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Current nucleoside-modified RNA lipid nanoparticle (modmRNA-LNP) technology has successfully paved the way for the highest clinical efficacy data from next-generation vaccinations against SARS-CoV-2 during the COVID-19 pandemic. However, such modmRNA-LNP technology has not been characterized in common pre-existing inflammatory or immune-challenged conditions, raising the risk of adverse clinical effects when administering modmRNA-LNPs to deliver therapeutic proteins or vaccinate against infectious diseases. Herein, we induce an acute-inflammation model in mice with lipopolysaccharide (LPS) intratracheally (IT), 1 mg kg−1, or intravenously (IV), 2 mg kg−1, and then IV administer modmRNA-LNP, 0.32 mg kg−1, after 4 h, and screen for inflammatory markers, such as pro-inflammatory cytokines. ModmRNA-LNP at this dose caused no significant elevation of cytokine levels in naive mice. In contrast, shortly after LPS immune stimulation, modmRNA-LNP enhanced inflammatory cytokine responses, Interleukin-6 (IL-6) in serum and Macrophage Inflammatory Protein 2 (MIP-2) in liver by 95-fold and 52-fold, respectively. Our report identifies this phenomenon as inflammation exacerbation (IE), which was proven to be specific to the LNP, acting independent of mRNA cargo, and was demonstrated to be time- and dose-dependent. Macrophage depletion and TLR3 −/− and TLR4−/− knockout mouse studies revealed macrophages were the immune cells involved or responsible for IE. Finally, we show that pretreatment with anti-inflammatory drugs, such as corticosteroids, can partially alleviate IE response in mice. Our findings characterize the importance of LNP-mediated IE phenomena in gram negative bacterial inflammation, the generalizability of modmRNA-LNP in other forms of chronic or acute inflammatory and immune contexts needs to be addressed., Graphical abstract Unlabelled Image

The topic of the article is relevant — the problem of radioactive waste management, since the task of increasing the level of security of organizations of the country’s nuclear power-industrial complexes is one of the priorities for ensuring state and public security in the National Security Strategy of the Russian Federation. The growth of radioactive waste is a hazard to human health and the environment. The state needs a unified regulation of the radioactive waste management policy and prevention of radioactive disasters.

Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination. ispartof: SCIENCE ADVANCES vol:9 issue:12 ispartof: location:United States status: published

А method for monitoring wells productivity index dynamics from the moment of its start-ups is proposed. It allows detecting candidates for conducting well tests (WT) and well interventions for the increase of a daily production. The method is based on an integral analysis using pressure maps and well tests. Application of this method on the Salym group of oilfields has allowed concluding about wells stock status, about productivity index dynamics in time, also to make an assumption about the reasons for its change. The analysis showed that productivity index relative changes in horizontal wells lower than in slanted wells.

The paper considers a new engineering analytical tool for express oil reserves assessment. Proposed method is based on classifying oil reserves by complexity – reservoir complexity index (RCI). It allows to optimize the development system and form a well interventions program. The method is suggested to use three main parameters for development complexity estimation: reservoir permeability, start watercut (which contains the parameters of the curve of relative permeability, saturation and viscosity) and geological heterogeneity (pattern efficiency). An economic estimation of the well profitability is carried out by calculating PV UDC indicator (unit development cost, CAPEX / total oil production). The advantages of this indicator is that it allows to determine the economic attractiveness and does not require macro parameters and costs for the building well pads Due to the economic assessment and well ranking, it is possible to obtain profitable well pads and select candidates for sidetracking. The novelty of the work lies in the use of an updated methodology for the reservoir complexity index estimation for the remaining recoverable reserves classification. As a result, high-quality tool is created that integrates RCI and economic model. It is aimed for solving reservoir engineering problems and increasing the project cost The proposed method can be applied to other fields with minor modifications.

