Biomedical Nanosystems for In Vivo Detoxification: From Passive Delivery Systems to Functional Nanodevices and Nanorobots.

The problem of low efficiency of nanotherapeutic drugs challenges the creation of new alternative biomedical nanosystems known as robotic nanodevices. In addition to encapsulating properties, nanodevices can perform different biomedical functions, such as precision surgery, in vivo detection and imaging, biosensing, targeted delivery, and, more recently, detoxification of endogenous and xenobiotic compounds. Nanodevices for detoxification are aimed at removing toxic molecules from biological tissues, using a chemical- and/or enzyme-containing nanocarrier for the toxicant to diffuse inside the nanobody. This strategy is opposite to drug delivery systems that focus on encapsulating drugs and releasing them under the influence of external factors. The review describes various kinds of nanodevices intended for detoxification that differ by the type of poisoning treatment they provide, as well as the type of materials and toxicants. The final part of the review is devoted to enzyme nanosystems, an emerging area of research that provides fast and effective neutralization of toxins in vivo.

Pentagonal-bipyramidal 4d and 5d complexes with unquenched orbital angular momentum as a unique platform for advanced single-molecule magnets: current state and perspectives.

This article overviews the current state and prospects of the concept of advanced single-molecule magnets (SMMs) based on low-spin (S = 1/2) pentagonal-bipyramidal (PBP) 4d3 and 5d3 complexes with unquenched orbital angular momentum. This approach is based on the unique property of PBP 4d3 and 5d3 complexes to cause highly anisotropic spin coupling of perfect uniaxial symmetry, -JzSziSzj - Jxy(SxiSxj + SyiSyj), regardless of the local geometric symmetry. The M(4d/5d)-M(3d) exchange-coupled pairs in the apical positions of the PBP complexes produce Ising-type exchange interactions (|Jz| > |Jxy|), which serve as a powerful source of uniaxial magnetic anisotropy of a SMM cluster. In polynuclear heterometallic 4d/5d-3d complexes embodying PBP 4d/5d units and high-spin 3d ions, anisotropic Ising-type exchange interactions produce a double-well potential with high energy barriers Ueff, which is controlled by the anisotropic exchange parameters Jz, Jxy. Theoretical analysis shows that the barrier is proportional to the difference |Jz - Jxy| and to the number n of the apical 4d/5d-3d pairs in a SMM cluster, Ueff ∝ |Jz - Jxy|n, which provides an opportunity to scale up the barrier Ueff and blocking temperature TB up to the record values. A novel family of 4d/5d complexes with forced PBP coordination provided by structurally rigid planar pentadentate Schiff-base ligands in the equatorial plane is discussed as a better alternative to the cyanometallates. The possibility of a significant increase in the anisotropic exchange parameters Jz, Jxy in PBP complexes with monoatomic apical µ-bridging ligands is examined. The basic principles of molecular engineering the highest barrier through anisotropic exchange interactions of PBP 4d/5d complexes are formulated. The theoretical and experimental results taken together indicate that the concept of high-performance SMMs based on 4d/5d PBP complexes with unquenched orbital angular momentum is an attractive alternative to the currently dominant lanthanide-based SMM strategy.

(Et4N)[WIII(DAPBH)(CN)2], the first pentagonal-bipyramidal W(III) complex with unquenched orbital angular momentum: a novel Ising-type magnetic building block for single-molecule magnets.

The first pentagonal-bipyramidal tungsten(III) complex (Et4N)[WIII(DAPBH)(CN)2] with a N3O2-type Schiff-base ligand and two apical cyanide groups was synthesized and characterized structurally and magnetically. The complex has a low-spin (S = 1/2) ground state and features unquenched orbital angular momentum ML = ±1 causing very strong Ising-type magnetic anisotropy.

[Management of the patient with renal artery fibromuscular dysplasia: clinical case].

Fibromuscular dysplasia (FMD) is a rare disease that affects small and medium-sized arteries. Clinical manifestations of FMD depend on its localization. In many cases, FMD of renal arteries (RA) is associated with arterial hypertension. Young age, particularly of female patients, suspected RA dissection or kidney infarction, absence of atherosclerosis or presence of FMD in other arteries of such patients evidence for RA FMD. In invasive treatment of hemodynamically significant stenoses, transluminal balloon angioplasty (TBA) of renal arteries is preferrable. Taking into account initial alterations of the vascular wall and unevenness of the lumen of the affected blood vessel, stent implantation is associated with an increased risk of complications and is recommended only if ballooning complications develop. An open reconstructive surgery is indicated in complicated narrowing anatomy, a high risk of the endovascular treatment, or after failure of the endovascular intervention. This article presents a clinical case of a young female patient with RA FMD and renovascular arterial hypertension who successfully underwent renal TBA with a drug-coated balloon.

