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A major barrier to adeno-associated virus (AAV) gene therapy is the inability to re-dose patients due to formation of vector-induced neutralizing antibodies (Nabs). Tolerogenic nanoparticles encapsulating rapamycin (ImmTOR) provide long-term and specific suppression of adaptive immune responses, allowing for vector re-dosing. Moreover, co-administration of hepatotropic AAV vectors and ImmTOR leads to an increase of transgene expression even after the first dose. ImmTOR and AAV Anc80 encoding the methylmalonyl-coenzyme A (CoA) mutase (MMUT) combination was tested in a mouse model of methylmalonic acidemia, a disease caused by mutations in the MMUT gene. Repeated co-administration of Anc80 and ImmTOR was well tolerated and led to nearly complete inhibition of immunoglobulin (Ig)G antibodies to the Anc80 capsid. A more profound decrease of plasma levels of the key toxic metabolite, plasma methylmalonic acid (pMMA), and disease biomarker, fibroblast growth factor 21 (FGF21), was observed after treatment with the ImmTOR and Anc80-MMUT combination. In addition, there were higher numbers of viral genomes per cell (vg/cell) and increased transgene expression when ImmTOR was co-administered with Anc80-MMUT. These effects were dose-dependent, with the higher doses of ImmTOR providing higher vg/cell and mRNA levels, and an improved biomarker response. Combining of ImmTOR and AAV can not only block the IgG response against capsid, but it also appears to potentiate transduction and enhance therapeutic transgene expression in the mouse model.

To ensure traffic safety of railway transport, non-destructive tests of rails are regularly carried out by using various approaches and methods, including eddy-current flaw detection methods. An automatic analysis of large data sets (defectograms) that come from the corresponding equipment is an actual problem. The analysis means a process of determining the presence of defective sections along with identifying structural elements of railway tracks in defectograms. At the same time, severity estimation of defined defects is also of great interest. This article continues the cycle of works devoted to the problem of automatic recognition of images of defects and rail structural elements in eddy-current defectograms. In the process of forming these images, only useful signals are taken into account, the threshold levels of amplitudes of which are determined automatically from eddy-current data. The article is devoted to the issue of constructing severity estimation of found defects with various lengths. The construction of the severity estimation is based on a concept of the generalized relative amplitude of useful signals. A relative amplitude is a ratio of an actual signal amplitude to a corresponding threshold level of useful signals. The generalized relative amplitude is calculated by using the entropy of the half-normal distribution, which is assumed to be a model for a probability distribution of an appearance of certain relative amplitudes in an evaluated defect. Tuning up the formula for calculating severity estimation of a defect is carried out on the basis of eddy-current records of structural elements. As a reference of the most dangerous defect, the bolted rail joint is considered. It models a fracture of a rail. A reference weak defect is a flash butt weld, a defectogram of which contains signals with low amplitude values. The proposed approach to severity estimation of defects is shown by examples.

To ensure traffic safety of railway transport, non-destructive tests of rails are regularly carried out by using various approaches and methods, including eddy-current flaw detection methods. An automatic analysis of large data sets (defectograms) that come from the corresponding equipment is an actual problem. The analysis means a process of determining the presence of defective sections along with identifying structural elements of railway tracks in defectograms. This article continues the cycle of works devoted to the problem of automatic recognizing images of defects and structural elements of rails in eddy-current defectograms. In the process of forming these images, only useful signals are taken into account, the threshold levels of amplitudes of which are determined automatically from eddy-current data. The previously used algorithm for finding threshold levels was focused on situations in which the vast majority of signals coming from the flaw detector is a rail noise. A signal is considered useful and is subject to further analysis if its amplitude is twice the corresponding noise threshold. The article is devoted to the problem of correcting threshold levels, taking into account the need to identify extensive surface defects of rails. An algorithm is proposed for finding the values of threshold levels of rail noise amplitudes with their subsequent correction in the case of a large number of useful signals from extensive defects. Examples of the algorithm’s operation on real eddy-current data are given.

To ensure traffic safety of railway transport, non-destructive test of rails is regularly carried out by using various approaches and methods, including eddy-current flaw detection methods. An automatic analysis of large data sets (defectograms) that come from the corresponding equipment is an actual problem. The analysis means a process of determining the presence of defective sections along with identifying structural elements of railway tracks in defectograms. This article is devoted to the problem of recognizing images of long structural elements of rails in eddy-current defectograms. Two classes of rail track structural elements are considered: 1) rolling stock axle counters, 2) rail crossings. Long marks that cannot be assigned to these two classes are conditionally considered as defects and are placed in a separate third class. For image recognition of structural elements in defectograms a convolutional neural network is applied. The neural network is implemented by using the open library TensorFlow. To this purpose each selected (picked out) area of a defectogram is converted into a graphic image in a grayscale with size of 30 x 140 points.