A long-standing goal of nanomedicine is to improve a drug’s benefit by loading it into a nanocarrier that homes solely to a specific target cell and organ. Unfortunately, nanocarriers usually end up with only a small percentage of the injected dose (% ID) in the target organ, due largely to clearance by the liver and spleen. Further, cell-type-specific targeting is rarely achieved without reducing target organ accumulation. To solve these problems, we introduce DART (dual affinity to RBCs and target cells), in which nanocarriers are conjugated to two affinity ligands, one binding red blood cells, and one binding a target cell (here, pulmonary endothelial cells). DART nanocarriers first bind red blood cells, then transfer to the target organ’s endothelial cells as the bound red blood cells squeeze through capillaries. We show that within minutes after intravascular injection in mice, nearly 70 % ID of DART nanocarriers accumulate in the target organ (lungs), more than doubling the % ID ceiling achieved by a multitude of prior technologies, finally achieving a majority % ID in a target organ. Humanized DART nanocarriers in ex vivo perfused human lungs recapitulate this phenomenon. Furthermore, DART enhances the selectivity of delivery to target endothelial cells over local phagocytes within the target organ by 6-fold. DART’s marked improvement in both organ- and cell-type targeting may thus be helpful in localizing drugs for a multitude of medical applications.

The article describes new decline curves (DC) forecasting method for project wells. The method is based on the integration of manual grouping of DC and machine learning (ML) algorithms appliance. ML allows finding hidden connections between features and the output. Article includes the decline curves analysis of two well completion types: horizontal and slanted wells, which illustrates that horizontal wells are more effective than slanted.

Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.

Social networks are different from traditional companies, therefore, the article discusses the methodology of social networks valuation is considered, as well as the features arising by the specifics of the activities of such companies. The results are interpreted and the conclusions are made regarding the accuracy of social network valuation by discounting cash flows of the company.

Deformability of injectable nanocarriers impacts rheological behavior, drug loading, and affinity target adhesion. Here, we present atomic force microscopy (AFM) and spectroscopy measurements of nanocarrier Young's moduli, tune the moduli of deformable nanocarriers with cross-linkers, and demonstrate vascular targeting behavior that correlates with Young's modulus. Homobifunctional cross-linkers were introduced into lysozyme-dextran nanogels (NGs). Single particle-scale AFM measurements determined NG moduli varying from ∼50-150 kPa for unmodified NGs or NGs with a short hydrophilic cross-linker (2,2'-(ethylenedioxy)bis(ethylamine), EOD) to ∼350 kPa for NGs modified with a longer hydrophilic cross-linker (4,9-dioxa-1,12-dodecanediamine, DODD) to ∼10 MPa for NGs modified with a longer hydrophobic cross-linker (1,12-diaminododecane, DAD). Cross-linked NGs were conjugated to antibodies for plasmalemma vesicle associated protein (PLVAP), a caveolar endothelial marker that cannot be accessed by rigid particles larger than ∼100 nm. In previous work, 150 nm NGs effectively targeted PLVAP, where rigid particles of similar diameter did not. EOD-modified NGs targeted PLVAP less effectively than unmodified NGs, but more effectively than DODD or DAD modified NGs, which both yielded low levels of targeting, resembling results previously obtained with polystyrene particles. Cross-linked NGs were also conjugated to antibodies against intracellular adhesion molecule-1 (ICAM-1), an endothelial marker accessible to large rigid particles. Cross-linked NGs and unmodified NGs targeted uniformly to ICAM-1. We thus demonstrate cross-linker modification of NGs, AFM determination of NG mechanical properties varying with cross-linker, and tuning of specific sterically constrained vascular targeting behavior in correlation with cross-linker-modified NG mechanical properties.

