31 research outputs found
Topological quantum field theory and invariants of graphs for quantum groups
On basis of generalized 6j-symbols we give a formulation of topological
quantum field theories for 3-manifolds including observables in the form of
coloured graphs. It is shown that the 6j-symbols associated with deformations
of the classical groups at simple even roots of unity provide examples of this
construction. Calculational methods are developed which, in particular, yield
the dimensions of the state spaces as well as a proof of the relation,
previously announced for the case of by V.Turaev, between these
models and corresponding ones based on the ribbon graph construction of
Reshetikhin and Turaev.Comment: 38 page
String theory and the Kauffman polynomial
We propose a new, precise integrality conjecture for the colored Kauffman
polynomial of knots and links inspired by large N dualities and the structure
of topological string theory on orientifolds. According to this conjecture, the
natural knot invariant in an unoriented theory involves both the colored
Kauffman polynomial and the colored HOMFLY polynomial for composite
representations, i.e. it involves the full HOMFLY skein of the annulus. The
conjecture sheds new light on the relationship between the Kauffman and the
HOMFLY polynomials, and it implies for example Rudolph's theorem. We provide
various non-trivial tests of the conjecture and we sketch the string theory
arguments that lead to it.Comment: 36 pages, many figures; references and examples added, typos
corrected, final version to appear in CM
Protestant women in the late Soviet era: gender, authority, and dissent
At the peak of the anti-religious campaigns under Nikita Khrushchev,
communist propaganda depicted women believers as either naïve
dupes, tricked by the clergy, or as depraved fanatics; the Protestant
“sektantka” (female sectarian) was a particularly prominent folk-devil.
In fact, as this article shows, women’s position within Protestant
communities was far more complex than either of these mythical
figures would have one believe. The authors explore four important,
but contested, female roles: women as leaders of worship, particularly
in remote congregations where female believers vastly outnumbered
their male counterparts; women as unofficial prophetesses,
primarily within Pentecostal groups; women as mothers, replenishing
congregations through high birth rates and commitment to their
children’s religious upbringing; and women as political actors in the
defence of religious rights. Using a wide range of sources, which
include reports written by state officials, articles in the church journal,
letters from church members to their ecclesiastical leaders in
Moscow, samizdat texts, and oral history accounts, the authors
probe women’s relationship with authority, in terms of both the
authority of the (male) ministry within the church, and the authority
of the Soviet state
Разработка оптимальных условий нанофильтрации в технологии производства иммуноглобулина G человека нормального для внутривенного введения
Scientific relevance. Medicinal products based on immunoglobulin class G (IgG) from human plasma are widely used in clinical practice to treat bacterial and viral infections, primary and secondary immunodeficiencies, and autoimmune diseases. Nanofiltration is a way to mitigate the risk of in-process contamination of raw materials with various pathogens, including viruses. Therefore, it is relevant to investigate the development and implementation of additional viral inactivation and/or elimination steps.Aim. This study aimed to develop and validate optimum nanofiltration conditions and to scale up the nanofiltration step for the manufacturing of human IgG for intravenous administration.Materials and methods. The study used a solution of IgG from plasma fractions II and III. The authors paired nanofilters manufactured by Planova 20N and BioEx (Asahi Kasei, Japan), Viresolve Pro (Merck Millipore, USA), Virosart HC and HF (Sartorius, Germany), and Pegasus SV4 and Prime (Pall, USA) with Sartopore polyethersulphone prefilters by Sartorius (Germany), Virosart MAX polyamide prefilters by Sartorius (Germany), and EKX-P regenerated cellulose prefilters by Pall (Germany). Virus reduction validation studies were performed with model viruses (human immunodeficiency virus type 1, porcine transmissible gastroenteritis virus, porcine parvovirus, murine encephalomyocarditis virus, and bovine viral diarrhoea virus) in the laboratories of the N.F. Gamaleya centre. The sample data analysis involved calculating mean values with 95% confidence intervals.Results. For all the selected combinations of prefilters and filters, the maximum nanofiltration throughput depended on the IgG concentration in the test solution. With the combination of an EKX-P