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Background: miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis. Methods: We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics. Results: The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes ( Col2a1, Col3a1, Col1a2, Fn1 , etc) and tissue inhibitor of metalloproteinase 3 ( Timp3 ) and downregulation of Mmp12 in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33. Conclusions: This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.

Acidity can be a useful alternative biomarker for the targeting of metabolically active cells in certain diseased tissues, as in acute inflammation or aggressive tumors. We investigated the targeting of activated macrophages by pH low insertion peptides (pHLIPs), an established technology for targeting cell-surface acidity.The uptake of fluorescent pHLIPs by activated macrophages was studied in cell cultures, in a mouse model of lung inflammation, and in a mouse tumor model. Fluorescence microscopy, whole-body and organ imaging, immunohistochemistry, and FACS analysis were employed.We find that cultured, activated macrophages readily internalize pHLIPs. The uptake is higher in glycolytic macrophages activated by LPS and INF-γ compared to macrophages activated by IL-4/IL-13. Fluorescent pHLIPs target LPS-induced lung inflammation in mice. In addition to marking cancer cells within the tumor microenvironment, fluorescent pHLIPs target CD45pHLIP peptides sense low cell surface pH, which triggers their insertion into the cell membrane. Unlike cancerous cells, activated macrophages do not retain inserted pHLIPs on their surfaces, instead their highly active membrane recycling moves the pHLIPs into endosomes. Targeting activated macrophages in diseased tissues may enable clinical visualization and therapeutic opportunities.

Samarium-sodium double sulfate crystalline hydrate NaSm(SO4)2·H2O was obtained by the crystallization from an aqueous solution containing equimolar amounts of ions. The anhydrous salt of NaSm(SO4)2 was formed by a thermally induced release of the equivalent of water from NaSm(SO4)2·H2O. The kinetic parameters of thermal decomposition were determined (Ea = 102 kJ/mol, A = 9·106). The crystal structures of both compounds were refined from the X-ray powder diffraction data. Sulfate hydrate NaSm(SO4)2·H2O crystallizes in the trigonal symmetry, space group P3121 (a = 6.91820(3) and c = 12.8100(1) A, V = 530.963(7) A3). The anhydrous salt crystallizes in the triclinic symmetry, space group P-1 (a = 6.8816(2), b = 6.2968(2) and c = 7.0607(2) A, α = 96.035(1), β = 99.191(1) and γ = 90.986(1)°, V = 300.17(1) A3). The vibrational properties of compounds are mainly determined by the sulfate group deformations. The luminescence spectra of both sulfates are similar and are governed by the transitions of samarium ions 4G5/2 → 6HJ (J = 5/2, 7/2, 9/2 and 11/2). The anhydrous sulfate is stable up to 1100 K and undergoes an almost isotropic expansion when heated. After 1100 K, the compound decomposes into Sm2(SO4)3 and Na2SO4.

Acidity is a useful biomarker for the targeting of metabolically active cells in tumors. pH Low Insertion Peptides (pHLIPs) sense the pH at the surfaces of tumor cells and can facilitate intracellular delivery of cell-permeable and cell-impermeable cargo molecules. In this study we have shown the targeting of malignant lesions in human bladders by fluorescent pHLIP agents, intracellular delivery of amanitin toxin by pHLIP for the inhibition of urothelial cancer cell proliferation, and enhanced potency of pHLIP-amanitin for cancer cells with 17p loss, a mutation frequently present in urothelial cancers. Twenty-eight ex-vivo bladder specimens, from patients undergoing robotic assisted laparoscopic radical cystectomy for bladder cancer, were treated via intravesical incubation for 15-60 minutes with pHLIP conjugated to indocyanine green (ICG) or IR-800 near infrared fluorescent (NIRF) dyes at concentrations of 4-8 μM. White light cystoscopy identified 47/58 (81%) and NIRF pHLIP cystoscopy identified 57/58 (98.3%) of malignant lesions of different subtypes and stages selected for histopathological processing. pHLIP NIRF imaging improved diagnosis by 17.3% (p < 0.05). All carcinoma-in-situ cases missed by white light cystoscopy were targeted by pHLIP agents and were diagnosed by NIRF imaging. We also investigated the interactions of pHLIP-amanitin with urothelial cancer cells of different grades. pHLIP-amanitin produced concentration- and pH-dependent inhibition of the proliferation of urothelial cancer cells treated for 2 hrs at concentrations up to 4 μM. A 3-4x enhanced cytotoxicity of pHLIP-amanitin was observed for cells with a 17p loss after 2 hrs of treatment at pH6. Potentially, pHLIP technology may improve the management of urothelial cancers, including imaging of malignant lesions using pHLIP-ICG for diagnosis and surgery, and the use of pHLIP-amanitin for treatment of superficial bladder cancers via intravesical instillation.