One of the goals of nanomedicine is targeted delivery of therapeutic enzymes to the sub-cellular compartments where their action is needed. Endothelial caveolae-derived endosomes represent an important yet challenging destination for targeting, in part due to smaller size of the entry aperture of caveolae (ca. 30–50 nm). Here, we designed modular, multi-molecular, ferritin-based nanocarriers with uniform size (20 nm diameter) for easy drug-loading and targeted delivery of enzymatic cargo to these specific vesicles. These nanocarriers targeted to caveolar Plasmalemmal Vesicle-Associated Protein (Plvap) deliver superoxide dismutase (SOD) into endosomes in endothelial cells, the specific site of influx of superoxide mediating by such pro-inflammatory signaling as some cytokines and lipopolysaccharide (LPS). Cell studies showed efficient internalization of Plvap-targeted SOD-loaded nanocarriers followed by dissociation from caveolin-containing vesicles and intracellular transport to endosomes. The nanocarriers had a profound protective anti-inflammatory effect in an animal model of LPS-induced inflammation, in agreement with the characteristics of their endothelial uptake and intracellular transport, indicating that these novel, targeted nanocarriers provide an advantageous platform for caveolae-dependent delivery of biotherapeutics.

Nucleoside-modified messenger RNA (mRNA)-lipid nanoparticles (LNPs) are the basis for the first two EUA (Emergency Use Authorization) COVID-19 vaccines. The use of nucleoside-modified mRNA as a pharmacological agent opens immense opportunities for therapeutic, prophylactic and diagnostic molecular interventions. In particular, mRNA-based drugs may specifically modulate immune cells, such as T lymphocytes, for immunotherapy of oncologic, infectious and other conditions. The key challenge, however, is that T cells are notoriously resistant to transfection by exogenous mRNA. Here, we report that conjugating CD4 antibody to LNPs enables specific targeting and mRNA interventions to CD4+ cells, including T cells. After systemic injection in mice, CD4-targeted radiolabeled mRNA-LNPs accumulated in spleen, providing ∼30-fold higher signal of reporter mRNA in T cells isolated from spleen as compared with non-targeted mRNA-LNPs. Intravenous injection of CD4-targeted LNPs loaded with Cre recombinase-encoding mRNA provided specific dose-dependent loxP-mediated genetic recombination, resulting in reporter gene expression in about 60% and 40% of CD4+ T cells in spleen and lymph nodes, respectively. T cell phenotyping showed uniform transfection of T cell subpopulations, with no variability in uptake of CD4-targeted mRNA-LNPs in naive, central memory, and effector cells. The specific and efficient targeting and transfection of mRNA to T cells established in this study provides a platform technology for immunotherapy of devastating conditions and HIV cure.

The non-cooperative game model of public private partnership is considered in this paper. Such partnerships is carried out through the implementation of social or infrastructure projects in relation to state and municipal property. In this paper the problem of identifying the best private partner is modeled as a static non-cooperative game with full information. A compromise solution is choosed as optimality principle. An algorithm of compromise solution is given in this paper. The numerical example is solved.

The investigation subject is an Oil Collector Case which is a thin axisymmetric stator part with console binding to the turbine rear frame. It had been suffering from high level vibrations and needed fixing measures to apply. Self-excited vibrations supposed as the main reason for defects to occur. The problem was examined in the engine and test rig conditions. The energetic method which is usually applied to blade flutter problems was used for aeroelastic stability analysis. Radial surface displacements were set according to the harmonic oscillation function that corresponds to the oil collector’s first bending eigenmode with two nodal diameters. 3D aerodynamic model represents a 180° sector, thus ensures that surface displacements and gas parameters on periodic surfaces are equal. A set of simulations was carried out and calculated; the aerodynamic damping coefficient values showed aeroelastic instability predisposition in both the engine and test rig conditions for most test cases. Influence of such model parameters as seal radial clearance, pressure ratio, inlet air temperature, wave propagation direction and rotor speed was investigated. A detailed analysis showed that for instability case positive aerodynamic work region lies inside the oil collector cavern downstream labyrinth seal where pressure wave and surface displacement speed wave are close to synchrony. Probable excitation mechanisms were described and discussed. It was demonstrated that aeroelastic instability of the same type as it was in the engine conditions can be reproduced in the test rig conditions.

