SRSF1 modulates the organization of splicing factors in nuclear speckles and regulates transcription

The mammalian cell nucleus is compartmentalized into non-membranous subnuclear domains that regulate key nuclear functions. Nuclear speckles are subnuclear domains that contain pre-mRNA processing factors and non-coding RNAs. Many of the nuclear speckle constituents work in concert to coordinate multiple steps of gene expression, including transcription, pre-mRNA processing and mRNA transport. The mechanism that regulates the formation and maintenance of nuclear speckles in the interphase nucleus is poorly understood. In the present study, we provide evidence for the involvement of nuclear speckle resident proteins and RNA components in the organization of nuclear speckles. SR-family splicing factors and their binding partner, long non-coding MALAT1 RNA, can nucleate the assembly of nuclear speckles in the interphase nucleus. Depletion of SRSF1 in human cells compromises the association of splicing factors to nuclear speckles and influences the levels and activity of other SR proteins. Furthermore, on a stably integrated reporter gene locus, we demonstrate the role for SRSF1 in RNA polymerase II-mediated transcription. Our results suggest that SR proteins mediate the assembly of nuclear speckles and regulate gene expression by influencing both transcriptional and posttranscriptional activities within the cell nucleus

ПЕРФОРАТИВНАЯ ЯЗВА ДВЕНАДЦАТИПЕРСТНОЙ КИШКИ. КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ ИЗ ПРАКТИКИ СУДОВОЙ МЕДИЦИНЫ

We report a favorable outcome of late diagnosed and operated (delayed for several days) perforated duodenal ulcer from the practice of medical support for the modern oil-tanker fleet. Main features of medical care for shipboard personnel are discussed as well.Из опыта медицинского обеспечения современного танкерного флота приведен пример благоприятного исхода поздней диагностики и запоздалого, отсроченного на несколько суток оперативного лечения перфоративной язвы двенадцатиперстной кишки. Разобраны основные особенности медицинской помощи лицам плавсостава

A Tailward Moving Current Sheet Normal Magnetic Field Front Followed by an Earthward Moving Dipolarization Front

A case study is presented using measurements from the Cluster spacecraft and ground-based magnetometers that show a substorm onset propagating from the inner to outer plasma sheet. On 3 October 2005, Cluster, traversing an ion-scale current sheet at the near-Earth plasma sheet, detected a sudden enhancement of Bz, which was immediately followed by a series of flux rope structures. Both the local Bz enhancement and flux ropes propagated tailward. Approximately 5 min later, another Bz enhancement, followed by a large density decrease, was observed to rapidly propagate earthward. Between the two Bz enhancements, a significant removal of magnetic flux occurred, possibly resulting from the tailward moving Bz enhancement and flux ropes. In our scenario, this flux removal caused the magnetotail to be globally stretched so that the thinnest sheet formed tailward of Cluster. The thinned current sheet facilitated magnetic reconnection that quickly evolved from plasma sheet to lobe and generated the later earthward moving dipolarization front (DF) followed by a reduction in density and entropy. Ground magnetograms located near the meridian of Cluster's magnetic foot points show two-step bay enhancements. The positive bay associated with the first Bz enhancement indicates that the substorm onset signatures propagated from the inner to the outer plasma sheet, consistent with the Cluster observation. The more intense bay features associated with the later DF are consistent with the earthward motion of the front. The event suggests that current disruption signatures that originated in the near-Earth current sheet propagated tailward, triggering or facilitating midtail reconnection, thereby preconditioning the magnetosphere for a later strong substorm enhancement

Classical swine fever: a retrospective analysis of the epizootic situation in the Russian Federation (2007–2021) and forecast for 2022

The paper presents trends in the epizootic situation on classical swine fever (CSF) in the Russian Federation, for 2007–2021. Most likely, a drop in the number of CSF outbreaks throughout the country results from two factors: a geographical shift of the disease outbreaks from the European part of Russia to the eastern regions bordering on China (into the wild boar population), as documented between 2015 and 2021, and a large-scale vaccination of domestic pigs practiced in the recent years. The introduction and spread of CSF in the Russian Federation are, most likely, associated with the internal risk factors (i.e. quality of anti-epizootic measures, mainly vaccination) and with the territories, where the virus circulates in wild boars. Expansion of vaccination coverage since 2011 is one of the factors contributing to a decrease in the number of clinical CSF cases registered in domestic pigs of the Russian Federation. The infection spread in domestic pigs is still on a downward trend. For purposes of analysis, current trends of CSF spread in domestic pigs and wild boars in the Russian Federation, as well as the volume of the vaccine used, were visualized in relative numbers (taking into account total number of pigs in the country) used to build a regression model. Currently, vaccination against classical swine fever in the Russian Federation (and its good quality) is an essential prerequisite to contain the infection spread in the country