Mixed conducting cobaltites PrBaCo2−xFexO6−δ (x = 0–0.6) with a double perovskite structure are promising materials for ceramic semi-permeable membranes for oxygen separation and purification due to their fast oxygen exchange and diffusion capability. Here, we report the results of the detailed study of an interplay between the defect chemistry, oxygen nonstoichiometry and oxygen transport in these materials as a function of iron doping. We show that doping leads to a systematic variation of both the thermodynamics of defect formation reactions and oxygen transport properties. Thus, iron doping can be used to optimize the performance of mixed conducting oxygen-permeable double perovskite membrane materials.

A sparsely cross-linked copolymer was synthesized, and was composed of acrylic acid, acrylamide, and starch. Swelling of the copolymer in an aqueous solution resulted in the formation of hydrogel particles; this formulation was used as a partially biodegradable soil conditioner. The hydrogel was characterized with the following main conclusions: (a) the degree of copolymer swelling increases from 300 to 550 when altering the pH of the solution from 3 to 9. (b) After mixing with sand and soil, the degree of swelling decreases because of restricted volumes of sand/soil-filled containers and a mechanical resistance from the sand/soil particles. (c) Initial sand and soil additions demonstrate unsatisfactory water-retaining properties; the addition of the hydrogel significantly increases the maximum water capacity, while a substantial part of the water in the hydrogel remains available to plants. (d) Upon deposition of the hydrogel formulation over sand/soil and drying out, a protective coating forms on the surface, composed of hydrogel and sand/soil particles, resistant to wind and water erosion. (e) The starch-containing hydrogel is non-toxic towards bacterial and fungal microorganisms; the latter can utilize the microgel in order to support their own development. The results of the work indicate that cross-linked anionic copolymers are promising for use as combined soil conditioners.

To ensure traffic safety of railway transport, non-destructive test of rails is regularly carried out by using various approaches and methods, including magnetic and eddy current flaw detection methods. An automatic analysis of large data sets (defectgrams) that come from the corresponding equipment is an actual problem. The analysis means a process of determining the presence of defective sections along with identifying structural elements of railway tracks on defectograms. This article is devoted to the problem of recognition of rail structural element images in magnetic and eddy current defectograms. Three classes of rail track structural elements are considered: 1) a bolted joint with straight or beveled connection of rails, 2) a butt weld of rails, and 3) an aluminothermic weld of rails. Images that cannot be assigned to these three classes are conditionally considered as defects and are placed in a separate fourth class. For image recognition of structural elements in defectograms a neural network is applied. The neural network is implemented by using the open library TensorFlow. To this purpose each selected (picked out) area of a defectogram is converted into a graphic image in a grayscale with size of 20 x 39 pixels.

ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to induce a durable tolerogenic immune response to co-administered biologics and gene therapy vectors. Prior mechanism of action studies have demonstrated selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration. In the spleen, ImmTOR has been shown to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomy of mice resulted in partial but incomplete abrogation of the tolerogenic immune response induced by ImmTOR. Here we investigated the ability of ImmTOR to enhance the tolerogenic environment in the liver. All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. LSEC isolated from ImmTOR treated mice inhibited antigen-specific activation of ovalbumin-specific OT-II T cells. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4+ and CD8+ T cells, and the emergence of a large population of CD4–CD8– (double negative) T cells. ImmTOR treatment protected mice in a concanavalin A-induced model of acute hepatitis, as evidenced by reduced production of inflammatory cytokines, infiltrate of activated leukocytes, and tissue necrosis. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR treatment.

Global warming has posed a number of challenges for agriculture. The key problem is water retention in soil. Existing irrigation methods are costly and ineffective. To solve this problem, a synthesis of a rare-cross-linked hydrophilic polymer material with the properties of a pectin-based superabsorbent was conducted. The paper considers the structure and moisture absorption of the polymer material “Solid water”. The hydration properties of the superabsorbent in its original state and after contact with pectins were determined using IR spectroscopy. Our research showed that the water-adsorbing ability is ensured by the presence of short-sized acrylamide residues, fragments with residues of carboxyl groups and polysaccharide units in the structure. The superabsorbent with pectin as a biodegradable component is able to retain a portion of water of hydration even during prolonged drying. The effect of the pH of the medium on the water absorption capacity and swelling of the superabsorbent “Solid water” was shown. This superabsorbent can be used in different types of soils, as confi rmed by the studies conducted in distilled water, as well as in alkaline and acidic media. The polymer is characterised by the highest swelling values in an alkaline medium due to the electrostatic repulsion of dissociated carboxyl groups, formed as a result of the hydrolysis of acrylamide. This makes it suitable for use in leached soils, such as leached black soil (Chernozem) in the Voronezh region. IR spectroscopy showed the presence of the superabsorbent’s functional groups that form supramolecular structures including bound water molecules with no additional coordinate covalent bonds present. Thus, the reactions can be characterised as processes with the elements of system self-organisation.