Targeted drug delivery to the endothelium has the potential to generate localized therapeutic effects at the blood-tissue interface. For some therapeutic cargoes, it is essential to maintain contact with the bloodstream to exert protective effects. The pharmacokinetics (PK) of endothelial surface-targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy. To bridge this gap, we site-specifically radiolabeled mono- (scFv) and bivalent (mAb) affinity ligands specific for the endothelial cell adhesion molecules, PECAM-1 (CD31) and ICAM-1 (CD54). Radiotracing revealed similar lung biodistribution at 30 minutes post-injection (79.3% ± 4.2% vs 80.4% ± 10.6% ID/g for αICAM and 58.9% ± 3.6% ID/g vs. 47.7% ± 5.8% ID/g for αPECAM mAb vs. scFv), but marked differences in organ residence time, with antibodies demonstrating an order of magnitude greater area under the lung concentration vs. time curve (AUCinf 1698 ± 352 vs. 53.3 ± 7.9 ID/g*hrs for αICAM and 1023 ± 507 vs. 114 ± 37 ID/g*hrs for αPECAM mAb vs scFv). A physiologically based pharmacokinetic model, fit to and validated using these data, indicated contributions from both superior binding characteristics and prolonged circulation time supporting multiple binding-detachment cycles. We tested the ability of each affinity ligand to deliver a prototypical surface cargo, thrombomodulin (TM), using one-to-one protein conjugates. Bivalent mAb-TM was superior to monovalent scFv-TM in both pulmonary targeting and lung residence time (AUCinf 141 ± 3.2 vs 12.4 ± 4.2 ID/g*hrs for ICAM and 188 ± 90 vs 34.7 ± 19.9 ID/g*hrs for PECAM), despite having similar blood PK, indicating that binding strength is more important parameter than the kinetics of binding. To maximize bivalent target engagement, we synthesized an oriented, end-to-end anti-ICAM mAb-TM conjugate and found that this therapeutic had the best lung residence time (AUCinf 253 ± 18 ID/g*hrs) of all TM modalities. These observations have implications not only for the delivery of TM, but also potentially all therapeutics targeted to the endothelial surface.

Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood-brain barrier, thus benefiting numerous brain pathologies.

The bloodstream is the main transporting pathway for drug delivery systems (DDS) from the site of administration to the intended site of action. In many cases, components of the vascular system represent therapeutic targets. Endothelial cells, which line the luminal surface of the vasculature, play a tripartite role of the key target, barrier, or victim of nanomedicines in the bloodstream. Circulating DDS may accumulate in the vascular areas of interest and in off-target areas via mechanisms bypassing specific molecular recognition, but using ligands of specific vascular determinant molecules enables a degree of precision, efficacy, and specificity of delivery unattainable by non-affinity DDS. Three decades of research efforts have focused on specific vascular targeting, which have yielded a multitude of DDS, many of which are currently undergoing a translational phase of development for biomedical applications, including interventions in the cardiovascular, pulmonary, and central nervous systems, regulation of endothelial functions, host defense, and permeation of vascular barriers. We discuss the design of endothelial-targeted nanocarriers, factors underlying their interactions with cells and tissues, and describe examples of their investigational use in models of acute vascular inflammation with an eye on translational challenges., Graphical abstract Unlabelled Image

Decoration of one-dimensional multi-walled carbon nanotubes (MWCNTs) with zero-dimensional Co nanoparticles leads to hybrid structures with chemical and electromagnetic features that are not available to the individual components. This work addresses the influence of the nature and structure of MWCNTs on the localization of Co nanoparticles. Depending on synthesis conditions, Co can be deposited on the external or in inner surfaces of the nanotubes. Co/MWCNTs hybrids have been characterized by in situ X-ray powder diffraction, high-resolution transmission electron microscopy and 59Co internal field nuclear magnetic resonance. It has been shown that the average diameter (7.2, 9.4 and 18.6 nm), number of walls (5–7, 12–15, 15–20), and functional composition of the MWCNTs have a remarkable effect on the size of Co nanoparticles and their distribution in the structure of MWCNTs. The observed phenomenon has been rationalized in terms of nanotubes surface properties. Parent MWCNTs being hydrophobic and having limited porosity do not stabilize Co nanoparticles and, therefore, they are localized on the outside surface with relatively large average size and broad size distribution. On the other hand, the oxidation of the MWCNTs resulted in the penetration of Co nanoparticles inside of the nanotubes, presumably because of pore opening as well as increased hydrophilicity of the nanotubes.

