From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma

Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat's oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with “Rosetta stone”-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite's capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease

Conscious Self-Regulation and Academic Motivation as Resources for Students to Perform Research Project Work

The article presents the results of an empirical study of the relationship between the regulatory competencies of students, different types of academic motivation and successful performance of the research project work. Diagnostics of regulatory competencies was carried out by means of Morosanova&rsquo;s "Self-regulation profile of learning activities questionnaire - SRPLAQ-M"; academic motivation was assessed using Gordeeva&rsquo;s "Scales of academic motivation of schoolchildren". The diagnostics was carried out at the beginning of the academic year. Criteria-based assessments, set by the expert teachers, were used as indicators of the project work success. The study, performed on a sample of 9th grade students (N=187, 15-16 years old), provided evidence that regulatory competencies and motivation serve as prerequisites for the students&rsquo; success in research project work. The study allowed to empirically distinguish between the universal and special regulatory competencies. The data analysis revealed the resource role of regulatory competencies in performing an individual research project. It is shown that the general level of the conscious self-regulation development characterizes the universal resources for successful performance of an individual project and is positively associated with all expert criteria for assessment research project success. Special regulatory resources are the modeling of significant conditions and evaluating the results of actions. The study also revealed a mediator role of the regulatory competence of evaluating results in the relationship between the students&rsquo; academic motivation and the final assessment of the research project.</p

Оценка противоопухолевого эффекта 2-(6,8-диметил-5-нитро-4-хлорхинолин-2-ил)-5,6,7-трихлор-1,3-трополона на подкожных ксенографтах культуры опухолевых клеток А-549

Rationale: Chemotherapy is one of the lung cancer treatment methods. The search for new substances with antitumor effect against malignant lung neoplasms is relevant because of low efficacy and side effects of cytotoxic agents. A promising substance class with various biological activities, including antitumor, includes alkaloids of the tropolone family, such as heptamerous non-benzoid aromatic compounds. 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)- 5,6,7-trichloro-1,3-tropolone has been synthesized in Institute of Physical and Organic Chemistry; it is a  new compound belonging to 2-quinoline-2-yl derivatives of 1,3-tropolone.Aim: To assess the antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)- 5,6,7-trichloro-1,3-tropolone on subcutaneous xenografts of A-549 lung tumor cells in immunodeficient Balb/c Nude mice.Materials and methods: The study included 50  immunodeficient Balb/c Nude mice divided into 4  experimental groups depending on the dosage of the study substance (0.0055, 0.055, 0.55, and 2.75  mg/g); group 5  was the control group. A-549  cells of lung cancer were used as a xenograft. The antitumor effect of tropolone was evaluated by the inhibition of tumor growth and the index of tumor growth. The experiment lasted for 36 days starting from the first administration of the substances.Results: The mean tumor volumes on day 36  of the experiment in the control group and four experimental groups were 2729.5; 2150.8; 1746.4; 952.3  and 678.9  mm3 , respectively. The indices of tumor growth in groups  1, 2, 3 and 4 were significantly lower than in group 5 (control) starting from days 24, 21, 21 and 15, respectively, and till the end of the experiment. Maximal differences between groups 4 and 5 were observed at days 33 and 36 (by  3.7, p=0.01 and 4.1, p=0.003  times, respectively).Discussion: The anti-tumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)- 5,6,7-trichloro-1,3-tropolone demonstrated in the study could be related to various mechanisms. For example, numerous studies have shown that its related compound hinokitiol exerts a cytotoxic effect associated with cessation of the cell cycle, apoptosis induction, DNA damage, and autophagic death of tumor cells.Conclusion: The study demonstrated significant differences in xenograft volumes in all experimental groups, compared to the control group. In mice, 2.75  mg/g bodyweight was the most effective dosage of the studied compound leading to a slow decrease in tumor growth rates and a  decrease in the volumes of subcutaneous xenografts.Актуальность. Химиотерапия – один из методов лечения рака легкого. В связи с невысокой эффективностью цитотоксических препаратов и  их побочными эффектами актуален поиск новых веществ. Перспективную группу соединений, проявляющих различные виды биологической активности, в том числе противоопухолевую, составляют алкалоиды трополонового ряда  – семичленные небензоидные ароматические соединения. 2-(6,8-диметил-5-нитро-4- хлорхинолин-2-ил)-5,6,7-трихлор-1,3-трополон, синтезированный в НИИ физической и органической химии Южного федерального университета, относится к новым соединениям в ряду 2-хинолин-2-ил-производных 1,3-трополона.Цель  – оценить противоопухолевый эффект 2-(6,8-диметил-5-нитро-4-хлорхинолин-2-ил)- 5,6,7-трихлор-1,3-трополона в  отношении подкожных ксенографтов культуры рака легкого А-549 на иммунодефицитных мышах Balb/c Nude.Материал и  методы. Исследование проводили на 50  иммунодефицитных мышах линии Balb/c Nude, разделенных на 4  опытные группы в  зависимости от дозы исследуемого вещества  – 0,0055, 0,055, 0,55 и  2,75  мг/г и  на 5-ю  – контрольную. В  качестве ксенотрансплантата использовали клеточную линию рака легкого А-549. Противоопухолевый эффект трополона оценивали с учетом показателя торможения роста опухоли и  индекса роста опухоли. Длительность эксперимента составляла 36 дней начиная с первого введения веществ.Результаты. Показатель среднего объема опухоли на 36-е  сутки эксперимента в  группе контроля и  опытных группах  1, 2, 3 и  4 составил 2729,5; 2150,8; 1746,4; 952,3 и  678,9  мм3 соответственно. Значения индекса роста опухоли в  группах  1, 2, 3 и  4 были статистически значимо ниже в сравнении с 5-й группой (контроль) начиная с  24, 21, 21 и  15  суток соответственно и до конца эксперимента. Наибольшие различия между группами 4 и 5 наблюдались на 33- и  36-е  сутки исследования  – в  3,7  (р=0,01) и 4,1 (p=0,003) раза соответственно.Обсуждение. Выявленный в  данном исследовании противоопухолевый эффект 2-(6,8-диметил-5-нитро-4-хлорхинолин-2-ил)-5,6,7- трихлор-1,3-трополона может быть связан с  различными механизмами. Например, его близкородственное соединение хиноктиол, по результатам многочисленных исследований, проявляет цитотоксическое действие, связанное с остановкой клеточного цикла, индукцией апоптоза, повреждением ДНК, аутофагической гибелью опухолевых клеток.Заключение. Получены статистически значимые различия показателей объемов ксенографтов во всех опытных группах по сравнению с  группой контроля. Наиболее эффективной дозой исследуемого соединения, приводящей к  медленному снижению темпов роста опухолей и уменьшению объемов подкожных ксенографтов, была 2,75 мг/г массы мыши