Structural insights into thrombolytic activity of destabilase from medicinal leech

Destabilase from the medical leech Hirudo medicinalis belongs to the family of i-type lysozymes. It has two different enzymatic activities: microbial cell walls destruction (muramidase activity), and dissolution of the stabilized fibrin (isopeptidase activity). Both activities are known to be inhibited by sodium chloride at near physiological concentrations, but the structural basis remains unknown. Here we present two crystal structures of destabilase, including a 1.1 Å-resolution structure in complex with sodium ion. Our structures reveal the location of sodium ion between Glu34/Asp46 residues, which were previously recognized as a glycosidase active site. While sodium coordination with these amino acids may explain inhibition of the muramidase activity, its influence on previously suggested Ser49/Lys58 isopeptidase activity dyad is unclear. We revise the Ser49/Lys58 hypothesis and compare sequences of i-type lysozymes with confirmed destabilase activity. We suggest that the general base for the isopeptidase activity is His112 rather than Lys58. pKa calculations of these amino acids, assessed through the 1 μs molecular dynamics simulation, confirm the hypothesis. Our findings highlight the ambiguity of destabilase catalytic residues identification and build foundations for further research of structure–activity relationship of isopeptidase activity as well as structure-based protein design for potential anticoagulant drug development.</p

Anthrax in the East Kazakhstan Region

Almost every year in Kazakhstan, cases of diseases of animals and people with anthrax are recorded. The incidence rate of people with anthrax in the period from 2000 to 2018 ranged from 0.01 to 0.24 per 100 thousand people. In the territory of the East Kazakhstan region, the incidence rate is higher than in the republic.Objective: a retrospective analysis of anthrax outbreaks in the East Kazakhstan region from 2000 to 2018.Methods: a retrospective analysis using statistical, cadastral data, archival funds, the results of participation in the investigation of outbreaks of infection.Results. Since 1938, cases of animal and human disease of anthrax have been recorded in East Kazakhstan. Infection of humans occurs during the slaughter of animals. In Zharma, Urjar, and Ayagozskiy areas most of all are anthrax foci of soil. In 67 % of cases, outbreaks of anthrax were recorded in these areas.Conclusion. The relative incidence rate of anthrax in people in East Kazakhstan is from 0.07 to 0.27, since 2001 it is higher than the republican indicator.In the East Kazakhstan region from 1997 to 2018, 37 people fell ill with anthrax. The form of the disease is skin, in 8.1 % secondary sepsis. In the remaining patients, the diseases were mild (70.3 %), ended in recovery. The source of human infection is mainly cattle. The isolated strains of B. anthracis have typical properties, they are included in cluster A1a, A3b (MLVA-8). The strains isolated in 2016 are similar to the strains isolated in the Almaty region (MLVA-25). Grouped with a number of European, Asian and African strains from France, Germany, Italy, Tajikistan, Pakistan, Korea and Namibia. The presence of a significant number of soil foci of anthrax in the territory of the East Kazakhstan region, not fully the implementation of veterinary and sanitary preventive measures leads to an exacerbation of the situation for anthrax

Potential of Magnetic Hyperthermia to Stimulate Localized Immune Activation

Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n = 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response

Approaches to Reduce Adverse Effect of Vaccinia Virus in Orally Immunized Mice

Objective of the investigation was to model the adverse action of vaccinia virus (VV), caused by oral immunization of mice and to evaluate efficacy of its reduction, using therapeutic and prophylactic drugs. Materials and methods. Virological and immunological research methods were used. Results and conclusions. Reproduced was pathological action of VV in the orally infected mice. The ability to reduce the side effect and protect mice from lethal infection was demonstrated by such preparations as Metisazon, Likopid, and NIOCH-14 orally administered in the investigated schemes. Moreover preliminary single oral immunization with TEOVak smallpox vaccine before oral infection with Neurovaccine-92 strain of VV also lowered pathogenic effect and protected mice against death. All the investigated schemes of drug administration did not affect the immune response if used alongside with TEOVak smallpox vaccine and can be deployed to develop safe schemes of primary oral vaccination against smallpox. In addition, such drugs as Ribomunil, Immudon, Ingavirin can be used as means to enhance the immune response to smallpox vaccines

