Darinaparsin Is a Multivalent Chemotherapeutic Which Induces Incomplete Stress Response with Disruption of Microtubules and Shh Signaling

Chemotherapeutics and other pharmaceuticals are common sources of cellular stress. Darinaparsin (ZIO-101) is a novel organic arsenical under evaluation as a cancer chemotherapeutic, but the drug's precise mechanism of action is unclear. Stress granule formation is an important cellular stress response, but the mechanisms of formation, maintenance, and dispersal of RNA-containing granules are not fully understood. During stress, small, diffuse granules initially form throughout the cytoplasm. These granules then coalesce near the nucleus into larger granules that disperse once the cellular stress is removed. Complete stress granule formation is dependent upon microtubules. Human cervical cancer (HeLa) cells, pre-treated with nocodazole for microtubule depolymerization, formed only small, diffuse stress granules upon sodium arsenite treatment. Darinaparsin, as a single agent, also induced the formation of small, diffuse stress granules, an effect similar to that of the combination of nocodazole with sodium arsenite. Darinaparsin inhibited the polymerization of microtubules both in vivo and in vitro. Interestingly, upon removal of darinaparsin, the small, diffuse stress granules completed formation with coalescence in the perinuclear region prior to disassembly. These results indicate that RNA stress granules must complete formation prior to disassembly, and completion of stress granule formation is dependent upon microtubules. Finally, treatment of cells with darinaparsin led to a reduction in Sonic hedgehog (Shh) stimulated activation of Gli1 and a loss of primary cilia. Therefore, darinaparsin represents a unique multivalent chemotherapeutic acting on stress induction, microtubule polymerization, and Shh signaling

Educational Tourism: Tribute to Fashion or New Educational Opportunities?

The relevance of this article lies in the need to study educational tourism as one of the ways to motivate students in educational process.  The article discusses new technologies in the educational process, which must be made more saturated and practically applicable. Visualization and the ability to implement the acquired knowledge can interest students and increase their interest in learning the information included in the curriculum. The purpose of the study is to analyze the importance of educational tourism for students. Research methods: As research methods, the following ones were used: questionnaire survey of participants of educational tours and free-style interviews with teachers and organizers of educational tourism, allowing identifying such characteristics of educational tourism’s value for students as awareness of participants about the project, previous personal experience, interest and satisfaction with the project. Research results: the article considers the importance of educational tourism from the point of view of its participants like students, accompanying teachers, from the point of view of the organizers of the tourist and educational project. The novelty and originality of the research lies in the fact that educational tourism is considered as an alternative to educational activities, which allows not only to make a trip, but also to acquire new knowledge, skills and abilities during it, which will be learned much better than just memorizing the material from the book. It is shown that the value of educational tourism can be assessed if there is knowledge about its components such as interest and personal experience of its participants, satisfaction or dissatisfaction with certain elements of the educational tour, awareness of the project possibilities, features of the organization and implementation of the tour. It is revealed that educational tourism performs not only directly educational, but also socially significant functions for society. The study shows that the project participants perceive the educational component easily and without difficulties and there is a high interest of students in educational tours. It is revealed that the accompanying notes a positive dynamic in the interest in the educational process after participation in the project. Both its participants and its organizers perceive the possibility of expanding the project positively. It is determined that the greatest difficulty in the organization of educational tourism is caused by the lack of support of state structures, which in turn causes difficulty in entering new sites where the project can be implemented. It is shown that the educational component of the project is positively evaluated by both direct consumers and teachers in terms of the correctness in the construction of the narrative and semantic parts. It is shown that to the positive aspects of educational tourism can be attributed the emotional involvement of participants in the educational process during the excursion service, as well as increasing the level of their interest in further study. Practical significance: the data obtained in this work can be used in social psychology, pedagogy, age psychology, pedagogical psychology, as well as for further theoretical development of this issue