To ensure traffic safety of railway transport, non-destructive testing of rails is regularly carried out by using various approaches and methods, including magnetic and eddy current flaw detection methods. An automatic analysis of large data sets (defectgrams) that come from the corresponding equipment is still an actual problem. The analysis means a process of determining the presence of defective sections along with identifying structural elements of railway tracks on defectograms. At the same time, under the conditions of significant volumes of incoming information, fast and efficient algorithms of data analysis are of most interest. This article is an addition to the previous article devoted to the problem of automatic determination of a threshold level of amplitudes of useful signals (from defects and structural elements of a railway track) during the analysis of defectograms (records) of magnetic and eddy current flaw detectors, which contains an algorithm for finding the threshold level of a rail noise and its theoretical justification with examples of its operation on several fragments of real magnetic and eddy current defectograms. The article presents a simple and effective implementation of the algorithm, which is successfully used in practice for the automatic analysis of magnetic and eddy current defectograms.

Stimuli-responsive particles of crosslinked poly-N-vinylcaprolactam and poly-N,N-(dimethylamino)ethyl methacrylate (microgels) have been synthesized in oil-in-water emulsion without using of emulsifi er. Dispersions of spherical particles of about 200 nm in size rather narrowly distributed as defi ned by dynamic light scattering and TEM microscopy were stable in time in case of 50 and more mol. % of N,N-(dimethylamino)ethyl methacrylate. Zeta potential, measured by laser Doppler microelectrophoresis, revealed negative (-4.4 mV) and low positive (+6.6 mV) charges on particle surface. Positive charge in the case of 70 mol. % of N,N-(dimethylamino)ethyl methacrylate is provided by the protonated nitrogen atom of the monomer on the interphase surface. Low positive and negative instead of expected more positive value of zeta potential can be explained by specifi c sorption SO4 2- ions on the particle surface during the polymerization, which are formed by decomposition of initiator K2S2O8. Investigation of the effect of pH on the stability and particles size of the microgel with 50 mol. % of N,N-(dimethylamino)ethyl methacrylate showed that they remain stable in a wide range of pH values. An increase in the size of particles caused by polyelectrolyte swelling is observed in an acidic medium. Synthesized microgels exhibit thermosensitive properties. It is shown that, with an increase of N,N-(dimethylamino)ethyl methacrylate units, the volume phase transition temperature shifts to a lower temperatures, while the degree of particle compression is decreasing. It should also be noted that the change in particles size under the effect of temperature is reversible.

To ensure traffic safety of railway transport, non-destructive testing of rails is regularly carried out by using various approaches and methods, including magnetic and eddy current flaw detection methods. The paper is devoted to the problem of automatic determination of a threshold level of amplitudes of useful signals (from defects and structural elements of a railway track) during the analysis of defectograms (records) of magnetic and eddy current flaw detectors. A signal is considered useful (and is subject to further analysis) if a deviation of its value from an average of all signals is at least twice the threshold noise level of rails. The probability of obtaining a signal from a section without structural elements (a rail noise signal) is characterized by the normal distribution law. Thus, the rule of three sigma can be used to calculate the threshold noise level. And a signal is useful if its amplitude deviation from a sample mean exceeds twice the threshold noise level. The paper proposes an algorithm for finding the threshold level of a rail noise and gives its theoretical justification, and it also examines examples of its operation on several fragments of real magnetic and eddy current defectograms.

