Репозиторий Университета

In the search for anti-SARS-CoV-2 drugs, much attention is given to safe and widely available native compounds. The green tea component epigallocatechin 3 gallate (EGCG) is particularly promising because it reportedly inhibits viral replication and viral entry in vitro. However, conclusive evidence for its predominant activity is needed. We tested EGCG effects on the native virus isolated from COVID-19 patients in two independent series of experiments using VERO cells and two different treatment schemes in each series. The results confirmed modest cytotoxicity of EGCG and its substantial antiviral activity. The preincubation scheme aimed at infection prevention has proven particularly beneficial. We complemented that finding with a detailed investigation of EGCG interactions with viral S-protein subunits, including S2, RBD, and the RBD mutant harboring the N501Y mutation. Molecular modeling experiments revealed N501Y-specific stacking interactions in the RBD-ACE2 complex and provided insight into EGCG interference with the complex formation. Together, these findings provide a molecular basis for the observed EGCG effects and reinforce its prospects in COVID-19 prevention therapy.

Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

A correlation between the crystal structure and magnetic properties of system (1-x)BiFeO3 – (x)BaTiO3 with compounds across the morphotropic phase boundary was studied using X-ray and neutron diffraction, magnetometry, and Mössbauer spectroscopy measurements. Increase in the dopants content leads to the structural transition from the rhombohedral phase to the cubic phase via a formation of the two-phase region (0.2 < x < 0.33), wherein the magnetic structure changes from the modulated G-type antiferromagnetic to the collinear antiferromagnetic via a stabilization of the non-collinear antiferromagnetic phase with non-zero remanent magnetization. The value of magnetic moment calculated per iron ion based on the Mössbauer and neutron diffraction data decreases from m ≈ 4.4 μB for the compound with x = 0.25 to m = 3.2 μB for the compound with x = 0.35 testifying a dominance of 3 + oxidation state of the iron ions. Increase in the amount of the cubic phase leads to a reduction in the remanent magnetization from 0.02 emu/g for the compounds with the dominant rhombohedral phase (x < 0.27) down to about 0.001 emu/g for the compounds with dominant cubic structure (x ≥ 0.27). Rapid decrease in the remanent magnetization observed in the compounds across the phase coexistence region points at no direct correlation between the type of structural distortion and non-zero remanent magnetization, while the oxygen octahedra tilting is the key factor determining the presence of non-zero remanent magnetization.

© 1995-2012 IEEE. In this review, we discuss the crucial role of cranial and the extracranial lymphatics in keeping the central nervous system (CNS) health. We talk about the important lymphatic mechanism of removal of metabolites and toxins from the brain, which orchestrates the regenerative processes in CNS. We debate a novel knowledge about the lymphatic mechanism responsible for maintaining the balance between the exit and the entrance of molecules and cells from and into CNS. Finally, we highlight the pioneering technologies of biophotonic stimulation of lymphatic drainage function that can open a new era for the development of novel bedside, readily applicable and commercially viable technologies for the treatment of brain diseases.

© 1995-2012 IEEE. In this review, we discuss the crucial role of cranial and the extracranial lymphatics in keeping the central nervous system (CNS) health. We talk about the important lymphatic mechanism of removal of metabolites and toxins from the brain, which orchestrates the regenerative processes in CNS. We debate a novel knowledge about the lymphatic mechanism responsible for maintaining the balance between the exit and the entrance of molecules and cells from and into CNS. Finally, we highlight the pioneering technologies of biophotonic stimulation of lymphatic drainage function that can open a new era for the development of novel bedside, readily applicable and commercially viable technologies for the treatment of brain diseases.

© 1995-2012 IEEE. In this review, we discuss the crucial role of cranial and the extracranial lymphatics in keeping the central nervous system (CNS) health. We talk about the important lymphatic mechanism of removal of metabolites and toxins from the brain, which orchestrates the regenerative processes in CNS. We debate a novel knowledge about the lymphatic mechanism responsible for maintaining the balance between the exit and the entrance of molecules and cells from and into CNS. Finally, we highlight the pioneering technologies of biophotonic stimulation of lymphatic drainage function that can open a new era for the development of novel bedside, readily applicable and commercially viable technologies for the treatment of brain diseases.