Анализ многолетнего опыта изучения инактивированных культуральных вакцин для профилактики f клещевого энцефалита отечественного и зарубежного производства по показателю качества -специфическая активность (иммуногенность)

The analysis of the use of the method for the evaluation of specific (immunogenic) activity of vaccines for preventing tick-borne encephalitis (TBE vaccines) against protective dilution (PD50) and the minimum immunizing dose (MID50) has been performed. The method was standardized and submitted to the regulatory documents for TBE vaccines authorized in the Russian Federation. When analyzing the results of the study of specific (immunogenic) activity of TBE vaccines (107 TBE vaccine batches by different manufacturers have been studied) it was confirmed that the choice of real lethal dose (RLD50) indicator of TBE virus (test strain «Absettarov») in the range of 100-3000 LD50, the reasonability of using BALB /c cell-line mice, the effectiveness of the national method of determining immunogenicity in terms of MlD50 for TBE vaccines authorized in the Russian Federation. The reasonability of using immunogenicity reference standard for TBE-OSO 42-28-48 to assess the reproducibility of the experiments, and the homogeneity of laboratory animals in terms of quality. Methods for determining TBE vaccine immunogenicity («specific activity (immunogenicity)» in terms of PD50 and MID50 is applicable both for Russian commercial TBE vaccines and for FSME-Immun vaccine, manufactured by «Baxter Vaccine AG», Austria.Проведен анализ применения метода оценки специфической (иммуногенной) активности современных вакцин клещевого энцефалита (вакцины КЭ) по протективному разведению (ПР50) и минимальной иммунизирующей дозе (МИД50). Метод стандартизован и внесен в нормативные документы на зарегистрированные в Российской Федерации вакцины КЭ. При анализе результатов изучения специфической (иммуногенной) активности вакцин КЭ (исследовано 107 серий вакцин КЭ различных производителей) подтверждены: выбор показателя реальной летальной дозы (РЛД50) вируса КЭ (тест-штамм «Абсеттаров») в пределах 100-3000 ЛД50, целесообразность применения линейных мышей BALB/с, эффективность применения отечественного метода определения иммуногенности по показателю МИД50 для вакцин КЭ, зарегистрированных в Российской Федерации. Подтверждена целесообразность применения стандартного образца иммуногенности вакцины КЭ - ОСО 42-28-48 для оценки сходимости результатов постановки экспериментов и однородности лабораторных животных по качеству. Метод определения иммуногенности вакцин КЭ (показатель качества «Специфическая активность (иммуногенность)» по показателям ПР50 и МИД50 применим как для российских коммерческих вакцин КЭ, так и для вакцины ФСМЕ-Иммун, производства компании «Бакстер вакцины АГ», Австрия

Morphological, Physiological and Genetic Characteristics of Populations of the Main Plague Host Rhombomys opimus Licht., 1823 in the Central Asian Desert Natural Focus of Plague

Revealed by morphological characters, physiological status, and genetic diversity of populations of the main plague host Rhombomys opimus Licht., 1823 in Central Asia desert natural focus is described.Differences in the skull parameters of R. opimus from different populations were revealed. It’s shown that gerbils from Moyunkum are separate autonomous populations group. Samples from Moyunkum and Mangyshlak differed from other samples. In Balkhash-Alakol depression found two regional complexes: Pre-Balkhash and Dzungarian.Study results of free amino acids level in R. opimus blood serum obtained by gas-liquid chromatography of blood sera from animals captured in different zones of Central Asian focus gave statistically significant differences. To determine genetic variability in ecological and geographical isolation of R. opimus populations the DNA was genotyped.DNA samples analysis combined the studied gerbil from the desert focus into four clusters with eighteen haplotypes. R. opimus sequence analysis taking into account data from territories of Iran, Kazakhstan and China, clustered into three large clusters. First cluster combined the sequences of Kazakhstan and China samples, while great gerbil captured in Kazakhstan is located in a separate treasure. Second and third clusters include sequences of a great gerbil captured in Iran