Экстракорпоральная иммунофармакотерапия

Extracorporal immunophamiacotherapy is a cellular engineer immunocorrection mode allowing to use pharmacologically activated ex corpora cells-regulators of the immune system and corticodistant mediators produces. This way is carried out technically by following manner: leucocytes are extracted from blood with the fractionator and are incubated in the drug solution during some hours, then are washed and reinfused to a patient. This method allows to evacuate a part of lymphocytes from the action media of suppressor factors an d after their activation with drugs to use for the functional activity reparation of the patient immunity. This way provides the sharp reparation of the decreased parameters of the immunity activity up to normal values. In the study, the experimental basing and results of its clinical trials on models of heavy atopic syndrome, Liell’s syndrome, and atopic bronchial asthma treatment.Экстракорпоральная иммупофармакотерапия представляет собой клеточно-инженерный способ иммунокоррекции, позволяющий использовать с целью лечения активированные вне организма (экстракорпорально) фармакологическими препаратами клетки-регуляторы иммунной системы, продуценты кортикодистантных медиаторов. Технически этот прием выполняется следующим образом: с помощью фракционатора клеток крови получают лейкоциты, обрабатывают их лекарственным препаратом (несколько часов), отмывают и реинфузируют пациенту. Метод позволяет вывести часть лимфоцитов из-под действия эндогенных супрессорных факторов и после их активации лекарственными препаратами использовать для восстановления функциональной активности иммунной системы больного. Этот прием обеспечивает быстрое (в течение 1—3 суток) восстановление до нормы значительно сниженных показателей активности иммунитета. В работе приведено экспериментальное обоснование метода и результаты его клинических испытаний на примере лечения тяжелого атопического синдрома , синдрома Лайела, атопической бронхиальной астмы

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies

Investigation of the Structure of Layered Copper–Molybdenum Samples Produced by Explosion Welding and Construction of a 3D Model of Fractal Elements of a New Structure

Слоистый композит медь-молибден обладает высокой твердостью и высокой химической стойкостью, получен сваркой взрывом. Использование такой технологии получения композита связано с малой взаимной растворимостью меди и молибдена. При сварке взрывом образование соединения происходит благодаря кратковременному расплавлению и очень быстрому затвердеванию на контактной поверхности. Сварка взрывом уменьшает активационный барьер химической реакции и позволяет получать интерметаллиды из двух невзаимодействующих компонентов со скоростью, близкой к скорости переключения химической связи. Формируются продукты механохимических реакций в зоне контакта разнородных металлов. Продукты механохимических реакций обнаружены методами рентгеновской дифракции и микроанализа. Высокие скорости физико-химических превращений инициируются нелинейными волнами локализованной пластической деформации. Волны пластической деформации выявлены после травления шлифа поперечного среза многослойного образца и исследования микроструктуры. Сделана оценка потока энергии на образец во время сварки взрывом, а также проведен анализ особенностей структуры зон соединения меди и молибдена. Определена фрактальная размерность границы соединения меди и молибдена. Построена кластерная модель структуры среднего порядка (мезоструктуры) зон соединения меди и молибденаThe layered copper-molybdenum composite has high hardness and high chemical resistance, obtained by explosion welding. The use of this technology for obtaining a composite is associated with a low mutual solubility of copper and molybdenum. In explosion welding, the formation of a joint occurs due to short-term melting and very rapid solidification at the contact surface. Explosive welding reduces the activation barrier of a chemical reaction and makes it possible to obtain intermetallic compounds from two non-interacting components at a rate close to the rate of chemical bond switching. Products of mechanochemical reactions are formed in the contact zone of dissimilar metals. The products of mechanochemical reactions were detected by X‑ray diffraction and microanalysis. High rates of physicochemical transformations are initiated by nonlinear waves of localized plastic deformation. Waves of plastic deformation were revealed after etching of a thin section of a cross section of a multilayer sample and a study of the microstructure. An estimate of the energy flux to the sample during explosion welding was made, and an analysis was made of the structural features of the copper and molybdenum bonding zones. The fractal dimension of the interface between copper and molybdenum is determined. A cluster model of the medium order structure (mesostructure) of the zones of copper and molybdenum bonding is constructe