© 2021 Elsevier Ltd Objectives: Metabolic syndrome (MetS) and its components (high blood pressure, BMI≥30, altered fasting glucose, low HDL cholesterol and high triglycerides) may undermine early perioperative outcomes after radical prostatectomy (RP). We tested this hypothesis. Materials & methods: Within the National Inpatient Sample database (2008–2015) we identified RP patients. The effect of MetS was tested in four separate univariable analyses, as well as in multivariable regression models predicting: 1) overall complications, 2) length of stay, 3) total hospital charges and 4) non-home based discharge. All models were weighted and adjusted for clustering, as well as all available patient and hospital characteristics. Results: Of 91,618 patients: 1) 50.2% had high blood pressure, 2) 8.0% had BMI≥30, 3) 13.0% had altered fasting glucose, 4) 22.8% had high triglycerides and 5) 0.03% had low HDL cholesterol. Respectively, one vs. two vs. three vs. four MetS components were recorded in 36.2% vs. 19.0% vs. 5.5% vs. 0.8% patients. Of all patients, 6.3% exhibited ≥3 components and qualified for MetS diagnosis. The rates of MetS increased over time (EAPC:+9.8%; p < 0.001). All four tested MetS components (high blood pressure, BMI≥30, altered fasting glucose and high triglycerides) achieved independent predictor status in all four examined endpoints. Moreover, a highly statistically significant dose-response was also confirmed for all four tested endpoints. Conclusion: MetS and its components consistently and strongly predict early adverse outcomes after RP. Moreover, the strength of the effect was directly proportional to the number of MetS components exhibited by each individual patient, even if formal MetS diagnosis of ≥3 components has not been met.

© 2021 Elsevier Inc. Introduction: Diazepam is a well-known psychoactive drug widely used worldwide for the treatment of anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, sleeplessness, agitation, and pre/post-operative sedation. It is part of the benzodiazepine family, substances known to primarily act by binding and enhancing gamma-aminobutyric acid (GABAA) receptors. The objective of the present work was to investigate the influence of short and medium-term diazepam exposures on neurotransmitters measured through targeted metabolomics using a zebrafish embryo model. Methods: Short-term (2.5 h) and medium-term (96 h) exposures to diazepam were performed at drug concentrations of 0.8, 1.6, 16, and 160 μg/L. Intervention groups were compared with a vehicle control group. Each group consisted of 20 zebrafish eggs/larvae. Metabolites related with neurotransmission were determined by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Results: Thirty-six compounds were quantified. Significantly increased tryptophan and serotonin concentrations were found in the intervention groups receiving higher doses of diazepam in 2.5 h exposure (p < 0.05 control versus intervention groups). Tyrosine concentrations were higher (p < 0.05) at higher concentrations in 2.5 h exposure, but lower (p < 0.05) at higher concentrations in 96 h exposure. Both phenylalanine and aspartic acid concentrations were higher (p < 0.05) at higher doses in 2.5 h and 96 h exposure. Conclusions: Short- and medium-term exposures to diazepam induce dose- and time-dependent metabolomic alterations associated with the serotonergic, dopaminergic/adrenergic, and aspartic acid neurotransmitter systems in zebrafish.

© 2021 Elsevier Inc. Introduction: Diazepam is a well-known psychoactive drug widely used worldwide for the treatment of anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, sleeplessness, agitation, and pre/post-operative sedation. It is part of the benzodiazepine family, substances known to primarily act by binding and enhancing gamma-aminobutyric acid (GABAA) receptors. The objective of the present work was to investigate the influence of short and medium-term diazepam exposures on neurotransmitters measured through targeted metabolomics using a zebrafish embryo model. Methods: Short-term (2.5 h) and medium-term (96 h) exposures to diazepam were performed at drug concentrations of 0.8, 1.6, 16, and 160 μg/L. Intervention groups were compared with a vehicle control group. Each group consisted of 20 zebrafish eggs/larvae. Metabolites related with neurotransmission were determined by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Results: Thirty-six compounds were quantified. Significantly increased tryptophan and serotonin concentrations were found in the intervention groups receiving higher doses of diazepam in 2.5 h exposure (p < 0.05 control versus intervention groups). Tyrosine concentrations were higher (p < 0.05) at higher concentrations in 2.5 h exposure, but lower (p < 0.05) at higher concentrations in 96 h exposure. Both phenylalanine and aspartic acid concentrations were higher (p < 0.05) at higher doses in 2.5 h and 96 h exposure. Conclusions: Short- and medium-term exposures to diazepam induce dose- and time-dependent metabolomic alterations associated with the serotonergic, dopaminergic/adrenergic, and aspartic acid neurotransmitter systems in zebrafish.