Ferritin subunits of heavy and light polypeptide chains self-assemble into a spherical nanocage that serves as a natural transport vehicle for metals but can include diverse cargoes. Ferritin nanoparticles are characterized by remarkable stability, small and uniform size. Chemical modifications and molecular re-engineering of ferritin yield a versatile platform of nanocarriers capable of delivering a broad range of therapeutic and imaging agents. Targeting moieties conjugated to the ferritin external surface provide multivalent anchoring of biological targets. Here, we highlight some of the current work on ferritin as well as examine potential strategies that could be used to functionalize ferritin via chemical and genetic means to enable its utility in vascular drug delivery.

Inflammatory mediators binding to Toll-Like receptors (TLR) induce an influx of superoxide anion in the ensuing endosomes. In endothelial cells, endosomal surplus of superoxide causes pro-inflammatory activation and TLR4 agonists act preferentially via caveolae-derived endosomes. To test the hypothesis that SOD delivery to caveolae may specifically inhibit this pathological pathway, we conjugated SOD with antibodies (Ab/SOD, size ~ 10 nm) to plasmalemmal vesicle-associated protein (Plvap) that is specifically localized to endothelial caveolae in vivo and compared its effects to non-caveolar target CD31/PECAM-1. Plvap Ab/SOD bound to endothelial cells in culture with much lower efficacy than CD31 Ab/SOD, yet blocked the effects of LPS signaling with higher efficiency than CD31 Ab/SOD. Disruption of cholesterol-rich membrane domains by filipin inhibits Plvap Ab/SOD endocytosis and LPS signaling, implicating the caveolae-dependent pathway(s) in both processes. Both Ab/SOD conjugates targeted to Plvap and CD31 accumulated in the lungs after IV injection in mice, but the former more profoundly inhibited LPS-induced pulmonary inflammation and elevation of plasma level of interferon-beta and -gamma and interleukin-27. Taken together, these results indicate that targeted delivery of SOD to specific cellular compartments may offer effective, mechanistically precise interception of pro-inflammatory signaling mediated by reactive oxygen species.

The pulmonary vasculature plays an important role in many lung pathologies, such as pulmonary arterial hypertension, primary graft dysfunction of lung transplant, and acute respiratory distress syndrome. Therapy for these diseases is quite limited, largely due to dose-limiting side effects of numerous drugs that have been trialed or approved. High doses of drugs targeting the pulmonary vasculature are needed due to the lack of specific affinity of therapeutic compounds to the vasculature. To overcome this problem, the field of targeted drug delivery aims to target drugs to the pulmonary endothelial cells, especially those in pathological regions. The field uses a variety of drug delivery systems (DDSs), ranging from nano-scale drug carriers, such as liposomes, to methods of conjugating drugs to affinity moieites, such as antibodies. These DDSs can deliver small molecule drugs, protein therapeutics, and imaging agents. Here we review targeted drug delivery to the pulmonary endothelium for the treatment of pulmonary diseases. Cautionary notes are made of the risk–benefit ratio and safety—parameters one should keep in mind when developing a translational therapeutic.