A double holmium-silver sulfate was obtained for the first time. The temperature intervals for the formation and stability of the compound were determined by differential scanning calorimetry. The crystal structure of AgHo(SO4)2 was determined by Rietveld method. The X-ray diffraction (XRD) analysis showed that the compound crystallizes in the monoclinic syngony, space group P21/m, with the unit cell parameters a = 4.71751 (4) A, b = 6.84940 (6) A and c = 9.89528 (9) A, β = 95.1466 (4)°, V = 318.448 (5) A3, Z = 2, RB = 1.55 %, T = 303 K. Two types of sulfate tetrahedra were found in the structure, which significantly affected the spectral properties in the infrared range. In the temperature range of 143−703 K, a negative thermal expansion along the b direction accompanied by a positive thermal expansion along the a and c directions was observed. It was established that negative thermal expansion is the result of the deformation of sulfate tetrahedra, which is affected by the movement of holmium and silver atoms. The excitation in the blue spectral range (457.9 nm) produces a luminescence in light blue (489 nm), green (545 nm) and red (654 nm) spectral ranges, and the latter two were of comparable intensity that is favorable for WLED sources. The observed luminescent band distribution is ascribed to the specific crystal field at Ho3+ ion sites rather than a variation of radiationless probability.

Purpose: pHLIPs (pH-Low Insertion Peptides) target cell surface acidity resulting from the metabolism of cells in a solid tumor. The acidity causes pHLIPs to insert as transmembrane helices, and attached cargoes can be delivered into targeted cells. STING agonists can trigger an immune response when they are inside cells. pHLIP targeted delivery of a STING agonist (STINGa) effectively triggers cytokine secretion to mobilize the immune system to eradicate tumors while avoiding side effects. Experimental Procedures: Constructs consisting of a pHLIP peptide (Var3) linked to a STINGa (diABZI) via a self-immolating linker were synthesized and characterized. Activation of the STING pathway by the agent was confirmed in cells. Small (100 mm3) and large (400-700 mm3) tumors were grown in female Balb/c mice following flank injections of CT26 colorectal cancer cells. Randomized groups of mice were injected i.p. or i.v. with pHLIP-STINGa made with L- or D- amino acid pHLIP peptides, STINGa alone, pHLIP alone or vehicle. Tumor size and body weight were then measured 3 times per week. The durability of the response to the agent was tested by a second injection of CT26 cells after 60 days. In separate experiments, the identities of targeted immune and stromal cells, the production of cytokines, the PK, tumor targeting and biodistribution were assessed. Results and Conclusions: pHLIP extends the lifetime of a STINGa in the blood 6-fold and delivers STINGa to acidic cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid derived suppressor cells (mMDSCs), and dendritic cells (DCs). The resulting activation of cytokines within the tumor microenvironment (TME) triggers the eradication of small and large CT26 tumors in mice after a single dose of pHLIP-STINGa. The tumor stroma was destroyed, intratumoral hemorrhage developed, and the TME pH increased, which is important for the efficient cytotoxic activity of immune cells. Further, no tumors developed in 20 out of 25 tumor-free mice re-challenged by an additional injection of cancer cells. The therapeutic effect on CT26 tumors was insignificant in nude mice lacking T-cells. Inhibition of MHC-I negative B16F10 melanoma tumor growth was also observed in Balb/c mice. Thus, targeted delivery of the STINGa to the tumor stroma and TAMs activates signaling, potentially resulting in the recruitment and infiltration of both T-cells and NK-cells, which gain access to the tumor core. The cytotoxic activity of immune cells is enhanced, and immune memory is developed. Citation Format: Donald M. Engelman, Yana K. Reshetnyak, Oleg A. Andreev. Durable eradication of tumors by single injections of a pHLIP-STING agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1804.