Evaluation of the Fractional Flow Reserve by Computer Tomography Data: Comparison of the Calculated Parameters with the Results of Invasive Measurements.

Aim      To create a three-dimensional mathematical model of coronary flow in patients with ischemic heart disease based on findings of computed tomography angiography (CTA) with subsequent calculation of the fractional flow reserve (FFRCTA) and comparison of estimated FFRCTA with FFR reference values measured by coronary angiography (CAG).Material and methods  The study included 10 patients with borderline stenosis (50-75 %) as determined by CTA performed with a 640­slice CT-scanner. Based on CTA findings, three-dimensional mathematical models were constructed for further calculation of FFRCTA. Later, an invasive measurement of FFR (FFRINV) was performed for all patients. FFR values <0.8 indicated the hemodynamic significance of stenosis.Results FFRCTA and FFRINV values differed insignificantly in most cases (n=9) and exceeded 5% in only one case. The regression analysis showed a close correlation between estimated and invasively measured FFR values.Conclusion      Preliminary results showed a good consistency of calculated and measured FFR values. Therefore, further development of the method for mathematical modeling of three-dimensional blood flow by CTA findings is promising. Noninvasive evaluation of FFR is particularly relevant for analysis of hemodynamic significance of borderline (50-75 %) coronary stenoses.

Computed Tomography Myocardial Perfusion Imaging With Transesophageal Atrial Pacing Stress Test in Patients With Borderline Stenoses in the Coronary Arteries: a Comparison With Fractional Flow Reserve.

Aim      To evaluate the diagnostic accuracy of cardiac perfusion computed tomography (PCT) with transesophageal electrocardiostimulation (TE ECS) for detection of ischemia in patients with borderline coronary stenosis (50-75 %) compared to measurements of fractional flow reserve (FFR).Material and methods  The study included 25 patients with borderline (50-75 %) coronary stenosis as per data of computed tomography angiography (CTA) or coronary angiography (CAG). Later the patients underwent invasive measurement of FFR and cardiac PCT on a 320-row detector tomograph in combination with the TE ECS stress test.  FFR values <0.8 indicated the hemodynamic significance of stenosis. Myocardial perfusion was evaluated visually based on consensus of two experts.Results All patients completed the study protocol. Cardiac pacing duration was 6 min for all patients. Four patients required intravenous administration of atropine sulphate. PCT with TE ECS detected significant for FFR stenoses with sensitivity, specificity, and predictive value of a positive result and predictive value for a negative result of 47, 90, 87, and 53 %, respectively.Conclusion      PCT with TE ECS in combination with CTA can be considered as an informative method for simultaneous evaluation of the condition of coronary arteries and detection of myocardial ischemia. This method is particularly relevant for assessing the hemodynamic significance of borderline coronary stenoses.

[Computed Tomography Coronary Angiography Possibilities in "High Risk" Plaque Identification in Patients with non-ST-Elevation Acute Coronary Syndrome: Comparison with Intravascular Ultrasound].

Aim      To evaluate structural characteristics of atherosclerotic plaques (ASP) by coronary computed tomography arteriography (CCTA) and intravascular ultrasound (IVUS).Material and methods  This study included 37 patients with acute coronary syndrome (ACS). 64-detector-row CCTA, coronarography, and grayscale IVUS were performed prior to coronary stenting. The ASP length and burden, remodeling index (RI), and known CT signs of unstable ASP (presence of dot calcification, positive remodeling of the artery in the ASP area, irregular plaque contour, presence of a peripheral high-density ring and a low-density patch in the ASP). The ASP type and signs of rupture or thrombosis were determined by IVUS.Results The IVUS study revealed 45 unstable ASP (UASP), including 25 UASP with rupture and 20 thin-cap fibroatheromas (TCFA), and 13 stable ASP (SASP). No significant differences were found between distribution of TCFA and ASP with rupture among symptom-associated plaques (SAP, n=28) and non-symptom-associated plaques (NSAP, n=30). They were found in 82.1 and 73.3 % of cases, respectively (p>0.05), which indicated generalization of the ASP destabilization process in the coronary circulation. However, the incidence of mural thrombus was higher for SAP (53.5 and 16.6 % of ASP, respectively; p<0.001). There was no difference between UASP and SASP in the incidence of qualitative ASP characteristics or in values of quantitative ASP characteristics, including known signs of instability, except for the irregular contour, which was observed in 92.9 % of UASP and 46.1 % of SASP (p=0.0007), and patches with X-ray density ≤46 HU, which were detected in 83.3 % of UASP and 46.1 % of SASP (р=0.01). The presence of these CT criteria 11- and 7-fold increased the likelihood of unstable ASP (odd ratio (OR), 11.1 at 95 % confidence interval (CI), from 2.24 to 55.33 and OR, 7.0 at 95 % CI, from 5.63 to 8.37 for the former and the latter criterion, respectively).Conclusion      According to IVUS data, two X-ray signs are most characteristic for UASP, the irregular contour and a patch with X-ray density ≤46 HU. The presence of these signs 11- and 7-fold, respectively, increases the likelihood of unstable ASP.