© 2021 Elsevier GmbH The expanding phylogenetic tree of trypanosomatid flagellates (Kinetoplastea: Trypanosomatidae) contains a long-known and phylogenetically well-supported species-rich lineage that was provisionally named as the ‘jaculum’ clade. Its members were found in representatives of several unrelated families of heteropteran bugs captured in South and Central America, Europe, Africa, and Asia. However, this group resisted introduction into the culture, a needed prerequisite for its proper characterization. Here we describe four new cultivable species, which parasitize various parts of their hosts’ intestine, including the thoracic and abdominal part of the midgut, hindgut, and Malpighian tubules. Morphologically, the cultured flagellates vary from relatively short stumpy promastigotes to long slender leptomonad cells. Some species form straphangers (cyst-like amastigotes) both in vivo and in vitro, initially attached to the basal part of the flagellum of the mother cell, from which they subsequently detach. To formally classify this enigmatic monophyletic cosmopolitan clade, we erected Obscuromonas gen. nov., including five species: O. modryi sp. nov. (isolated from the true bug host species Riptortus linearis captured in the Philippines), O. volfi sp. nov. (from Catorhintha selector, Curaçao), O. eliasi sp. nov. (from Graptostethus servus, Papua New Guinea), O. oborniki sp. nov. (from Aspilocoryphus unimaculatus, Madagascar), and O. jaculum comb. nov. (from Nepa cinerea, France). Obscuromonas along with the genus Blastocrithidia belongs to the newly established Blastocrithidiinae subfam. nov.

© 2020 Elsevier B.V. Ecosystems are facing increased pressure due to the emission of many classes of emerging contaminants. However, very little is known about the interactions of these pollutants, such as bisphenols (BPs), plasticizers or pharmaceuticals. By employing bioluminescent bacteria (Microtox assay), we were able to define interactions between selected emerging pollutants (namely BPA, BPS, BPF, BADGE, BADGE·2HCl, DEP, DBP) in ternary mixtures, at environmentally relevant concentration levels (down to as low as 1.89, 1.42, 3.08, and 0.326 μM for, respectively, BPA, BPF, BPS and BADGE·2HCl). We provide the first systematic analysis of bisphenols and phthalates in three component mixtures. Using this system, we performed toxicity modelling with concentration addition (CA) and independent action (IA) approaches, followed by data interpretation using Model Deviation Ratio (MDR) evaluation. Interestingly, we mathematically and experimentally confirmed a novel synergy between BPA, BADGE and BADGE·2HCl. The synergy of BPA, BADGE and BADGE·2HCl is distinct, with both models suggesting these analytes have a similar mode of action (MOA). Moreover, we unexpectedly found a strong antagonistic impact with DEP, in mixtures containing BPA and BADGE analogues, which is confirmed with both mathematical models. Our study also shows that the impact of BPS and BPF in many mixtures is highly concentration dependent, justifying the necessity to perform mixture studies using wide concentration ranges. Overall, this study demonstrates that bioluminescent bacteria are a relevant model for detecting the synergistic and antagonist actions of environmental pollutants in mixtures, and highlights the importance of analyzing combinations of pollutants in higher order mixtures.

© 2020 Elsevier Ltd Background: Grammar includes not only the ability to use verbs but also the ability to express and understand the relationships existing among the words in a sentence. Since the initial description of agrammatism (Kussmaul, 1877) it was proposed that there are two different types of agrammatism: Aktaphasie and Agrammatismus. The first one has been extensively studied, while the second one has been mostly overlooked. Aims: To analyze the brain areas involved in understanding the relationships existing among the words in a sentence. Its disturbances would correspond to the second type of agrammatism. Outcomes & results: Prepositions, adverbs, and grammatical cases are used to indicate the relationships among sentence words. This is a quasi-spatial ability supported by the left posterior parietal lobe. Almost one century ago a type of aphasia referred to as “semantic aphasia”, associated with left posterior parietal damage and characterized by the inability to use and understand the relationships among the language words, was described. Excepting a few papers, this type of aphasia has been usually ignored in the contemporary neuroscience literature. From the historical perspective, it has been proposed that grammar evolved in two steps: (1) proto-grammar, consisting of flat verb-noun compounds, and (2) hierarchical syntax or complex grammar. The first one is associated with the ability to use and understand verbs. The second one can be related to the ability to use verbally mediate spatial concepts. Some recently published cases of semantic aphasia corroborate its clinical manifestations and the locus of pathology. Functional studies support the participation of the left posterior parietal lobe in grammar. Conclusions: It is concluded that evidence suggests that semantic aphasia is a real type of aphasia and indeed there are two grammatical subsystems in the brain and two agrammatic types of aphasia.