The MnS–Tb2S3 phase diagram has been plotted by using physico-chemical methods of analysis. This diagram refers to the transition type from the eutectic system MnS–Gd2S3 to the systems with the formation of intermediate compounds. Two MnTb4S7 and MnTb2S4 complex sulfides are formed in the MnS–Tb2S3 system. The thermal effects of solid-phase decomposition of complex sulfides are as follows: ΔH = 27.4 kJ/mol at 1643 K for MnTb4S7 and ΔH = 16 kJ/mol at 1574 K for MnTb2S4. The solubility of MnS in γ-Tb2S3 at 1650 K is 16 mol.%, and 5 mol.% of MnS is dissolved in α-Tb2S3 at 1170 K. The solubility of Tb2S3 in α-MnS-based solid solution (SS) is 6 mol.% at 1650 K and 3 mol.% of Tb2S3 at 1170 K. The temperature of the γ-Tb2S3 solid solution eutectoid decomposition is equal to 1350 K, and the composition of the eutectoid is 87 mol.% of Tb2S3. The coordinates of the eutectic between MnS-based solid solution and γ-Tb2S3-based solid solution is assumed to be equal to 27 mol.% of Tb2S3 and 1666 K. Calculations of the liquidus line, carried out using the Van Laar's equation, are in agreement with the experimental data. The Gibbs excess partial energies are calculated for the MnS–Tb2S3 system, and their negative values are correlated with the formation of two complex sulfides MnTb2S4 and MnTb4S7 in the system.

The purpose of the study is to analyze a separate group of sources: memories and testimonies of participants in the events of constructing defensive frontiers in the territory of the ChASSR in 1941–1942, revealing their typical characteristics and assessment as a historical source. The scientific novelty consists in attracting new sources of personal character in the history of erecting defensive structures in the territory of Chuvashia in autumn-winter 1941–1942. As a result of the study, general, typical characteristics of memories and testimonies of participants of the historical event were revealed: the predominance of household details, emphasizing such conditions of the construction as transport accessibility of construction objects, weather conditions, accommodation of builders, supplying with products, workers’ interrelations, emotional saturation of the historical event perception, impact on verbal folklore.

The proposed article considers the need to recognize the economic utility and social value of human resources, the development of which requires investment in comparison with other types of economic resources. The urgency of solving the problem of functioning of higher education system is dictated by the need to apply new approaches to the management of an educational institution. Successful companies focus their efforts on creating and developing a management system for educational institutions designed to work effectively with intellectual resources that are becoming less used today. All these circumstances explain the emergence of a special interest of scientists and practitioners in the management of intellectual capital and the effectiveness of the knowledge process. In this regard, there is a need for constant updating and change, which means that knowledge is always innovative. At the same time, the most interesting are the ways of transforming universities into a new type of organization focused on meeting the needs of the market, making a profit, developing innovative technologies, supporting high-tech research projects and managing them. Close interaction of business corporations with the University community, forms a diversified financial base, develops contacts with business, society and the state, and encourages the widespread use of initiative and support for innovation in the scientific and educational environment. The new conceptual approach has enriched the practice with progressive methods and technologies for managing people in a complex innovative environment. The priorities were flexible forms of labor use, continuous improvement of the quality of human resources, new approaches to organizing and stimulating labor, and addressing cultural and ethical factors of labor productivity and quality of life. The main components of scientific novelty are the regulation and mutual influence of the functioning infrastructure and the applied methodology of higher education.

The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation., T-cell activation primarily occurs in the lymph nodes, highly organized and specialized secondary lymphoid organs. Here the authors show that the acidic extracellular pH in lymph node paracortical zones limits cytokine production by effector T-cells, but does not alter their activation by antigen-presenting cells.