Prediction-Determining Outcomes and Their Predictors in Atrial Fibrillation Patients Receiving Multicomponent Antithrombotic Therapy in Real Clinical Practice.

Aim      Searching for clinical, angiographic, and biochemical predictors of cardiovascular complications (CVC) and hemorrhagic complications in patients with atrial fibrillation (AF) receiving a multicomponent antithrombotic therapy (MAT) for an elective percutaneous coronary intervention (PCI). Patients with ischemic heart disease (IHD) and AF who require MAT for PCI are at a high risk of thrombotic complications (stroke, systemic embolism, coronary events) and hemorrhage. This warrants searching for new risk factors determining prediction of the outcome.Materials and methods This study included 207 patients (146 males aged 70.1±8.3 years) with IHD and AF who received direct oral anticoagulants (DOAC) as a part of their MAT therapy. Median duration of the follow-up was 12 [8.0; 12.0] months. The efficacy endpoint was a sum of CVCs combining cardiovascular death, ischemic stroke, venous thromboembolic complications, acute coronary syndrome (ACS), and requirement for an unscheduled PCI. "Coronary events", including ACS and requirement for an unscheduled PCI were analyzed separately. The safety endpoint was BARC type 2-5 bleeding. Upon admission, biomarkers (growth-differentiation factor 15 (GDF-15), D-dimer, thrombin-activated fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor-1 (PAI-1)) were measured for all patients. Searching for prognostically significant indexes was performed with the Cox proportional hazards regression.Results Incidence of all CVCs was 16.4 %. Independent predictors of CVC included the DOAC treatment at a reduced dose (odds ratio (OR) 2.5 at 95 % confidence interval (CI) 1.02-6.15; p=0.0454), GDF-15 >1191 pg /ml (OR 3.76 at 95 % CI, 1.26-11.18; p=0.0172), PAI-1 >13.2 U/ml (OR 2.67 at 95 % CI, 1.13-6,26; p=0.0245). Incidence of coronary complications was 9.2 %. Independent predictors of coronary complications included a SYNTAX index >26.5 (OR 4.5 at 95 % CI, 1.45-13.60; p=0.0090), PCI for chronic coronary occlusion (OR 3.21 at 95 % CI, 1.10-9.33; p=0.0326), a GDF-15 >1191 pg/ml (ОR 4.70 at 95 % CI, 1.32-16.81; p=0.0172). Incidence of BARC type 2-5 bleeding was 26.1 %. The only independent predictor for hemorrhage complications was the total PRECISE-DAPT score >30 (ОR 3.22; 95 % CI, 1.89-5.51; р<0.0001).Conclusion      Three independent predictors of CVC were identified for patients with IHD and AF treated with MAT following an elective PCI: treatment with a reduced dose of DOAC, GDF-15 >1191 pg /ml, and PAI-1>13.2 U/ml. Independent predictors of coronary complications included a SYNTAX index >26.5, PCI for chronic coronary occlusion, and GDF-15 >1191 pg/ml. The factor associated with a risk of bleeding was the total PRECISE-DAPT score >30.

Primary 3D Culture of Human Thyroid Follicle-Like Structures in Platelet Lysate-Based Gel.

The results of 3D culturing of human thyroid follicle-like structures in a gel based on platelet lysate at the gel-air interface are presented. During culturing up to 4 months, no new follicle-like structures were formed and none were destroyed. During the first 2 months, most follicle-like structures increased in size; then, their grown decelerated, but they retained viability. Ki-67+ cells were observed in the majority of follicle-like structures. Most of them produced thyroglobulin. Follicle-like structures get closer, the number of contacts between them increased, and cluster appeared. Thus, the developed 3D culturing system in a gel based on platelet lysate is an adequate approach for maintaining structure and functional activity of human follicle-like structures in vitro for at least 2 months.