ELECTRONIC STRUCTURE OF FeSi

The full set of high-energy spectroscopy measurements including X-ray photoelectron valence band spectra and soft X-ray emission valence band spectra of both components of FeSi (Fe K_beta_5, Fe L_alpha, Si K_beta_1,3 and Si L_2,3) are performed and compared with the results of ab-initio band structure calculations using the linearized muffin-tin orbital method and linearized augmented plane wave method.Comment: 11 pages + 3 PostScript figures, RevTex3.0, to be published in J.Phys.:Cond.Matte

Stocks and fraction composition of phosphorus in the Ili Alatau foothill soils and their change under long-term use

In soils of Ili Alatau (dark kastanozems, light kastanozems, mountain chernozems) both in continuous cropping system of sugar beet and in crop rotation with prolonged use of fertilizers the soil agrochemical indices, phosphorus reserves and group composition (total, organic and mineral) vary significantly. The total phosphorus content in the soils was 1720–2330 mg/kg and decreased in the series: virgin mountain chernozems > arable dark kastanozems > arable mountain chernozems > light kashtanozems > virgin dark kastanozems. It was observed, that in arable dark kastanozems, as compared to virgin soils, the content of available forms of phosphorus (loose-bound phosphates Ca-PI and miscellaneous calcium phosphates Ca-PII) increased, and the content of plant unavailable forms of phosphorus (poorly soluble Ca phosphates Ca-PIII, phosphates of aluminum Al-P and iron Fe-P) decreased. In arable mountain chernozems, in comparison with virgin mountain chernozems, the content of all fractions of phosphorus decreased. Arable light kastanozems contain the least amount of available phosphates and the highest of phosphates of aluminum and iron. When cultivating beets on light kastanozems, the content of all fractions of phosphorus, except iron phosphates, increased with increasing dose of fertilizers. The effectiveness of the application of the organic-mineral fertilizers was comparable to the introduction of NK + P1.5 and NK + P2, the yield of sugar beet in the crop rotation in these variants is the highest and amounts to 614 and 577 centner/ha; in the control value (obtained without fertilizers) – 197 centner/ha, and in the variant with application of only NK fertilizers – 277 centner/ha. In continuous cropping system these values were 576 and 561 centner/ha; 311 and 327 centner/ha respectively. Close values of crop yield were obtained in two variants: with the organo-mineral system and NK + P1.5, due to the additional use by the plants of sugar beet phosphorus of newly formed organic compounds

How Neanderthals gripped retouchers: experimental reconstruction of the manipulation of bone retouchers by Neanderthal stone knappers

When studying bone retouchers, researchers pay close attention to the morphological characteristics of the tool’s active zone, and the lithic raw material processed. In our research, we found that the orientation of the bone retoucher in the hand and the grip employed to retain and manipulate it are crucial factors that affect the morphological characteristics of the retoucher’s active zone. By examining two alternative grips for manipulating bone retouchers ((1) Using all the fingers of one hand in a power grip; (2) Using only the first three digits of one hand in a pinch grip), we found that when the retoucher is held in the first manner, the active area is larger, as is the amount of bone removed by the retoucher. When the retoucher was pinched with only three fingers in a precision grip, retouch damage was more densely concentrated and less bone was removed. The orientation of the retoucher in the hand and the grip employed have a greater influence on the active area than the extent of retoucher use, which we assessed by measuring the number of stone tool edges processed. By gripping the retoucher with all the fingers of one hand, the knapper automatically applies greater force, which results in the removal of more bone. Comparison of experimental bone retouchers with those recovered from Middle Paleolithic archaeological contexts in Chagyrskaya Cave (Altai, Russia) revealed that Altai Neanderthals practiced two methods of grasping bone retouchers, with a three-finger pinch grip being dominant. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature

Individual features of the pharmacokinetics of fludarabin phosphate in the treatment of patients with chronic lymphocytic leukemia

