IMMUNE PREDICTORS OF FIBROGENESIS AND THEIR APPLICATION FOR NON-INVASIVE DIAGNOSTICS OF LIVER FIBROSIS IN PATIENTS WITH CHRONIC VIRAL HEPATITIS

The study was devoted to development of non-invasive methods for diagnosis of liver fibrosis in patients with chronic viral hepatitis (CVH). The stepwise logistic multivariate regression analysis of biochemical (PTI, glucose, albumin, AST, LDH) and immunological parameters (the functional activity of neutrophils and monocytes, the relative content of CD8+ T- and CD19+B-cells) was used for the establishment of diagnostic model. Based on the multiple regression analysis we derived a 2 novel Integral Indexes of Liver Fibrosis (IILF-biochem and IILF-immun, respectively). It is shown that IILF-biochem allows, without resorting to liver biopsy to predict the appropriate stage of fibrosis in CHV patients with diagnostic accuracy of 86—87 %, and in combination with IILF — at 97.7 %

Preclinical studies of antiviral activity of the RPH-137 fusion protein and molnupiravir against COVID-19

Finding effective and safe medicines to fight SARS-CoV-2 infection is an urgent task. RPH-137 is an original trap fusion protein against SARS-CoV-2 virus. It comprises the angiotensin-converting enzyme type 2 extracellular domain and the human IgG1 Fc fragment.The aim of the study was to carry out a preclinical evaluation of the efficacy of RPH-137 and molnupiravir against SARS-CoV-2 infection.Materials and methods: the authors analysed RPH-137 expressed in a stable CHO cell line and molnupiravir used as an active pharmaceutical ingredient. Drug-mediated inhibition of virus-induced cytotoxicity was assessed in Vero cell culture. In vivo efficacy assessments were performed in Syrian hamsters. The animals were infected intranasally with SARS-CoV-2 (PIK35 clinical isolate) in the dose of 5 log TCID50. The authors evaluated body weight measurements, lung–body weight ratios, and lung histopathology findings and determined viral RNA levels in oropharyngeal swabs by RT-PCR using the amplification cycle threshold (Ct). The statistical analyses involved one- and two-way ANOVA, Student's t-test, and Mann–Whitney test.Results: RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells; the EC50 values of RPH-137 amounted to 4.69 μg/mL (21.3 nM) and 16.24 μg/mL (73.8 nM) for 50 TCID50 and 200 TCID50, respectively, whereas the EC50 values of molnupiravir were 0.63 μg/mL (1900 nM) for both doses. Intramuscular RPH-137 (30 and 80 mg/kg) had no effect on the infection process in Syrian hamsters. The comparison with the challenge control group showed that intraperitoneal RPH-137 (100 mg/kg) had statistically significant effects on a number of parameters, including a 27% reduction in inflammation and a 30% reduction in the total lesion area of the lungs by Day 7. Intragastric molnupiravir (300 mg/kg twice daily) significantly inhibited SARS-CoV-2 infection.Conclusions: both RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells. In Syrian hamsters, molnupiravir demonstrated a more pronounced inhibition of SARS-CoV-2 infection than RPH-137. However, RPH-137 had statistically significant effects on a range of parameters. This offers additional perspectives for further research

Доклинические исследования противовирусной активности гибридного белка RPH-137 и молнупиравира в отношении COVID-19