filter with a Pegasus SV4 nanofilter, the maximum throughput and the IgG yield reached 6300 g/m2 and 95%, respectively. When combined with a Planova 20N nanofilter, EKX-P and Sartopore (polyethersulphone) filters provided a maximum throughput of up to 2980 g/m2 and an IgG yield of almost 100%, provided that the test solution had an IgG concentration of 10 g/L. With different filter combinations, virus reduction levels ranged from 4.00±0.05 to 4.75±0.04 log10 for human immunodeficiency virus type 1, from 4.30±0.04 to 4.55±0.06 log10 for porcine transmissible gastroenteritis virus, from 5.38±0.08 log10 to 5.57±0.04 log10 for murine encephalomyocarditis virus, 5.12±0.10 log10 to 5.25±0.08 log10 for porcine parvovirus, and exceeded 5.00 log10 for bovine viral diarrhoea virus. The virus reduction levels achieved were not statistically associated with prefilter brands.Conclusions. The study demonstrated that nanofiltration was effective at removing viruses with various virion sizes and physicochemical characteristics, including viruses as small as parvovirus B19. The levels of virus reduction exceeded 4 log10 and met the acceptance criteria.The laboratory-scale nanofiltration parameters and the corresponding filtration times, as well as IgG yields, did not change when the process was scaled up. Therefore, nanofiltration is an effective and productive technique that helps eliminate various types of viruses and considerably improve viral safety without affecting the quality of biological medicinal products.Актуальность. Лекарственные препараты на основе иммуноглобулина G (IgG) из плазмы крови человека широко применяются в терапии бактериальных и вирусных инфекций, первичных и вторичных иммунодефицитов, аутоиммунных заболеваний. Снизить риск производственной контаминации сырья различными патогенами, в том числе вирусами, позволяет процесс нанофильтрации. Для повышения вирусной безопасности необходимы исследования по разработке и внедрению дополнительных этапов инактивации и (или) элиминации вирусов.Цель. Разработка оптимальных условий процесса нанофильтрации, валидация и масштабирование данной стадии для производства лекарственного препарата иммуноглобулина G человека для внутривенного введения.Материалы и методы. Раствор IgG из фракции II+III плазмы крови, нанофильтры Planova — 20N и BioEx (Asahi Kasei, Япония), Viresolve Pro (Merck Millipore, США), Virosart — HC и HF (Sartorius, Германия), Pegasus — SV4 и Prime (Pall, США), предфильтры Sartopore из полиэфирсульфона, Virosart MAX (Sartorius, Германия) из полиамида, EKX-P (Pall, Германия) из регенерированной целлюлозы. Лабораторные исследования по валидации вирусной редукции выполняли с модельными тест-вирусами (ВИЧ-1, трансмиссивного гастроэнтерита (коронавируса) свиней, парвовирус свиней, вирус энцефаломиокардита мышей, вирус бычьей диареи) на базе ФГБУ «НИЦЭМ им. Н.Ф. Гамалеи» Минздрава России. Анализ данных по выборке проводили с помощью среднего значения при 95% доверительном интервале.Результаты. Установлено, что производительность нанофильтрации для всех выбранных комбинаций «предфильтр — нанофильтр» зависит от концентрации IgG в испытуемом растворе. Максимальная пропускная способность и выход продукта составили: предфильтр (фильтр) ЕКХ-P с нанофильтром Pegasus SV4 — 6300 г/м2 (выход IgG более 95%); EKX-P или Sartopore (полиэфирсульфон) с Planova 20N — до 2980 г/м2 (выход IgG — практически 100% при условии проведения процесса только при концентрации IgG 10 г/л). Для разных комбинаций фильтров уровень редукции соответствовал критериям приемлемости: ВИЧ-1 — от 4,00±0,05 до 4,75±0,04 log10; коронавирус свиней — от 4,30±0,04 до 4,55±0,06 log10; вирус энцефаломиокардита мышей — от 5,38±0,08 до 5,57±0,04 log10; вирус бычьей диареи — более 5,00 log10; парвовирус свиней — от 5,12±0,10 до 5,25±0,08 log10. Статистически достоверного различия в зависимости уровня редукции от марки предфильтров не выявили.Выводы. Подтверждена эффективность противовирусной нанофильтрации для вирусов с различными размерами вириона и физико-химическими характеристиками, включая мелкий парвовирус В19: уровень редукции вирусов для всех комбинаций составил более 4 log10, что соответствует критериям приемлемости. Разработанные в лабораторных условиях параметры и соответствующая им длительность нанофильтрации, а также выход целевого продукта для всех комбинаций исследованных фильтров не изменились при масштабировании. Нанофильтрация может служить эффективным и высокопродуктивным инструментом удаления различных типов вирусов, который не влияет на качество продукта и значительно повышает вирусную безопасность биологических препаратов
Quantum Gravity in 2+1 Dimensions: The Case of a Closed Universe
In three spacetime dimensions, general relativity drastically simplifies,
becoming a ``topological'' theory with no propagating local degrees of freedom.