Fludarabine is a purine antimetabolite with a pronounced immunosuppressive effect. The inhibitory effect of fludarabine depends on its concentration in blood plasma. In addition, the phenotypic characteristics of patients affect the pharmacokinetic and pharmacodynamic profile of the drug, which necessitates a personalized approach to the dosage regimen. The chromatography-mass spectrometric method for the quantitative determination of 2-fluorine in blood plasma was developed for studying the individual parameters of pharmacokinetics of the international non-proprietary name (INN) fludarabine in patients with B-cell chronic lymphocytic leukemia during the standard course. Such method for the quantitative determination of 2-fluorine in blood plasma was developed and validated in accordance with international requirements. Significant individual variability of the main pharmacokinetic parameters in patients with B-cell chronic lymphocytic leukemia with a single oral administration of the drug with INN fludarabine at a dose of 40 mg/m2 was established, so the coefficient of variability Cmax was 42 %, Tmax — 92 %, AUC0-t — 45 %, Kel — 23 %, T1/2 — 26 %. It should be noted that there is a high interindividual variability of fludarabine, for example, 24 hours after taking the study drug, the maximum and minimum plasma concentrations of the fludarabine metabolite 2-fluoro-ara-A in different in patients with B-cell chronic lymphocytic leukemia differed 9 times. Individual variability of pharmacokinetic parameters characterizing absorption (Cmax/AUC0-t) and total clearance of the active metabolite of fludarabine is statistically significantly associated with a combination of gender and anthropometric factors

Genetic insights into the social organization of Neanderthals

Genomic analyses of Neanderthals have previously provided insights into their population history and relationship to modern humans1–8, but the social organization of Neanderthal communities remains poorly understood. Here we present genetic data for 13 Neanderthals from two Middle Palaeolithic sites in the Altai Mountains of southern Siberia: 11 from Chagyrskaya Cave9,10 and 2 from Okladnikov Cave11—making this one of the largest genetic studies of a Neanderthal population to date. We used hybridization capture to obtain genome-wide nuclear data, as well as mitochondrial and Y-chromosome sequences. Some Chagyrskaya individuals were closely related, including a father–daughter pair and a pair of second-degree relatives, indicating that at least some of the individuals lived at the same time. Up to one-third of these individuals’ genomes had long segments of homozygosity, suggesting that the Chagyrskaya Neanderthals were part of a small community. In addition, the Y-chromosome diversity is an order of magnitude lower than the mitochondrial diversity, a pattern that we found is best explained by female migration between communities. Thus, the genetic data presented here provide a detailed documentation of the social organization of an isolated Neanderthal community at the easternmost extent of their known range

The local antibiotic therapy efficiency ground for the complex treatment of patients suffering from chronic generalized periodontitis

The polymorphisms of TNF-αgene in G(-308)→A in patients suffering from chronic generalized periodontitis were studied in connection with the local antibiotic therapy of periodontal tissues efficiency. The conducted course of antibiotic treatment ,that was administered with a glance for periodontal pocket microflora sensitivity to antibiotics, was established to be less effective in the patients suffering from chronic generalized periodontitis and being carriers of pathological polymorphisms «G / G» and «G / A» than in patients with chronic generalized periodontitis, carriers of the polymorphism A / A.Изучены полиморфизмы гена TNF-a при G(-308)→ A у больных хроническим генерализованным пародонтитом в ассоциации с эффективностью местной антибактериальной терапией тканей пародонта. Было выявлено, что у больных хроническим генерализованным пародонтитом, являющихся носителями патологических полиморфизмов «G/G» и «G/A», проводимое антибактериальное лечение, назначаемое с учётом чувствительности микрофлоры пародонтального кармана к антибиотикам, менее эффективно, чем у больных хроническим генерализованным пародонтитом, являющимися носителями полиморфизма а/а

ВЭЖХ-МС/МС методика количественного определения силденафила и его метаболита в плазме крови человека