Stevioside Has the Maximum Biological Activity among Natural Stevia Diterpenes.

The concentrations of steviol and its derivatives stimulating the growth of wheat plants were measured: 10-8 for stevioside and 10-9 М for steviol and isosteviol. It was found that stevioside increased the activity of amylolytic enzymes and protein content, as well as frost tolerance of the roots of wheat seedlings. Thus, stevioside can be recommended for the development of complex phytopreparations for stimulating the growth processes and increasing the resistance of wheat plants to low temperatures.

[The study of myocardial perfusion by cardiac volumetric computed tomography, combined with adenosine triphosphate test, in a patient with painless myocardial ischemia and atherosclerosis of the coronary arteries].

The presented clinical observation demonstrates the diagnostic capabilities of cardiac volumetric computed tomography (CT) with a pharmacological test by a vasodilator adenosine triphosphate (ATP) in the simultaneous assessment of coronary anatomy and changes in left ventricular myocardial perfusion (LV) in a patient with painless myocardial ischemia and coronary atherosclerosis. A 68-year-old patient with coronary heart disease (CHD) and atherosclerotic changes in the coronary arteries underwent cardiac volumetric CT in combination with a ATP pharmacological test. The study was performed on a Aquilion ONE 640 Vision Edition computer tomograph (Toshiba, Japan). Assessment of LV myocardial perfusion was carried out in comparison with other clinical, laboratory and instrumental examination methods. The results of clinical and instrumental examination of a patient with a low pre-test probability of coronary heart disease are presented. From the standpoint of modern recommendations on stable coronary heart disease, false-negative results of single-photon emission computed tomography of the heart and stress-echocardiography are discussed. Clinical observation demonstrates the feasibility of diagnosing LV myocardial ischemia by cardiac volumetric CT combined with ATP pharmacological test, confirmed by an invasive determination of the fractional flow reserve. The given clinical example represents the advantage of cardiac volumetric CT, combined with the ATP pharmacological test, as a method for visualizing LV myocardial perfusion in detecting myocardial ischemia.

The role of ion sources in synthesis of the super-heavy elements.

Since the early 1970s, attempts to synthesize Super Heavy Elements (SHE) have been made in many laboratories around the world. One of the main requirements of these experiments is a sufficiently large dose of target irradiation, which should be increased with a decrease in the reaction cross section. In this regard, the capacities of ion sources play an important role for the successful synthesis of SHE. At the FLNR JINR, the discovery and investigation of the new region of super heavy nuclei were based on fusion reactions of 48Ca with 238U-249Cf target nuclei. In these experiments, a technique for the production of metallic 48Ca was developed. The operation mode of the ECR ion source was set to optimize the intensity of 48Ca ions and attain maximum ionization efficiency. Because of the heaviest target for experiments on synthesis of SHE in heavy ion reactions is 249Cf, so further progress in the synthesis of elements with Z > 118 requires the production of intense beams of accelerated neutron enriched isotopes, such as 50Ti, 58Fe, and 64Ni.

Measurements of the energy distribution of electrons lost from the minimum B-field-The effect of instabilities and two-frequency heating.

Further progress in the development of electron cyclotron resonance (ECR) ion sources (ECRISs) requires deeper understanding of the underlying physics. One of the topics that remains obscure, though being crucial for the performance of the ECRIS, is the electron energy distribution (EED). A well-developed technique of measuring the EED of electrons escaping axially from the magnetically confined plasma of an ECRIS was used for the study of the EED in an unstable mode of plasma confinement, i.e., in the presence of kinetic instabilities. The experimental data were recorded for pulsed and CW discharges with a room-temperature 14 GHz ECRIS at the JYFL accelerator laboratory. The measurements were focused on observing differences between the EED escaping from stable and unstable plasmas. It was found that nonlinear phenomena alter the EED noticeably. The electron losses are enhanced in both unstable regimes, with two-frequency heating suppressing the instabilities. It has been shown earlier that two-frequency heating boosts the ECRIS performance presumably owing to the suppression of instabilities. We report the observed changes in EED introduced by the secondary frequency in different regimes, including an off-resonance condition, where the secondary frequency is lower than the minimum frequency satisfying the resonance condition for cold electrons at the magnetic field minimum. Finally, we suggest an experimental method of qualitative evaluation of the energy distribution of electrons confined in the magnetic trap using a method of measuring energy distribution of lost electrons during the plasma decay in pulsed operation of the ion source.