© 2021 Mathematical models for complex systems under random fluctuations often certain uncertain parameters. However, quantifying model uncertainty for a stochastic differential equation with an α-stable Lévy process is still lacking. Here, we propose an approach to infer all the uncertain non-Gaussian parameters and other system parameters by minimizing the Hellinger distance over the parameter space. The Hellinger distance measures the similarity between an empirical probability density of non-Gaussian observations and a solution (as a probability density) of the associated nonlocal Fokker-Planck equation. Numerical experiments verify that our method is feasible for estimating single and multiple parameters. Meanwhile, we find an optimal estimation interval of the estimated parameters. This method is beneficial for extracting governing dynamical system models under non-Gaussian fluctuations, as in the study of abrupt climate changes in the Dansgaard-Oeschger events.

© 2020 Elsevier Ltd Color is an important environmental factor that in multiple ways affects human and animal behavior and physiology. Widely used in neuroscience research, various experimental (animal) models may help improve our understanding of how different colors impact brain and behavioral processes. Complementing laboratory rodents, the zebrafish (Danio rerio) is rapidly emerging as an important novel model species to explore complex neurobehavioral processes. The growing utility of zebrafish in biomedicine makes it timely to consider the role of colors in their behavioral and physiological responses. Here, we summarize mounting evidence implicating colors as a critical variable in zebrafish models and neurobehavioral traits, with a particular relevance to CNS disease modeling, genetic and pharmacological modulation, as well as environmental enrichment and animal welfare. We also discuss the growing value of zebrafish models to study color neurobiology and color-related neurobehavioral phenomics, and outline future directions of research in this field.

© 2021 Elsevier Ltd This review examines investigations into the functionalization of polysaccharides by substituents containing multiple (C[dbnd]C) bonds and thiol (SH) groups that are prone to (co)polymerization in the presence of thermal, redox and photoinitiators or Michael addition reactions. A comparative analysis of the approaches to grafting the mentioned substituents onto the polysaccharide macromolecules was conducted. The use of the modified polysaccharides for the design of the 3D structures, including for the development of the pore bearing matrixes of cells or scaffolds utilized in regenerative medicine was examined. These modified polymers were also examined toward the design of excipient matrixes in pharmacological compositions, including with controllable release of active pharmaceuticals, as wel as of antibacterial and antifungal agents and others. In addition, a few examples of the use of modified derivatives in other areas are given.

© 2021 Elsevier GmbH Background: Ultrasound is a routine procedure performed during pregnancy to monitor the status of the human fetus, including the development of the digestive tract. The aim of this publication was to determine the shape of the fetal sigmoid colon mesentery during the first and second trimester of pregnancy by means of ultrasound. Methods: The study was performed in 45 pregnant women (age: 36.4 years on average, range 25–45) during a routine ultrasound examination. The fetuses were between 12 and 22 weeks of pregnancy. The shape of the fetal sigmoid colon mesentery was analyzed. Results: We visualized the triangular shape of the mesentery in all 45 cases. A prevalence of scalene or isosceles acute triangles was found in both trimesters. At the 12−13 weeks we observed 5 different forms of mesenteric triangles – the scalene or isosceles acute triangles appeared at 33.3% and 28.6%, respectively. The obtuse scalene was present in 23.8 %. In the 2nd trimester (20−22 weeks) 4 types were found, among them 37.5 % acute scalene and 33.3 % acute isosceles. Conclusions: The fetal sigmoid colon mesentery can be visualized from the 12th week of pregnancy. The triangular shape of the sigmoid colon mesentery is easy to follow during routine ultrasound examinations.