Age-Related Differences in Ocular Features of a Naturalistic Free-Ranging Population of Rhesus Macaques

This is the final version. Available on open access from the Association for Research in Vision and Ophthalmology via the DOI in this recordPURPOSE: Rhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We investigated if age was associated with clinically relevant ocular features in a large cohort of free-ranging rhesus macaques from Cayo Santiago, Puerto Rico. METHODS: We evaluated 120 rhesus macaques (73 males, 47 females) from 0 to 29 years old (mean ± SD: 12.6 ± 6.4) from September to December 2021. The ophthalmic evaluation included intraocular pressure (IOP) assessment, corneal pachymetry, biomicroscopy, A-scan biometry, automated refraction, and fundus photography after pupil dilation. The associations of age with the outcomes were investigated through multilevel mixed-effects models adjusted for sex and weight. RESULTS: On average, IOP, pachymetry, axial length, and automated refraction spherical equivalent were 18.37 ± 4.68 mmHg, 474.43 ± 32.21 µm, 19.49 ± 1.24 mm, and 0.30 ± 1.70 diopters (D), respectively. Age was significantly associated with pachymetry (β coefficient = -1.20; 95% confidence interval [CI], -2.27 to -0.14; P = 0.026), axial length (β coefficient = 0.03; 95% CI, 0.01 to 0.05; P = 0.002), and spherical equivalent (β coefficient = -0.12; 95% CI, -0.22 to -0.02; P = 0.015). No association was detected between age and IOP. The prevalence of cataracts in either eye was 10.83% (95% CI, 6.34-17.89) and was significantly associated with age (odds ratio [OR] = 1.20; 95% CI, 1.06-1.36; P = 0.004). Retinal drusen in either eye was observed in 15.00% (95% CI, 9.60-22.68) of animals, which was also significantly associated with age (OR = 1.14; 95% CI, 1.02-1.27; P = 0.020). CONCLUSIONS: Rhesus macaques exhibit age-related ocular associations similar to those observed in human aging, including decreased corneal thickness, increased axial length, myopic shift, and higher prevalence of cataract and retinal drusen.New Frontiers in Research FoundationNatural Sciences and Engineering Research CouncilCanada Research Chairs ProgramNational Aging InstituteBrightFocus FoundationNational Institutes of Health (NIH)University of Calgar

Mistakes and complications of endodontic treatment and ways to overcome them (literature review)

This review presents an analysis of domestic and foreign literature, which reflects the quality of endodontic treatment of complications of caries, errors and adverse outcomes of treatment in the immediate and long-term periods. Convincingly proved the need for new innovative methods of reuse of endodontic treatment. The expediency of using dental microscopy, and is represented by its effectiveness.В обзоре представлен анализ отечественной и зарубежной специальной литературы, отражающий качество эндодонтического лечения осложнений кариеса, ошибки и неблагоприятные исходы лечения в ближайшие и отдаленные сроки. Убедительно доказана необходимость поиска новых инновационных методов повторного эндодонтического лечения. Обоснована целесообразность использования дентальной микроскопии и представлена ее эффективность

Экстракорпоральная иммунофармакотерапия с преднизолоном и цианокобаламином атопической глюкокортикостероидозависимой бронхиальной астмы