Optical Identification of Candidates for Active Galactic Nuclei Detected by the Mikhail Pavlinsky ART-XC Telescope Onboard the SRG Observatory during an All-Sky X-ray Survey

Abstract: We present the results of our identification of eight objects from the preliminary catalogue of X-ray sources detected in the 4–12 keV energy band by the Mikhail Pavlinsky ART-XC telescope onboard the SRG observatory during the first all-sky survey. Three of them (SRGA J005751.0+210846, SRGA J014157.0-032915, SRGA J232446.8+440756) have been discovered by the ART-XC telescope, while five have already been known previously as X-ray sources, but their nature has remained unestablished. The last five sources have also been detected in soft X-rays by the eROSITA telescope of the SRG observatory. Our optical observations have been carried out at the 1.6-m AZT-33IK telescope of the Sayan Observatory and the 1.5-m Russian–Turkish telescope (RTT-150). All of the investigated objects have turned out to be active galactic nuclei (AGNs) at redshifts from 0.019 to 0.283. Six of them are Seyfert 2 galaxies (including one Seyfert 1.9 galaxy), one (SRGA J005751.0+210846) is a ‘‘hidden’’ AGN (in an edge-on galaxy), and one (SRGA J224125.9+760343) is a narrow-line Seyfert 1 galaxy. The latter object is characterized by a high X-ray luminosity (~(2-13) × 1044 erg s-1 in the 4–12 keV band) and, according to our black hole mass estimate (~2 × 107Mꙩ), an accretion rate close to the Eddington limit. All three AGNs discovered by the ART-XC telescope (which are not detected by the eROSITA telescope) are characterized by a high absorption column density (Formula presented.). The results obtained confirm the expectations that the ART-XC telescope is an efficient instrument in searching for heavily obscured and other interesting AGNs in the nearby (Formula presented.) Universe. The SRG sky survey will last for another 3 years or more, which must allow many such objects to be discovered