A definition of bioinks and their distinction from biomaterial inks.

Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384-402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.

(Et4N)[MoIII(DAPBH)Cl2], the first pentagonal-bipyramidal Mo(iii) complex with a N3O2-type Schiff-base ligand: manifestation of unquenched orbital momentum and Ising-type magnetic anisotropy.

The first paramagnetic pentagonal-bipyramidal complex of Mo(iii) with a N3O2-type Schiff-base ligand was synthesized by the comproportionation reaction between Mo(ii) and Mo(iv) congeners. The complex has a low-spin (S = 1/2) ground state of MoIII(4d3) with double orbital degeneracy and unquenched orbital momentum, which result in strong Ising-type magnetic anisotropy.

The study of acute and chronic toxicity of the sodium-, calcium-, iron-polygalacturonate pharmacological substance in rabbits.

The purpose of this study is the assessment of the acute and chronic toxicity of pharmacological substance sodium, calcium, iron-polygalacturonate (PG Na,Ca,Fe) in rabbits as one of the stages of preclinical studies. We studied an acute and chronic oral toxicity of PG Na,Ca,Fe, which stimulates the process of hemopoiesis, in male and female rabbits of the "Chinchilla". According to the results of the study of acute toxicity of PG Na,Ca,Fe, treating with it the rabbits of both sexes in doses of 0.5-5 g/kg has no toxic effect (LD50 greater than 5 g/kg). The histostructure of studied organs of animals, treated with preparations in a dose of 5 g/kg, did not differ from that of the animals of the control group. This study allow to classify PG Na,Ca,Fe as a preparation of the 6th class with respect to harmless drugs. An estimate of the chronic toxicity of PG Na,Ca,Fe at administration of preparation in the form of boluses to rabbits in doses 0.025, 0.262 and 0.5 g/kg of the body weight demonstrated that the general condition and behavior of animals did not differ from the norm. The data of hematological and biochemical studies of blood serum and urine, electrocardiographic studies, the study of the mass coefficients of the internal organs of the experimental rabbits, treated with PG Na,Ca,Fe in the mentioned doses for 60 days, compared to those obtained in the 30-day post-observation period, did not show significant changes with respect to the control and intact group of rabbits.

Molecular Heterogeneity of Lectins in Wheat Seedlings under the Action of Stevioside and Heavy Metals.

The effect of the diterpene glycoside stevioside and high concentrations of heavy metals on the molecular heterogeneity of lectins was studied in seedlings of Kazanskaya 560 winter wheat cultivar. Stevioside induced the emergence of a new 45-kDa lectin. Cultivation of wheat seedlings in CdSO4 and ZnSO4 solutions resulted in the emergence of the protein with Mr = 88 kDa. We detected the presence of both lectins in seedlings during combined treatment with stevioside and heavy metals.

A new Mo(iv) complex with the pentadentate (N3O2) Schiff-base ligand: the first non-cyanide pentagonal-bipyramidal paramagnetic 4d complex.

A heptacoordinate complex [MoIV(DAPBH)Cl2] (H2DAPBH is 1,1'-(pyridine-2,6-diyl)bis(ethan-1-yl-1-ylidene)dibenzohydrazine) has been synthesized and characterized structurally and magnetically. It exhibits a slightly distorted pentagonal bipyramidal geometry and reveals paramagnetic behaviour resulting from two unpaired electrons (S = 1) with large positive zero-field splitting (D = +50 cm-1) and pronounced temperature-independent paramagnetism.

Magnetic Force Microscopy of Nanostructured Co/Pt Multilayer Films with Perpendicular Magnetization.

We present the results of magnetic force microscopy investigations of domain structures in multilayer [Co (0.5 nm)/Pt (1 nm)]5 thin film structures (denoted hereafter as Co/Pt) modified by additional Co capping layers and by ion irradiation. It is demonstrated that a Co capping layer essentially changes the domain structure and decreases the threshold of magnetization reversal, due to the formation of noncollinear magnetization in Co/Pt. It is shown that local irradiation with a focused He⁺ ion beam enables the formation of regions with decreased easy-axis anisotropy (magnetic bubbles) that have the inverse magnetization direction in the demagnetized state of Co/Pt. The experimental results demonstrate that the magnetic bubbles can be switched using a probe of a magnetic force microscope. The possible application of these effects for the development of magnetic logic and data storage systems is discussed.