A high demand for sildenafil-based drugs puts a premium on the development of methods for quantitation of sildenafil in bio-substrates to facilitate pharmacokinetic analysis in bioequivalence studies. High performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was proposed for the method development due to its high sensitivity, selectivity, reproducibility, and performance. The aim of the study was to develop and validate an HPLC-MS/MS method for quantitative determination of sildenafil and its active metabolite N-desmethyl sildenafil in human plasma. Approbation of the developed technique in the study of the pharmacokinetic profiles of sildenafil and N-desmethyl sildenafil in healthy volunteers in the study of the bioequivalence of the drug sildenafil in the form of a spray. Materials and methods: the method was implemented using the Agilent 1200 high-performance liquid chromatography system with the Agilent 6440 triple quadrupole system, and Poroshell 120 EC-C18 chromatographic column, 4.6 m × 150 mm × 2.7 μm. Calibration samples were prepared using sildenafil citrate and N-desmethyl sildenafil reference standards with 99.5 and 98.5% purity, respectively. Vardenafil was used as an internal standard. Pharmacokinetic profiles of sildenafil and N-desmethyl sildenafil were studied in 44 healthy male volunteers as part of a bioequivalence study approved by the Ministry of Health of the Russian Federation. The primary data processing was performed using Mass Hunter software version B 06.00, and statistical processing was performed using Microsoft Office Excel 2010 and Statistica 6.1. Results: the authors developed and validated a method for quantitation of sildenafil and its active metabolite N-desmethyl sildenafil in human plasma. The developed method was used successfully to study pharmacokinetic profiles of the discussed compounds in healthy volunteers. Conclusions: the developed method of quantitative determination of sildenafil and its active metabolite N-desmethyl sildenafil in human plasma is simple, reproducible, fast, and robust. The results of the pharmacokinetic studies using the developed method demonstrated bioequivalence of the test product and the reference product.В силу высокой востребованности препаратов на основе силденафила актуальна разработка методик о ния силденафила в биосубстратах для обеспечения проведения фармакокинетического анализа при исследованиях биоэквивалентности лекарственных средств. Для разработки методики предложено использовать метод высокоэффективной жидкостной хроматографии с тандемной масс-спектрометрией (ВЭЖХ-МС/МС) как высокочувствительный, селективный, обладающий высокой воспроизводимостью и производительностью. Цель работы: разработка и валидация ВЭЖХМС/МС методики количественного определения силденафила и его активного метаболита N-десметилсилденафила в плазме крови человека. Апробация разработанной методики при изучении фармакокинетических профилей силденафила и N-десметилсилденафила у здоровых добровольцев в исследовании биоэквивалентности препарата силденафила в форме спрея. Материалы и методы: методика реализована на высокоэффективном жидкостном хроматографе Agilent 1200 с тройным квадруполем Agilent 6440, хроматографическая колонка Poroshell 120 EC-C18 4,6 м × 150 мм × 2,7 мкм. Для приготовления калибровочных образцов использовались стандарты с чистотой 99,5 и 98,5% для силденафила цитрата и N-десметилсилденафила соответственно, в качестве внутреннего стандарта использовался варденафил. Изучение фармакокинетических профилей силденафила и N-десметилсилденафила проведено у 44 здоровых добровольцев мужского пола в рамках исследования биоэквивалентности препаратов, одобренного Минздравом России. Первичную обработку данных проводили с помощью программного обеспечения Mass Hunter версия B 06.00, статистическую обработку — с помощью Microsoft Office Excel 2010 и Statistica 6.1. Результаты: разработана и валидирована методика определения силденафила и его активного метаболита N-десметилсилденафила в плазме человека. Разработанная методика успешно использована для изучения фармакокинетических профилей указанных соединений у здоровых добровольцев. Выводы: разработанная методика определения силденафила и его активного метаболита N-десметилсилденафила в плазме крови человека является простой, воспроизводимой, быстрой и надежной. По результатам фармакокинетических исследований с использованием разработанной методики изучаемый препарат и препарат сравнения были признаны биоэквивалентными