© 2021 Introduction: Synthetic cannabinoids are abused substances with strong psychoactive effects. Little is known about the effects on neurotransmission and the toxicity of the second-generation cannabinoid 5F-APINAC. The objective was to assess the influence of short- and long-term exposures of 5F-APINAC on metabolites associated with neurotransmission on zebrafish. Methods: Short-term (“acute”, 4 h) and long-term (“chronic”, 96 h) exposures to 5F-APINAC were performed at 0.001, 0.01, 0.1, 1.0 and 10 μM. Intervention groups were compared with a vehicle control. Each group n = 20 zebrafish eggs/larvae. Metabolites related to neurotransmission were determined. Results: In chronic exposure, larvae exposed to 10 μM 5F-APINAC presented morphological and developmental alterations. GABA had the lowest concentrations at higher exposure in acute (p < 0.01) and chronic (p < 0.001) experiments. Glutamine showed a descending trend in the acute experiment, but an ascending trend in the chronic exposure (p < 0.05). In chronic exposure, tryptophan presented an overall descending trend, but with a neat increase at 10 μM 5F-APINAC (p < 0.001). Tryptamine in acute exposure presented lower (p < 0.05) concentrations at higher doses. Dopamine and acetylcholine presented highest (p < 0.05) concentrations in the acute and chronic exposures, but with a drop at the highest doses in the chronic experiments. In chronic exposure, xanthurenic acid decreased, except for the highest dose. Picolinic acid was increased at the highest doses in the chronic experiment (p < 0.001). Conclusions: Short- and long-term exposures induced metabolomic alterations associated with the gamma-aminobutyric acid/glutamic acid, dopaminergic/adrenergic, cholinergic neurotransmitter systems, and the kynurenine pathway. Chronic exposure at 10 μM 5F-APINAC was associated with embryotoxicity confirmed by teratogenesis.

© 2021 Elsevier B.V. Innovative Mn-containing glass ceramic (Na2O[2.00]-K2O[0.09]-MgO[3.10]-MnO[2.07]-CaO[38.78]-CaF2[2.25]-P2O5[9.66]-SiO2[41.71] [wt%]) was obtained by sol-gel. It was investigated by High Resolution Field Emission Scanning Electron Microscopy, Energy Dispersive X-Ray Spectroscopy, X-Ray fluorescence, X-Ray Diffraction, and Fourier Transform Infrared Spectroscopy. Ion release characteristics of the glass ceramic powder were quantified via Inductively Coupled Plasma Optical Emission Spectroscopy. Biological tests were performed using equine adipose tissue mesenchymal stem cells (AMSCs). MTT assay demonstrated the cytocompatibility of the prepared material. AMSCs differentiation test showed that the glass ceramic favored the stem cell differentiation in adipogenic, chondrogenic, and osteogenic lineages, the last one being qualitatively more pronounced. The antimicrobial properties were evaluated against Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Salmonella typhi, and Staphylococcus aureus bacteria strains and Candida albicans fungus. The inhibition of Gram-negative bacteria (S. tiphy, E. coli), Gram-positive (E. faecalis) and fungus (C. albicans) was detected, while the inhibition of P. aeruginosa and S. aureus was not significant.

© 2021 Elsevier GmbH Purpose: Although the plantaris muscle is vestigial in humans, it is far too important to remain omitted. The aim of this study is to provide a comprehensive review of the existing literature focused on plantaris muscle clinical value, grafting usefulness and its morphological variations. Hopefully this study will be of great use for every medical practitioner due to its clarity and conciseness despite such broaden scope of this article. Material and Methods: The article is written based on 100 studies published since 1868 until 2020. During careful selection process 12 papers were dismissed due to their insufficient sample size, wrong methods used or results that were previously discovered. Results: Many aspects concerning the plantaris muscle are already well examined, summarized and described. However this study has shown how much we still do not know and which fields require further investigations. Conclusion: The anatomical variations of plantaris muscle morphology may cause mid-portion Achilles tendinopathy, tennis leg syndrome or increase the risk of failure while harvesting the tendons.

© 2021 Elsevier GmbH Purpose: Although the plantaris muscle is vestigial in humans, it is far too important to remain omitted. The aim of this study is to provide a comprehensive review of the existing literature focused on plantaris muscle clinical value, grafting usefulness and its morphological variations. Hopefully this study will be of great use for every medical practitioner due to its clarity and conciseness despite such broaden scope of this article. Material and Methods: The article is written based on 100 studies published since 1868 until 2020. During careful selection process 12 papers were dismissed due to their insufficient sample size, wrong methods used or results that were previously discovered. Results: Many aspects concerning the plantaris muscle are already well examined, summarized and described. However this study has shown how much we still do not know and which fields require further investigations. Conclusion: The anatomical variations of plantaris muscle morphology may cause mid-portion Achilles tendinopathy, tennis leg syndrome or increase the risk of failure while harvesting the tendons.