Prefrontal synthesis (PFS) is defined as the ability to juxtapose mental visuospatial objects at will. Paralysis of PFS may be responsible for the lack of comprehension of spatial prepositions, semantically-reversible sentences, and recursive sentences observed in 30 to 40% of individuals with autism spectrum disorder (ASD). In this report we present data from a three-year-long clinical trial of 6454 ASD children age 2 to 12 years, which were administered a PFS-targeting intervention. Tablet-based verbal and nonverbal exercises emphasizing mental-juxtaposition-of-objects were organized into an application called Mental Imagery Therapy for Autism (MITA). The test group included participants who completed more than one thousand exercises and made no more than one error per exercise. The control group was selected from the rest of participants by a matching procedure. Each test group participant was matched to the control group participant by age, gender, expressive language, receptive language, sociability, cognitive awareness, and health score at first evaluation using propensity score analysis. The test group showed a 2.2-fold improvement in receptive language score vs. control group (p < 0.0001) and a 1.4-fold improvement in expressive language (p = 0.0144). No statistically significant change was detected in other subscales not targeted by the exercises. These findings show that language acquisition improves after training PFS and that a further investigation of the PFS-targeting intervention in a randomized controlled study is warranted.

We previously reported that synthetic vaccine particles (SVP) encapsulating antigens and TLR agonists resulted in augmentation of immune responses with minimal production of systemic inflammatory cytokines. Here we evaluated two different polymer formulations of SVP-encapsulated antigens and tested their ability to induce cytolytic T lymphocytes (CTL) in combination with SVP-encapsulated adjuvants. One formulation led to efficient antigen processing and cross-presentation, rapid and sustained CTL activity, and expansion of CD8+ T cell effector memory cells locally and centrally, which persisted for at least 1-2 years after a single immunization. SVP therapeutic dosing resulted in suppression of tumor growth and a substantial delay in mortality in several syngeneic mouse cancer models. Treatment with checkpoint inhibitors and/or cytotoxic drugs, while suboptimal on their own, showed considerable synergy with SVP immunization. SVP encapsulation of endosomal TLR agonists provided superior CTL induction, therapeutic benefit and/or improved safety profile compared to free adjuvants. SVP vaccines encapsulating mutated HPV-16 E7 and E6/E7 recombinant proteins led to induction of broad CTL activity and strong inhibition of TC-1 tumor growth, even when administered therapeutically 13-14 days after tumor inoculation in animals bearing palpable tumors. A pilot study in non-human primates showed that SVP-encapsulated E7/E6 adjuvanted with SVP-encapsulated poly(I:C) led to robust induction of antigen-specific T and B cell responses.

The effectiveness of recombinant vaccines encoding full-length M2 protein of influenza virus or its ectodomain (M2e) have previously been tested in a number of models with varying degrees of success. Recently, we reported a strong cytotoxic effect exhibited by M2 on mammalian cells in vitro. Here we demonstrated a decrease in protection when M2 was added to a DNA vaccination regimen that included influenza NP. Furthermore, we have constructed several fusion proteins of conserved genes of influenza virus and tested their expression in vitro and protective potential in vivo. The four-partite NP-M1-M2-NS1 fusion antigen that has M2 sequence engineered in the middle part of the composite protein was shown to not be cytotoxic in vitro. A three-partite fusion protein (consisting of NP, M1 and NS1) was expressed much more efficiently than the four-partite protein. Both of these constructs provided statistically significant protection upon DNA vaccination, with construct NP-M1-M2-NS1 being the most effective. We conclude that incorporation of M2 into a vaccination regimen may be beneficial only when its apparent cytotoxicity-linked negative effects are neutralized. The possible significance of this data for influenza vaccination regimens and preparations is discussed.

Background: Lumbar disc surgery is among the more common spinal procedures. In this paper, we report the current treatment recommendations for patients with symptomatic disc herniation. Methods: This review is based on pertinent publications retrieved by a selective literature search in PubMed using the terms [timing] AND [lumbar disc herniation], supplemented by other relevant articles and guidelines. Results: Symptoms resolve in 60% to 80% of patients with herniated discs in 6--12 weeks, and in 80% to 90% over the long term (≥ 1 year). According to the guidelines, 6--12 weeks of conservative treatment are recommended in the absence of significant neurologic deficits. Early surgery is indicated in case of worsening pain or new onset of neurologic deficits. Lumbar disc herniation associated bladder or bowel dysfunction (cauda equina syndrome) is considered an absolute surgical emergency that requires immediate decompression (within 24 to 48 hours). Patients with severe motor deficits (MRC ≤ 3/5) benefit from early intervention and should be offered surgery within three days, if possible, for the best chance of recovery. The degree of weakness and the duration of symptoms have been identified as risk factors for incomplete recovery. Early surgery can be considered in patients with mild paresis (MRC 4/5) in case of functional impairment (e.g., quadriceps paresis). Conclusion: Longer symptom duration and lower motor scores are associated with worse outcome and a lower chance of neurologic recovery. The recovery rate for motor deficits ranges from 33% to 75%, depending on the timing and modality of treatment as well as the motor score. [ABSTRACT FROM AUTHOR]