Background: Pre-metastatic niche refers to the environment prepared for efficient colonization of disseminated cancer cells in specific organs. Primary tumor secretome facilitates pre-metastatic niche through a series of molecular and cellular changes. This study focuses on interstitial pH in organs with pre-metastatic niche because dysregulated pH homeostasis plays a well-established role in tumor metastasis. In primary tumor, extracellular acidification directly promotes invasion/migration of cancer cells for extravasation. Meanwhile, little is known regarding interstitial pH in organs that are distant from primary tumor. Methods: BALB/c mice were subcutaneously inoculated with 4T1.2 cells or 66cl4 cells (mouse breast cancer cell lines) with resistance against 6-thioguanine. Absence of metastatic cells in their lungs was confirmed by long-termed culture of dissociated pulmonary cells in presence of 6-thioguanine; it defines Day 21 from inoculation as a pre-metastatic phase. Alternatively, 4T1.2 cell-conditioned media (4T1.2-CM) or control media was intraperitoneally administered every day for 21 consecutive days. pH-low insertion peptide (pHLIP® peptide) stably labels cells exposed to acidic conditions, which is feasible to evaluate interstitial acidity in each organ. Alexa Fluor® 750-labelled pHLIP® peptide was injected into mice, and fluorescent signals in harvested organs were detected by IVIS Lumina XRMS Series III. For a metastasis model, mice first received 4T1.2-CM or in combination with sodium oxamate (a lactate dehydrogenase inhibitor) followed by an intravenous injection of 66cl4 cells expressing luciferase. Results: At the pre-metastatic phase, 4T1.2 tumor-bearing mice showed great accumulation of pHLIP® peptide and high amounts of lactate in their lungs. By contrast, there was no significant fluorescence from pHLIP® peptide in lungs of low-metastatic 66cl4 cell-inoculated mice. Notable accumulation of pHLIP® peptide was also observed in the lungs of 4T1.2-CM-given mice. Intravenously injected 66cl4 cells colonized more aggressively in the acidic lungs than in control ones. Suppression of the lung acidification by sodium oxamate attenuated the metastatic burden, which significantly improved survival of the mice. In the acidic lungs, pHLIP® peptide was localized in alveolar type II (AT2) cells expressing surfactant protein C. Sorted AT2 cells from the acidic lungs strongly expressed glycolysis-related proteins. Conclusions: This study using pHLIP® peptide indicates a highly glycolytic activity with increased lactic acid in the lungs of 4T1.2 tumor-bearing mice at the pre-metastatic phase. Mechanistically, soluble factors derived from 4T1.2 cells could transform AT2 cells into acidic cells, which might provide metastasis-promoting function. This study will shed light on understanding the whole picture of pre-metastatic niche and give scientific insights to develop novel diagnosis and therapy for tumor metastasis. Citation Format: Toma Matsui, Yuki Toda, Anna Mosnikova, Oleg A. Andreev, Shigekuni Hosogi, Yana K. Reshetnyak, Eishi Ashihara. pH-low insertion peptide detects lactic acidosis contributing metastatic niche formation in lungs [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B022.

We consider theoretically the process of two-electron one-photon (TEOP) transitions to the ground state with the emission of a single ${K}_{\ensuremath{\alpha}\ensuremath{\alpha}}$ photon in a He-like sequence of atomic ions: from boron to uranium. The corresponding transition probabilities and transition energies are calculated within the QED theory. The calculations of the transition probabilities are performed in various gauges. The intensity ratios between the TEOP transitions and the other major transitions are presented.