Nevertheless, many of the difficult conceptual problems of quantizing gravity
are still present. In this review, I summarize the rather large body of work
that has gone towards quantizing (2+1)-dimensional vacuum gravity in the
setting of a spatially closed universe.Comment: 61 pages, draft of review for Living Reviews; comments, criticisms,
additions, missing references welcome; v2: minor changes, added reference
The DEAD-box RNA Helicase DDX6 is Required for Efficient Encapsidation of a Retroviral Genome
Viruses have to encapsidate their own genomes during the assembly process. For most RNA viruses, there are sequences within the viral RNA and virion proteins needed for high efficiency of genome encapsidation. However, the roles of host proteins in this process are not understood. Here we find that the cellular DEAD-box RNA helicase DDX6 is required for efficient genome packaging of foamy virus, a spumaretrovirus. After infection, a significant amount of DDX6, normally concentrated in P bodies and stress granules, re-localizes to the pericentriolar site where viral RNAs and Gag capsid proteins are concentrated and capsids are assembled. Knockdown of DDX6 by siRNA leads to a decreased level of viral nucleic acids in extracellular particles, although viral protein expression, capsid assembly and release, and accumulation of viral RNA and Gag protein at the assembly site are little affected. DDX6 does not interact stably with Gag proteins nor is it incorporated into particles. However, we find that the ATPase/helicase motif of DDX6 is essential for viral replication. This suggests that the ATP hydrolysis and/or the RNA unwinding activities of DDX6 function in moderating the viral RNA conformation and/or viral RNA-Gag ribonucleoprotein complex in a transient manner to facilitate incorporation of the viral RNA into particles. These results reveal a unique role for a highly conserved cellular protein of RNA metabolism in specifically re-locating to the site of viral assembly for its function as a catalyst in retroviral RNA packaging
Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing
Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 μM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART
Characterization of LINE-1 Ribonucleoprotein Particles
The average human genome contains a small cohort of active L1 retrotransposons that encode two proteins (ORF1p and ORF2p) required for their mobility (i.e., retrotransposition). Prior studies demonstrated that human ORF1p, L1 RNA, and an ORF2p-encoded reverse transcriptase activity are present in ribonucleoprotein (RNP) complexes. However, the inability to physically detect ORF2p from engineered human L1 constructs has remained a technical challenge in the field. Here, we have employed an epitope/RNA tagging strategy with engineered human L1 retrotransposons to identify ORF1p, ORF2p, and L1 RNA in a RNP complex. We next used this system to assess how mutations in ORF1p and/or ORF2p impact RNP formation. Importantly, we demonstrate that mutations in the coiled-coil domain and RNA recognition motif of ORF1p, as well as the cysteine-rich domain of ORF2p, reduce the levels of ORF1p and/or ORF2p in L1 RNPs. Finally, we used this tagging strategy to localize the L1–encoded proteins and L1 RNA to cytoplasmic foci that often were associated with stress granules. Thus, we conclude that a precise interplay among ORF1p, ORF2p, and L1 RNA is critical for L1 RNP assembly, function, and L1 retrotransposition