Finding effective and safe medicines to fight SARS-CoV-2 infection is an urgent task. RPH-137 is an original trap fusion protein against SARS-CoV-2 virus. It comprises the angiotensin-converting enzyme type 2 extracellular domain and the human IgG1 Fc fragment.The aim of the study was to carry out a preclinical evaluation of the efficacy of RPH-137 and molnupiravir against SARS-CoV-2 infection.Materials and methods: the authors analysed RPH-137 expressed in a stable CHO cell line and molnupiravir used as an active pharmaceutical ingredient. Drug-mediated inhibition of virus-induced cytotoxicity was assessed in Vero cell culture. In vivo efficacy assessments were performed in Syrian hamsters. The animals were infected intranasally with SARS-CoV-2 (PIK35 clinical isolate) in the dose of 5 log TCID50. The authors evaluated body weight measurements, lung–body weight ratios, and lung histopathology findings and determined viral RNA levels in oropharyngeal swabs by RT-PCR using the amplification cycle threshold (Ct). The statistical analyses involved one- and two-way ANOVA, Student's t-test, and Mann–Whitney test.Results: RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells; the EC50 values of RPH-137 amounted to 4.69 μg/mL (21.3 nM) and 16.24 μg/mL (73.8 nM) for 50 TCID50 and 200 TCID50, respectively, whereas the EC50 values of molnupiravir were 0.63 μg/mL (1900 nM) for both doses. Intramuscular RPH-137 (30 and 80 mg/kg) had no effect on the infection process in Syrian hamsters. The comparison with the challenge control group showed that intraperitoneal RPH-137 (100 mg/kg) had statistically significant effects on a number of parameters, including a 27% reduction in inflammation and a 30% reduction in the total lesion area of the lungs by Day 7. Intragastric molnupiravir (300 mg/kg twice daily) significantly inhibited SARS-CoV-2 infection.Conclusions: both RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells. In Syrian hamsters, molnupiravir demonstrated a more pronounced inhibition of SARS-CoV-2 infection than RPH-137. However, RPH-137 had statistically significant effects on a range of parameters. This offers additional perspectives for further research.Поиск эффективных и безопасных лекарственных средств для борьбы с коронавирусной инфекцией, вызванной вирусом SARS-CoV-2, является актуальной задачей. RPH-137 – оригинальный гибридный белок-ловушка вируса SARS-CoV-2, состоящий из внеклеточного домена ангиотензинпревращающего фермента 2 типа и Fc-фрагмента IgG1 человека.Цель работы: доклиническая оценка эффективности RPH-137 и молнупиравира в отношении инфекции, вызванной SARS-CoV-2.Материалы и методы: RPH-137 получали в стабильной линии клеток китайского хомячка. В работе использовали субстанцию молнупиравира. Изучение ингибирования вирус-индуцированной цитотоксичности проводили в культуре клеток Vero. В исследовании эффективности in vivo сирийских хомячков заражали интраназально SARS-CoV-2 (вариант ПИК35) в дозе 5 lg ТЦД50. Оценивали массу тела, массовый коэффициент и гистологическую картину легких. В орофарингеальных мазках измеряли содержание вирусной РНК методом ОТ-ПЦР по показателю порогового цикла амплификации Ct. Статистическая обработка: однофакторный и двухфакторный дисперсионный анализ (ANOVA), t-тест Стьюдента, критерий Манна–Уитни.Результаты: RPH-137 и молнупиравир ингибировали цитопатическое действие вируса SARS-CoV-2 в культуре клеток Vero: для RPH-137 EC50=4,69 мкг/мл (21,3 нМ) и 16,24 мкг/мл (73,8 нМ) для доз 50 ТЦД50 и 200 ТЦД50 соответственно, для молнупиравира EC50=0,63 мкг/мл (1900 нМ) для обеих доз вируса. RPH-137 при внутримышечном введении в дозах 30 и 80 мг/кг не оказывал влияния на развитие инфекции у сирийских хомячков. RPH-137 при внутрибрюшинном введении в дозе 100 мг/кг показал статистически значимый эффект по ряду параметров по сравнению с животными контрольной группы (контроль заражения), в том числе вызывая снижение воспалительного процесса и общей площади поражения легких на 7 сут на 27 и 30% соответственно. Молнупиравир при пероральном введении в дозе 300 мг/кг 2 раза в сутки значимо подавлял развитие инфекции, вызванной SARS-CoV-2.Выводы: RPH-137 и  молнупиравир ингибируют цитопатическое действие вируса SARS-CoV-2 в культуре клеток Vero. У сирийских хомячков введение молнупиравира демонстрировало более выраженное подавление инфекции, вызванной SARS-CoV-2, по сравнению с RPH-137. Однако RPH-137 проявлял статистически значимое действие по ряду параметров, что открывает перспективы для его дальнейшего изучения.

Geometric morphometrics reveals shifts in flower shape symmetry and size following gene knockdown of CYCLOIDEA and ANTHOCYANIDIN SYNTHASE

Peer reviewe

Electron-phonon interaction and point contact enhanced superconductivity in trigonal PtBi2

PtBi2 is a Weyl semimetal, which demonstrates superconductivity with low critical temperature Tc ~ 0.6 K in the bulk. Here, we report our study of electron-phonon interaction (EPI) in trigonal PtBi2 by the Yanson point contact (PC) spectroscopy and presenting the observation of PC enhanced superconductivity. We show, that the Yansons PC spectra display a broad maximum around 15 meV, indicating, apparently, EPI mechanism of Cooper pairing in PtBi2. Moreover, we discovered a substantial increase of Tc up to ~ 3.5 K in PCs. The observed Tc is sufficiently higher than the bulk value, as well as detected at hydrostatic pressure. We calculated the phonon density of states and Eliashberg EPI function in PtBi2 within the framework of the density functional theory. A comparison of experimental data with theoretical calculations showed acceptable agreement. The theoretical Tc is 3.5 K, which corresponds to the experimental value.Comment: 13 pages, 4 figs, with supplement. Submitted to Low Temp. Phys. (Fiz. Nizk. Temp.