Aims In cardiomyocytes, acute disturbances to intracellular pH (pHi) are promptly corrected by a system of finely tuned sarcolemmal acid–base transporters. However, these fluxes become thermodynamically re-balanced in acidic environments, which inadvertently causes their set-point pHi to fall outside the physiological range. It is unclear whether an adaptive mechanism exists to correct this thermodynamic challenge, and return pHi to normal. Methods and results Following left ventricle cryo-damage, a diffuse pattern of low extracellular pH (pHe) was detected by acid-sensing pHLIP. Despite this, pHi measured in the beating heart (13C NMR) was normal. Myocytes had adapted to their acidic environment by reducing Cl−/HCO3− exchange (CBE)-dependent acid-loading and increasing Na+/H+ exchange (NHE1)-dependent acid-extrusion, as measured by fluorescence (cSNARF1). The outcome of this adaptation on pHi is revealed as a cytoplasmic alkalinization when cells are superfused at physiological pHe. Conversely, mice given oral bicarbonate (to improve systemic buffering) had reduced myocardial NHE1 expression, consistent with a needs-dependent expression of pHi-regulatory transporters. The response to sustained acidity could be replicated in vitro using neonatal ventricular myocytes incubated at low pHe for 48 h. The adaptive increase in NHE1 and decrease in CBE activities was linked to Slc9a1 (NHE1) up-regulation and Slc4a2 (AE2) down-regulation. This response was triggered by intracellular H+ ions because it persisted in the absence of CO2/HCO3− and became ablated when acidic incubation media had lower chloride, a solution manoeuvre that reduces the extent of pHi-decrease. Pharmacological inhibition of FAK-family non-receptor kinases, previously characterized as pH-sensors, ablated this pHi autoregulation. In support of a pHi-sensing role, FAK protein Pyk2 (auto)phosphorylation was reduced within minutes of exposure to acidity, ahead of adaptive changes to pHi control. Conclusions Cardiomyocytes fine-tune the expression of pHi-regulators so that pHi is at least 7.0. This autoregulatory feedback mechanism defines physiological pHi and protects it during pHe vulnerabilities.

Two-photon decay of the $2s$ state in H-like ions is investigated. We report that asymmetry in the emission of photons with left- and right-hand circular polarizations can be observed in this transition if the initial state has a certain polarization. This asymmetry can be used to measure the polarization of ion beams.

The process of high-temperature oxidation of EuS in the air was explored in the temperature range of 500–1000 °C. The oxidation reaction enthalpy was determined (ΔH0exp = −1718.5 kJ/mol). The study of oxidation products allowed to establish the mechanism of EuS oxidation with oxygen. At 500–600 °C, EuS is oxidized to a mixture of Eu3+-containing compounds (Eu3S4, Eu2O2S). In the range of 700–1000 °C, only europium oxysulfate Eu2O2SO4 is formed. The structure refinement for Eu2O2SO4 was performed by the Rietveld method. The luminescence intensity of europium oxysulfate Eu2O2SO4 with characteristic 4f-4f transitions from the 5D0 state was investigated as a function of oxidation temperature.

The crystal structures of the complex sulfides SrLnCuS3 (Ln = Sm, Gd, Er and Lu) have been determined and refined using powder X-ray diffraction. The crystals are found to be orthorhombic, with the structure type changing consecutively in the order BaLaCuS3 → Eu2CuS3 → KZrCuS3 as the Ln3+ ionic radius decreases in the order La/Pr → Sm/Gd → Er/Lu. Variations of the structure parameters along the series of compounds studied are analyzed, and an effect caused by crystallochemical contraction on the stabilization of the respective structure types is demonstrated.

PURPOSE: To develop a tool to measure the pH at the surfaces of individual cells. PROCEDURES: The SNARF pH-sensitive dye was conjugated to a pHLIP® peptide (pH-Low Insertion Peptide) that binds cellular membranes in tumor spheroids. A beam splitter allows simultaneous recording of two images (580 and 640 nm) by a CCD camera. The ratio of the two images is converted into a pH map resolving single spheroid cells. An average pH for each cell is calculated and a pH histogram is derived. RESULTS: Surface pH depends on cellular glycolytic activity, which was varied by adding glucose or deoxy-glucose. Glucose was found to decrease the surface pH relative to the pH of the bulk solution. The surface pH of metastatic cancer cells was lower than that of non-metastatic cells indicating a higher glycolytic activity. CONCLUSIONS: Our method allows cell surface pH measurement and its correlation with cellular glycolytic activity.

