A molecular assembly system for presentation of antigens on the surface of HBc virus-like particles

AbstractHepatitis B virus-like particles, icosahedral structures formed by multiple core protein dimers, are promising immune-enhancing vaccine carriers for foreign antigens. Insertions into the surface-exposed immunodominant loop are especially immunogenic. However, the need to conserve the particulate structure to ensure high immunogenicity imposes restraints on the nature of the heterologous sequence that can be inserted. We propose a new approach to constructing HBc particles linked to the target epitopes that relies on non-covalent interactions between the epitope and pre-assembled unmodified HBc particles. Interaction was enabled by fusion of the epitope to the GSLLGRMKGA peptide, binding to the spike tips. This peptide may be used as a “binding tag” allowing in vitro construction of HBc particles carrying the target peptide. Such virus-like particles carrying multiple copies of the extracellular domain of the M2 protein of different influenza strains appeared to be highly immunogenic and protected immunised mice against a lethal influenza challenge

Discovery of small molecules that activate RNA-methylation through cooperative binding to the METTL3/14/WTAP complex active site

Chemical modifications of RNA provide an additional, epitranscriptomic, level of control over cellular functions. N-6-methylated adenosines (m6As) are found in several types of RNA, and their amounts are regulated by methyltransferases and demethylases. One of the most important enzymes catalyzing generation of m6A on mRNA is the trimer N-6-methyltransferase METTL3-14-WTAP complex. Its activity has been linked to such critical biological processes as cell differentiation, proliferation, and death. We used in silico-based discovery to identify small-molecule ligands that bind to METTL3-14-WTAP and determined experimentally their binding affinity and kinetics, as well as their effect on enzymatic function. We show that these ligands serve as activators of the METTL3-14-WTAP complex

PCSK9 Inhibitors in Clinical Practice: Experience of a Specialized Lipid Center

Aim. To characterize patients receiving PCSK9 inhibitors, and assess the efficiency of their treatment in a specialized lipid center.Material and methods. A retrospective analysis of the medical records of patients who visited the Lipid clinic of the National Medical Research Center for Therapy and Preventive Medicine (Moscow, Russia), receiving PCSK9 inhibitor and having lipid profile in dynamics, was carried out (n=77). Cardiovascular risk (CVR) and low-density lipoprotein cholesterol (LDL-C) target levels were evaluated in accordance with the Russian guidelines for the diagnostics and correction of dyslipidemias 2020.Results. Of 77 patients taking PCSK9 inhibitors (44.2% males, the median of age 56 [47; 66] years), the majority (64.0%) had a probable or definite familial hypercholesterolemia (FH). The proportion of other lipid metabolism disorders, pure hypercholesterolemia and combined hyperlipidemia was 21% and 15%. More than half of the patients (68.8%) had a very high CVR, mainly due to the presence of coronary heart disease (84.9%). The proportion of patients receiving PCSK9 inhibitors as monotherapy was 7.8%, in combination with high-intensity statin therapy – 33.8%, as part of triple lipid-lowering therapy (high-intensity statin, ezetimibe, PCSK9 inhibitors) – 50.6%. Addition of PCSK9 inhibitors to combined lipid-lowering therapy enabled to reduce the LDL-C level to 1.02 [0.62; 1.39] mmol/l with its total decrease from the baseline by 87.3%. While taking PCSK9 inhibitors, LDL-C <1.8 mmol/l and <1.4 mmol/l achieved at 78.3% and 57.7% FH patients with high and very high CVR, respectively. Among patients with other hyperlipidemias, 74.1% of patients with very high CVR was achieved the target LDL-C level <1.4 mmol/l.Conclusion: In a specialized lipid center, PCSK9 inhibitors are prescribed to patients with high or very high CVR, most of whom are FH patients. The effectiveness of the use of PCSK9 inhibitors in real-world practice is comparable to the results of clinical trials

The Guillain-Barre syndrome as a complication of the new coronavirus infection COVID-19. Clinical case

The article describes a clinical case of a patient with Guillain-Barre syndrome (acute inflammatory demyelinating polyradiculoneuropathy) that occurred after a new coronavirus infection (COVID-19). Of interest is the development of flaccid paralysis and a rare disease - Guillain-Barre syndrome, as a rare complication of diseases, including infectious natureВ статье рассмотрен клинический случай пациентки с синдромом Гийена-Барре (острой воспалительной демиелинизирующей полирадикулоневропатией), возникшим после перенесенной новой коронавирусной инфекции (COVID-19). Представляет интерес развитие вялых параличей и редкого заболевания - синдрома Гийена-Барре, как возможного осложнения заболеваний, в том числе и инфекционной природы