Background: Since SARS-CoV-2 infection heavily affects vulnerable populations including those with immune suppression, it is of special value to study clinical course, treatment outcomes, and immunity in patients (pts) with hematological (hem) malignancies. Methods: CHRONOS19 is an ongoing observational study in adult pts (≥18 years) with hem diseases (malignant or non-malignant) and COVID-19 in Russia. This web-based registry collected de-identified data from 15 centers all over the country at 30, 90, and 180 days after lab-confirmed or suspected (based on CT and/or clinical symptoms) COVID-19 diagnosis. The primary endpoint was 30-day all-cause mortality. Results: As of data cut-off on April 14, 2021, 626 pts were enrolled in the study;562 were eligible for primary endpoint assessment, n (%): M/F 271 (48%) / 291 (52%), median age 56 [18-90] years, malignant disease in 516 (92%) pts, among them induction phase / relapse or refractory / remission / NA in 180 (35%) / 120 (23%) / 187 (36%) / 29 (6%) pts. Thirty-day all-cause mortality in pts with hem malignancies was 19%;83% of deaths were due to COVID-19 complications. No increase of hem disease relapse rate after COVID-19 was observed at Day 90 or Day 180, although 180-day data was still not mature at the time of analysis. IgG to SARS-CoV-2 was detected in 84% of pts with hem malignancies (167/199). The highest rate of detected antibody immunity was found in pts with chronic myeloproliferative neoplasms (100%;13/13), HL (100%;12/12), and multiple myeloma (97%;34/35), the lowest – in pts with CLL (62%;8/13) and NHL (60%;6/10 and 56%;10/18 for low-grade and high-grade lymphoma, respectively). igG detection rate in CD20+ lymphoma (60%) was significantly lower than in HL or T-cell lymphoma (p=0.004). Pts with ECOG 0-2 throughout the disease had a high rate of antibody immunity (90%;104/116) vs. those with ECOG 3-4 at the time of COVID-19 diagnosis (77.5%;31/40) or with worsening of ECOG to 3-4 during the disease (78%;36/46). Five cases of SARS-CoV-2 re-infection were described. Conclusions: Pts with hem malignancies and COVID-19 have higher mortality than the general population. Low post-disease antibody immunity to SARS-CoV-2 and cases of re-infection may justify vaccination of these pts and warrant further research. Clinical trial identification: NCT04422470. Legal entity responsible for the study: National Research Center for Hematology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Many cellular events are driven by changes in protein expression, measurable by mass spectrometry or antibody-based assays. However, using conventional technology, the analysis of transcription factor or membrane receptor expression is often limited by an insufficient sensitivity and specificity. To overcome this limitation, we have developed a high-resolution targeted proteomics strategy, which allows quantification down to the lower attomol range in a straightforward way without any prior enrichment or fractionation approaches. The method applies isotope-labeled peptide standards for quantification of the protein of interest. As proof of principle, we applied the improved workflow to proteins of the unfolded protein response (UPR), a signaling pathway of great clinical importance, and could for the first time detect and quantify all major UPR receptors, transducers and effectors that are not readily detectable via antibody-based-, SRM- or conventional PRM assays. As transcription and translation is central to the regulation of UPR, quantification and determination of protein copy numbers in the cell is important for our understanding of the signaling process as well as how pharmacologic modulation of these pathways impacts on the signaling. These questions can be answered using our newly established workflow as exemplified in an experiment using UPR perturbation in a glioblastoma cell lines.

The positive effect of alumina surface graphitization by CVD with ethylene on the activity of CoMo catalysts in hydrodesulfurization has been demonstrated. X-ray diffraction, Raman spectroscopy, High-resolution transmission electron microscopy, X-ray photoelectron spectroscopy and nitrogen physisorption showed that alumina surface graphitization does not significantly change the morphology and textural characteristics of the support. However, it has a significant impact on the morphology of supported sulfide component resulting in the formation of particles with a shorter slab length (2.9 vs 3.3 nm) and higher stacking number (2.4 vs 2.1) as compared to the sample based on γ-Al2O3. The results of CoMoS/γ-Al2O3 and CoMoS/C@γ-Al2O3 catalysts testing in hydrotreating reactions demonstrated a similar activity in hydrodenitrogenation of quinoline and 1.7 times higher activity of CoMoS/C@γ-Al2O3 in hydrodesulfurization of dibenzothiophene. Higher hydrodesulfurization activity of CoMoS/C@γ-Al2O3 sample is attributed to improved dispersion of the supported sulfide component and enhanced promotion of MoS2 by cobalt. Thus, the simple CVD approach presented here allows selective modification of the surface of commercially available alumina supports with a layer of graphite-like carbon and can be used to improve the activity of conventional hydrotreating catalysts.