Extracorporal Immunopharmacopherapy (EIPT) with Prednisolone and Ciancobalamini (В 12) is a method of the treatment of severe glucocorticosteroid (GCS) — dependent atopic bronchial asthma. •Leucocytes 4—8 billions collected to the collection-bag by means of blood cell separator, incubated with Prednisolone 30 mcg/ml and B12 1 mcg/ml for 3 houres at 37 °C, washed with sodium solution 3 times and then reinfused to patients. A therapeutic effect is isually reached after 3—5 procedures repeated every 3—5 days.We put EIPT into practice for treatment of 20 patients with atopic atshma. All that patients had got GCS-dependence before EIPT and exhibited evedence for remition for 6 to 24 months without sistem GCS after EIPT. Moreover these patients showed decreasment of histamine skin sensitivity and IgE-levels in plasma, elevation of plasma cortisol concentration. These patients mononuclear cells had got high level of histamine liberation activity before EIPT and had decreasment it after treatment.EIPT with Prednisolone and B12 appears to be an effective method for abolishing of GCS-dependence in patients with severe GCS-dependent atopic asthma and preventing severe complications of GCS-treatment.

Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies

Although numerous mouse models of B-cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B-cell malignancies using mice reconstituted with modified human hematopoietic stem cells (HSCs) remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven ‘double-hit’ lymphoma. By engrafting human HSCs transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab-resistant human ‘double-hit’ lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti-CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in ‘double-hit’ lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies.Kathy and Curt Marble Cancer Research FundSingapore-MIT Alliance for Research and TechnologyNational Institutes of Health (U.S.) (Grant R01-CA128803)Virginia and Daniel K. Ludwig Graduate FellowshipNational Institute of General Medical Sciences (U.S.) (Medical Scientist Training Program Grant T32GM007753)MIT School of Science (Cancer Research Fellowship

Speed, adaptation, and stability of the response to light in cone photoreceptors: The functional role of Ca-dependent modulation of ligand sensitivity in cGMP-gated ion channels

The response of cone photoreceptors to light is stable and reproducible because of the exceptional regulation of the cascade of enzymatic reactions that link visual pigment (VP) excitation to the gating of cyclic GMP (cGMP)-gated ion channels (cyclic nucleotide–gated [CNG]) in the outer segment plasma membrane. Regulation is achieved in part through negative feedback control of some of these reactions by cytoplasmic free Ca2+. As part of the control process, Ca2+ regulates the phosphorylation of excited VP, the activity of guanylate cyclase, and the ligand sensitivity of the CNG ion channels. We measured photocurrents elicited by stimuli in the form of flashes, steps, and flashes superimposed on steps in voltage-clamped single bass cones isolated from striped bass retina. We also developed a computational model that comprises all the known molecular events of cone phototransduction, including all Ca-dependent controls. Constrained by available experimental data in bass cones and cone transduction biochemistry, we achieved an excellent match between experimental photocurrents and those simulated by the model. We used the model to explore the physiological role of CNG ion channel modulation. Control of CNG channel activity by both cGMP and Ca2+ causes the time course of the light-dependent currents to be faster than if only cGMP controlled their activity. Channel modulation also plays a critical role in the regulation of the light sensitivity and light adaptation of the cone photoresponse. In the absence of ion channel modulation, cone photocurrents would be unstable, oscillating during and at the offset of light stimuli

Структурные и фазовые превращения в зонах контакта Al-Ti, Al-Ni и сплава AMr7 при пластической деформации

Work is devoted research of features of structure formation processes in the contact zone of limited solubility bimetals and alloys subjected to plastic deformation. It is established, that the plastic deformation of limited solubility metals (Al-Ti, Al-Ni), can significantly broaden the scope of their mutual solubility. The appearance of zones of local tensile and compressive stresses (curvature crystal lattice zones) leads to increased solubility, emergence of new phases and redistribution of their composition, reorientation of granular structureРабота посвящена исследованию особенностей процессов формирования структуры в зоне контакта биметаллов с ограниченной растворимостью и сплавов, подвергнутых пластической деформации. Установлено, что пластическая деформация металлов c ограниченной растворимостью (Al-Ti, Al-Ni) может значительно расширить область их взаимной растворимости. Появление зон локального растяжения и сжимающих напряжений (зон кривизны кристаллической решетки) приводит к увеличению растворимости, появлению новых фаз и перераспределению их состава, переориентации зернистой структур