Prevalence of respiratory symptoms and risk factors for obstructive pulmonary disease in the city of Yekaterinburg

The article considers the results of a study of the prevalence of respiratory symptoms and risk factors for obstructive pulmonary disease (bronchial asthma, chronic obstructive pulmonary disease, cross-syndrome "BA-COPD") in the population of Yekaterinburg, over 45 years.The relationship between the symptoms of BA, COPD and risk factors was revealed, which makes the use of elimination measures in the treatment of these diseases reasonable.В статье рассмотрены результаты исследования распространенности респираторных симптомов и факторов риска обструктивных болезней легких (бронхиальной астмы, хронической обструктивной болезни легких, перекрестного синдрома «БА-ХОБЛ») у населения г. Екатеринбургастарше 45 лет. Была выявленавзаимосвязь междусимптомами БА, ХОБЛ и факторами риска, что делает обоснованным применение элиминационных мероприятий в комплексной терапии данных заболеваний

ОЦЕНКА КОНЦЕНТРАЦИИ РАСТВОРИМОГО РЕЦЕПТОРА CD14 В ПЛАЗМЕ У ВИЧ-ИНФИЦИРОВАННЫХ ПОТРЕБИТЕЛЕЙ ОПИАТОВ

Chronic immune activation is one of the main causes of HIV disease progression. Bacterial components passed to the bloodstream from the gut as a result of microbial translocation, are known to induce immune activation. Component of Gram-negative bacteria’s cell walls, the lipopolysaccharide (LPS), is considered to be the major marker of microbial translocation. Through the activation of myeloid cells (predominantly monocytes) LPS causes the secretion of soluble CD14, thus making it a marker of LPS bioactivity. Besides sCD14 was shown to correlate with immune status in HIVinfected patients and to be an independent predictor of disease progression.Hypothesis: opiates increase microbial translocation from the gut in HIV-infected patients that is manifested by a higher concentration of sCD14 in plasma.Aim: to estimate the influence of opiate use on the level of sCD14 in plasma of HIV-infected patients.Materials and methods. Longitudinal study of 351 HIV positive individuals. Concentration of sCD14, was evaluated at 3 time points: baseline, after 12 and 24 months. Following groups were studied: 1) current opiate users – opiate use within past 30 days; 2) opiate users, who denied consumption of opiates within past 30 days; 3) people claiming to never have used opiates.Results. In dynamic assessment sCD14 mean was significantly higher in current opiate users (2222,46±39,02 ng/ml) against patients who denied opiates within past 30 days (1930±597 ng/ml) and those, claiming to never have used opiates (1915±577 ng/ml) (p<0,001).Conclusion. Opiate use in the course of HIV disease leads to increase in LPS induced monocyte activation which therefore signifies more intensive microbial translocation.Хроническая активация иммунной системы является одним из основных факторов патогенеза ВИЧ-инфекции. Значительная роль в хронической иммунной активации принадлежит транслокации бактериальных компонентов из кишечника в кровоток, в первую очередь липополисахарида (ЛПС) клеточной стенки грамотрицательных микроорганизмов. Растворимая форма рецептора CD14 (sCD14) является маркером моноцитарной активации, индуцированной ЛПС. Гипотеза исследования: у больных ВИЧ-инфекцией потребление опиатов способствует усилению микробной транслокации из кишечника, проявляющейся более высокой концентрацией sCD14 в плазме крови.Цель исследования: оценить влияние употребления опиатов на концентрацию sCD14 в плазме крови у больных ВИЧ-инфекцией.Материалы и методы: у 351 больного ВИЧ-инфекцией определена концентрация растворимого рецептора CD14 в плазме в трёх временных точках: при включении в исследование, через 12 и 24 мес. Сопоставлены значения концентрации sCD14 в группах: 1) активных потребителей опиатов; 2) наркопотребителей, отрицающих употребление опиатов за последние 30 дней; 3) пациентов, отрицающих факт употребления опиатов в анамнезе.Результаты: у активных опиатных наркопотребителей выявлено значимо более высокое среднее значение концентрации sCD14 в плазме крови (2213±596 нг/мл) в сравнении с пациентами, не употреблявшими опиаты за последние 30 дней (1930±597 нг/мл), и лицами, отрицающими употребление опиатов (1915±577 нг/мл) (р<0,001).Заключение: полученные результаты указывают, что у больных ВИЧ-инфекцией употребление опиатов приводит к усилению ЛПС-индуцированной моноцитарной активации, что, в свою очередь, свидетельствует о более интенсивной транслокации бактериальных компонентов