистрировались положительные результаты хотя бы к одному из аллергенов, 17,8 ± 1,71% из них демонстрировали наличие антител к перекрестно реагирующим карбогидратным цепям (CCD), которые могут вызывать неспецифические реакции. Установлено влияние антител к CCD на количество положительных маркеров на блоте (критерий Манна-Уитни, p <0,001). Процент выявления антител к CCD достоверно увеличивался у пациентов с 5 и более маркерами на одном блоте (p <0,05) и составлял от 22,72 ± 6,31% у пациентов с 5 маркерами до 54,83 ± 0,06% при 10 и более маркерах. Характер изменений после использования CCD-блокеров отличался для каждого пациента и зависел от индивидуальной сенсибилизации: 1) полное исчезновение положительных маркеров вероятно при сенсибилизации только к карбогидратным цепям, 2) неизменные результаты вероятно при сенсибилизации только к протеиновым эпитопам, 3) сенсибилизация к обоим составляющим одновременно может обусловливать частичное снижение количества и класса положительных реакций. Наибольший процент блокировки в разрезе групп аллергенов по происхождению занимали растительные аллергены (около 63%), аллергены инсектного происхождения и латекс (около 28%). Вывод. Показана целесообразность использования CCD-блокера у пациентов с полисенсибилизацией преимущественно к растительным и инсектным аллергенам

Topographical and Biological Evidence Revealed FTY720-Mediated Anergy-Polarization of Mouse Bone Marrow-Derived Dendritic Cells In Vitro

Abnormal inflammations are central therapeutic targets in numerous infectious and autoimmune diseases. Dendritic cells (DCs) are involved in these inflammations, serving as both antigen presenters and proinflammatory cytokine providers. As an immuno-suppressor applied to the therapies of multiple sclerosis and allograft transplantation, fingolimod (FTY720) was shown to affect DC migration and its crosstalk with T cells. We posit FTY720 can induce an anergy-polarized phenotype switch on DCs in vitro, especially upon endotoxic activation. A lipopolysaccharide (LPS)-induced mouse bone marrow-derived dendritic cell (BMDC) activation model was employed to test FTY720-induced phenotypic changes on immature and mature DCs. Specifically, methods for morphology, nanostructure, cytokine production, phagocytosis, endocytosis and specific antigen presentation studies were used. FTY720 induced significant alterations of surface markers, as well as decline of shape indices, cell volume, surface roughness in LPS-activated mature BMDCs. These phenotypic, morphological and topographical changes were accompanied by FTY720-mediated down-regulation of proinflammatory cytokines, including IL-6, TNF-α, IL-12 and MCP-1. Together with suppressed nitric oxide (NO) production and CCR7 transcription in FTY720-treated BMDCs with or without LPS activation, an inhibitory mechanism of NO and cytokine reciprocal activation was suggested. This implication was supported by the impaired phagocytotic, endocytotic and specific antigen presentation abilities observed in the FTY720-treated BMDCs. In conclusion, we demonstrated FTY720 can induce anergy-polarization in both immature and LPS-activated mature BMDCs. A possible mechanism is FTY720-mediated reciprocal suppression on the intrinsic activation pathway and cytokine production with endpoint exhibitions on phagocytosis, endocytosis, antigen presentation as well as cellular morphology and topography

Emerging role of the calcium-activated, small conductance, SK3 K ⁺ channel in distal tubule function: Regulation by TRPV4

The Ca2+-activated, maxi-K (BK) K+ channel, with low Ca2+-binding affinity, is expressed in the distal tubule of the nephron and contributes to flow-dependent K+ secretion. In the present study we demonstrate that the Ca2+-activated, SK3 (KCa2.3) K + channel, with high Ca2+-binding affinity, is also expressed in the mouse kidney (RT-PCR, immunoblots). Immunohistochemical evaluations using tubule specific markers demonstrate significant expression of SK3 in the distal tubule and the entire collecting duct system, including the connecting tubule (CNT) and cortical collecting duct (CCD). In CNT and CCD, main sites for K+ secretion, the highest levels of expression were along the apical (luminal) cell membranes, including for both principal cells (PCs) and intercalated cells (ICs), posturing the channel for Ca2+- dependent K+ secretion. Fluorescent assessment of cell membrane potential in native, split-opened CCD, demonstrated that selective activation of the Ca2+-permeable TRPV4 channel, thereby inducing Ca2+ influx and elevating intracellular Ca2+ levels, activated both the SK3 channel and the BK channel leading to hyperpolarization of the cell membrane. The hyperpolarization response was decreased to a similar extent by either inhibition of SK3 channel with the selective SK antagonist, apamin, or by inhibition of the BK channel with the selective antagonist, iberiotoxin (IbTX). Addition of both inhibitors produced a further depolarization, indicating cooperative effects of the two channels on Vm. It is concluded that SK3 is functionally expressed in the distal nephron and collecting ducts where induction of TRPV4-mediated Ca2+ influx, leading to elevated intracellular Ca2+ levels, activates this high Ca2+- affinity K+ channel. Further, with sites of expression localized to the apical cell membrane, especially in the CNT and CCD, SK3 is poised to be a key pathway for Ca2+-dependent regulation of membrane potential and K+ secretion. © 2014 Berrout et al