Mathematical induction is one of the main methods of the proof that students study and use it in their studies in higher education. This important method, in addition to mathematics, is widely used in computer science and a number of other related disciplines. However, even if the principles of proof using the method of induction are taught, understood and mastered by students well, many students have great difficulty with algebraic transformations necessary for proving, for example, finding the inductive step. The use of the Maple computer algebra system allows students to overcome this obstacle and, more attention and effort to pay to understanding the concept of proofs using the method of mathematical induction. In addition, students can prove more complex algebraic statements, and their activities can be of a pronounced research nature.

Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300 nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively.

For a variety of diseases, effective therapy is severely limited or rendered impossible due to an inability to deliver medications to the intended sites of action. Multiple barriers exist through the body, which have evolved over time to limit the migration of foreign compounds from entering the tissues. Turning toward biology as inspiration, it has been the general goal of drug delivery to create carrier strategies that mimic, in part, features of bacteria/ viruses that allow them overcome these barriers. By packaging drugs into nano and micron scale vehicles, it should be possible to completely change the biodistribution and residence times of pharmaceutically active compounds. Recently, due to advances in formulation technologies, it has become possible to control not just the material selection, surface chemistry, and/or size, but also the overall geometry and plasticity of the drug carriers. These approaches aid in the formulation of nonspherical particles such as, discs, rods, and even unique structures such as cubes and nanodiamonds. The adjustment of size and shape can be used for the aid or prevention in cellular uptake and also to overcome the vascular and mucosal barrier. In this review, we present a summary of some approaches used to control carrier shape and the impact these geometries have upon drug transport across biological barriers.

Game-theoretic models for two classes of players are considered in this paper. The first class will consist of mobile operators, who, based on information about competitors’ actions, will plan changes in prices for services. The second class will consist of dedicated user cohorts who, depending on the current situation, will plan their actions, namely, change or not change the operator. The presented models solve the problem of maximizing the income of mobile operators and minimizing the cost of communication by users. A turn-based game is considered where a possible strategy for a first-class player will be considered a non-zero price vector for the provided communication services. A possible strategy for a second-class player will be considered the sequence of choosing a mobile operator for each of the services. The payoff function of both classes players will be built at each stage. According to the winnings, there is a compromise solution for different classes of players.

Purpose The purpose of the paper is to substantiate possible and necessary use of restructuring of tax liabilities as an upcoming trend of economic diversification in modern Russia, and to develop practical recommendations. Methodology In this paper we apply a complex of general scientific methods, as well as methods of time-series analysis in economic statistics—horizontal and trend analysis. Information and empirical background is provided by data of the Center for Macroeconomic Analysis and Short-Term Forecasting of the Russian Federation, RIA Rating, and Federal State Statistics Service of the Russian Federation (Rosstat). To define the relevance of the mechanism for restructuring tax liabilities in modern Russia, the authors address to dynamic pattern of enterprises and closed down ones due to bankruptcy in 2007–2017. Results As a result, we had proved that the restructuring of tax liabilities is an upcoming trend of economic diversification in modern Russia. It is revealed that over recent years, the demand for this mechanism in relation to growing unprofitability of enterprises and their frequent close-down due to bankruptcy has increased in Russian economic system. However, the state introduces tight restrictions for enterprises restructuring their tax liabilities to protect own interests (guaranteed replenishment of budget and extra-budgetary funds). Recommendations In order to ensure widespread availability of the mechanism to restructure tax liabilities for modern Russian enterprises, it is advised legislative consolidation of priority implementation of restructured tax liabilities. To aim this mechanism at diversification of the Russian economy, we propose to grant preferential terms (reduced limit of tax liabilities and extended term of their restructuring) for enterprises of the most promising and strategically crucial branches of national economy in terms of economic diversification.

Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.

Molecular targeting of nanoparticle drug carriers promises maximized therapeutic impact to sites of disease or injury with minimized systemic effects. Precise targeting demands addressing to subcellular features, among which caveolae, invaginations in the cell membrane implicated in transcytosis and inflammatory signaling, are appealing targets. Caveolar geometry was reported to impose a ~50nm size cutoff on nanocarrier access to plasmalemma vesicle associated protein (PLVAP), a marker found in caveolae in the lungs. We explored the use of deformable nanocarriers to overcome that size cutoff. Lysozyme-dextran nanogels (NGs) were synthesized with ~150nm or ~300nm mean diameter. AFM indicated deformability of NGs on complementary surfaces. Quartz crystal microbalance data indicated that NGs formed softer monolayers (~60kPa) than polystyrene particles (~8MPa). NGs deformed during flow through microfluidic channels, and modeling of NG extrusion through porous filters yielded sieving diameters of less than 25nm for NGs with 150nm and 300nm hydrodynamic diameters. In mouse lungs, where PLVAP is primarily localized to caveolae, NGs of 150nm and 300nm diameter targeted PLVAP while rigid polystyrene particles did not. Our data indicate a role for mechanical deformability in targeting large high-payload drug delivery vehicles to sterically obscured targets like PLVAP.

Targeting drugs to endothelial cells has shown the ability to improve outcomes in animal models of inflammatory, ischemic and thrombotic diseases. Previous studies have revealed that certain pairs of ligands (antibodies and antibody fragments) specific for adjacent, but distinct, epitopes on PECAM-1 enhance each other’s binding, a phenomenon dubbed Collaborative Enhancement of Paired Affinity Ligands, or CEPAL. This discovery has been leveraged to enable simultaneous delivery of multiple therapeutics to the vascular endothelium. Given the known role of PECAM-1 in promoting endothelial quiescence and cell junction integrity, we sought here to determine if CEPAL might induce unintended vascular effects. Using a combination of in vitro and in vivo techniques and employing human and mouse endothelial cells under physiologic and pathologic conditions, we found only modest or non-significant effects in response to antibodies to PECAM-1, whether given solo or in pairs. In contrast, these methods detected significant elevation of endothelial permeability, pro-inflammatory vascular activation, and systemic cytokine release following antibody binding to the related endothelial junction protein, VE-Cadherin. These studies support the notion that PECAM-1-targeted CEPAL provides relatively well-tolerated endothelial drug delivery. Additionally, the analysis herein creates a template to evaluate potential toxicities of vascular-targeted nanoparticles and protein therapeutics.

The purpose of the article is to develop the innovational tools of provision of food security through state support for the agro-industrial complex (AIC) in the conditions of digital economy in modern Russia. For verification of the offered hypothesis and determination of connection between the level of national food security of modern Russia, state support for the AIC, and the use of the possibilities of digital economy, the article uses the method of correlation analysis. Also, the authors use the method of trend and horizontal statistical analysis, with the help of which the authors use the dynamics of change of the index of national food security in Russia in 2012–2017. The authors substantiate that state support for the AIC in modern Russia is not related to usage of existing possibilities of digital economy and does not fully ensure the national food security. The authors offer to supplement the traditional tools of financial support for national manufacturers of the AIC products with state subsidies, subsidized credits, etc., as well as innovational tools which is based on usage of the capabilities of digital economy. These tools allow achieving competitive advantages of domestic manufacturers of the AIC as to the quality and price. As compared to the traditional tools of state support, which belongs to the sphere of protectionism, the offered innovational tools do not limit the foreign competition and does not provide obvious preferences for domestic entrepreneurship. Instead, innovational tools increase competitiveness of domestic manufacturers of the AIC products, i.e., uses the market mechanism, leaving the choice to customers, hindering access to the market for dishonest entrepreneurs.