The europium oxysulfate crystal structure was solved by X-ray powder diffraction. The compound crystallizes in monoclinic crystal system. The unit cell parameters are a = 13.6952(1) A, b = 4.1929(4) A, c = 8.1393(2) A, β = 107.455(4)°, space group C2/c. The three major structural elements are recognized to be Eu atoms, SO4 tetrahedra, and μ-O atoms, and their coordination environments were analyzed. The specific structural elements are infinite screw chains composed of trigonal prisms [EuO9]; sulfate tetrahedra [(SO4)Eu8] enclosed into cubes built of europium atoms; and infinite chains composed of tetrahedra [OEu4]. Rationale was given to the splitting of the IR absorption bands corresponding to the vibrations of sulfate groups.

Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner., Graphical Abstract Graphical AbstractCBX-12 is a pH-sensitive peptide-drug conjugate that selectively delivers the TOP1 inhibitor exatecan into tumor cells in an antigen agnostic manner. The peptide forms an alpha helix only in the low pH tumor microenvironment, allowing directional insertion of the peptide across the tumor membrane, cleavage of the linker within the cytosol, and release of free exatecan within the tumor cell. This pH-based delivery approach results in a high therapeutic index universally across solid tumors.

Nowadays, one of the tasks in the agricultural industry is the use of tractors in indoor facilities. Greenhouses and indoor farm premises impose increased toxicity requirements for tractor ICE. This paper considers a solution to this problem by using electric traction on small traction tractors. When developing such machines, an essential element is the justification of its parameters, which are usually laid based on the tasks of a tractor. An essential part of the issue is the choice of the layout of a power unit and the type of energy used by it. Based on the work tasks, we analyzed the application of electric drive with consideration of the traction features of the tractor. The paper provides a comparative assessment and general provisions on this issue.

The relevance of the research is due to the situation in training agricultural engineers with the appropriate professional competencies. According to statistics, the industry currently lacks highly qualified specialists in agricultural engineering. The study of the theoretical and practical aspects of the technical and economic evaluation of design decisions in agricultural engineering is the main direction of training competitive personnel and ensuring the innovative development of agricultural production in Russia.

Hypoxia and tissue acidification occur in the macrophage-rich regions of advanced atherosclerotic lesions due to the higher oxygen demand of activated immune cells and insufficient oxygen supply. Our group and others originally identified microRNA-33 (miR-33) as critical regulator of cellular lipid homeostasis and lipoprotein metabolism controlling the development of atherosclerosis. Our prior work has demonstrated that pH Low-Insertion Peptides (pHLIP) can be used to direct miR-33 inhibitors to acidic microenvironments and protect against kidney fibrosis. Here we utilize anti-miR-33 conjugated pHLIP constructs to target macrophages located in atherosclerosis plaques. The inhibition of miR-33 using pHLIP-directed targeting increased collagen content and decreased lesional lipid accumulation within atherosclerotic plaques in a murine model of atherosclerosis regression. Single cell RNA sequencing analysis revealed higher expression of fibrotic genes (Col2a1, Col3a1, Fn1, Dcn, etc) and tissue inhibitor of metalloproteinase 3 (Timp3), and downregulation of matrix metallopeptidase 12 (Mmp12) in macrophages from atherosclerotic lesions targeted by pHLIP- anti-miR-33. These results suggest a potential application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33.

To advance mechanistic understanding of membrane-associated peptide folding and insertion, we have studied the kinetics of three single tryptophan pHLIP (pH-Low Insertion Peptide) variants, where tryptophan residues are located near the N terminus, near the middle, and near the inserting C-terminal end of the pHLIP transmembrane helix. Single-tryptophan pHLIP variants allowed us to probe different parts of the peptide in the pathways of peptide insertion into the lipid bilayer (triggered by a pH drop) and peptide exit from the bilayer (triggered by a rise in pH). By using pH jumps of different magnitudes, we slowed down the processes and established the intermediates that helped us to understand the principles of insertion and exit. The obtained results should also aid the applications in medicine that are now entering the clinic.

We have studied two-electron one-photon transitions in dielectronic recombination with H-like ions ($Z=5--54$) within ab initio QED theory. It was found that interference between dielectonic recombination with two-electron one-photon transitions and radiative recombination is prominent for light and medium ions being large enough for experimental observation. The interference manifests itself firstly in a sharp Fano-like resonance structure and secondly in a noticeable distortion of the photon angular distribution of the radiative recombination.