The diverse salt-stress response of Arabidopsis ctr1-1 and ein2-1 ethylene signaling mutants is linked to altered root auxin homeostasis

We explored the interplay between ethylene signals and the auxin pool in roots exposed to high salinity using Arabidopsis thaliana wild-type plants (Col-0), and the ethylene-signaling mutants ctr1-1 (constitutive) and ein2-1 (insensitive). The negative effect of salt stress was less pronounced in ctr1-1 individuals, which was concomitant with augmented auxin signaling both in the ctr1-1 controls and after 100 mM NaCl treatment. The R2D2 auxin sensorallowed mapping this active auxin increase to the root epidermal cells in the late Cell Division (CDZ) and Transition Zone (TZ). In contrast, the ethylene-insensitive ein2-1 plants appeared depleted in active auxins. The involvement of ethylene/auxin crosstalk in the salt stress response was evaluated by introducing auxin reporters for local biosynthesis (pTAR2::GUS) and polar transport (pLAX3::GUS, pAUX1::AUX1-YFP, pPIN1::PIN1-GFP, pPIN2::PIN2-GFP, pPIN3::GUS) in the mutants. The constantly operating ethylene-signaling pathway in ctr1-1 was linked to increased auxin biosynthesis. This was accompanied by a steady expression of the auxin transporters evaluated by qRT-PCR and crosses with the auxin transport reporters. The results imply that the ability of ctr1-1 mutant to tolerate high salinity could be related to the altered ethylene/auxin regulatory loop manifested by a stabilized local auxin biosynthesis and transport

Chronobiological approach to study the physiological activity of <i>Candida</i> species

Rythmometric markers can be identified within a day during the study of biological characteristics in order to be used for differential diagnostics of pathogens of different patients’ physical condition. These principles are based on analysis of clinical isolates С. albicans, С. tropicalis and C. krusei allocated from the vaginal microbiota at Candida dysbiosis condition. Control examples were the master samples from the American Type Culture Collection (ATCC). Detailed research was conducted on physiological characteristics through the formation of biofilms by yeast pathogens. Biological activity of Candida sp. biofilming was observed within 2 days with 4 hours interval in winter. Daily cultures were used for the experiment to correspond to their maximum adhesion to the glass surface. It was important to obtain 6 measurements per day with 3-5 times repetition of experiment conditions during the specified timeline. In order to determine the periodicity of the parameters studied, the data was statistically processed by Student’s t-test, using Mann–Whitney criteria and nonparametric method of least square method.It was found out that biofilming activity during 24 hours (р &lt; 0.05) of fungi exists and that all species have many principles in common. It was attested that the main rhythmometric parameters of diagnostic significance are the rhythm period and amplitude-phase stability. It was found that the daily dynamics of C. albicans 24433 biofilm formation from American Type Culture Collection was characterized by an ultradian (about 12-hours) contribution of the rhythm in the morning – 4 A.M and in the evening – 4 P.M. Significant circadian (approx. daily) rhythms of adhesion glass surface activity were revealed in C. non-albicans from American Type Culture Collection. The dynamic of biofilm formation isolates of yeast from female reproductive organs with Candida pathology was characterized by reliable ultradian (about 12-hour) harmonics which biological significance defines resistance to external impact and the ability to adaptively respond to periodic stimuli.To sum up, implementation of the chronobiological approach has opened up new prospects for studying the physiology of Сandida sp., as it enables us to predict the dynamics of microbial states and takes into account the specificity of emergency and long-term adaptation to different environmental factors. The detection of the circadian rhythm of biofilm formation activity of different Candida sp. strains provides the possibility to manage the vitality of the Society of Bacteria and Fungi and predicts its resistance to various antibiotics

Chronobiological approach to study microsymbiont catalase activity in female reproductive tract

Catalase is a heme-containing enzyme belonging to protection factors that destroys peroxide compounds. The presence of catalase activity is an important ability of microorganisms that allows them to be protected from unfavorable factors as well as adapt to macroorganism conditions. Catalase along with superoxide dismutase plays an important role in pathogen resistance to phagocyte oxygen-dependent bactericidal mechanisms. The aim of the study was to investigate microsymbiont catalase activity from female reproductive tract in normocenosis and candidiasis dysbiosis using the chronobiological approach. The study was conducted on clinical isolates, isolated from female reproductive tract microsymbiocenosis. The catalase activity was determined by spectrophotometry based on 24 hour-long hydrogen peroxide reduction with 3-hours interval in winter season. Dynamic hydrogen peroxide was assessed in 3–5 experiment replicates. In some Lactobacillus spp., catalase was found containing no heme group — pseudocatalase. Chronobiological approach allowed to reveal enzyme activity from all microsymbionts. The dominant and associative microbiota isolated from healthy females was characterized by circadian (24 hours) rhythms of catalase activity early in the morning — 5 a.m. (р 0.05). Hydrogen peroxide decomposes spontaneously or via non-enzymatic catalysts, and microorganisms cope with this situation under such conditions. In microsymbionts characteristic of female reproductive tract dysbiosis, and usually found in large numbers along with decreased Lactobacillus spp. ultradian rhythms with 12- and 8-hour harmonics of catalase activity with acrophase were recorded in the morning (8 a.m.) and evening hours (8 p.m.). The minimum values of enzyme production in all cultures were recorded at 12 p.m. and 5 p.m. Therefore, the contribution of the rhythm of the studied parameter at varying degree of vaginal sterility reflects the adaptive pathogen capabilities to the conditions of existence and can be the basis for studying related regulatory mechanisms. Mesor and amplitude phase stability are universal rhythmometric parameters used to evaluate patient’s condition independent of species assignment

Cystic Echinococcosis of the Breast - Diagnostic Dilemma or just a Rare Primary Localization

Introduction: Although the liver and lung are the most frequently affected organs in cystic echinococcosis, the cysts may develop in any viscera and tissues. Breast is a rare primary localization with few cases described in the literature. We present an updated and systematic review and discuss the possible mechanisms of spreading, diagnostic and treatment options.Materials and methods: We performed a literature search in PUBMED using the key words &lsquo;hydatid disease&rsquo;, &lsquo;cystic echinococcosis&rsquo; and &lsquo;breast echinococcosis&rsquo; without time limitation. Only studies reporting breast cystic echinococcosis were included.Results: Overall, 121 cases with cystic echinococcosis and 2 with alveolar echinococcosis were reported. A total of 52 cases were included in the analysis. The mean size of cysts was 5.5 cm (range 1.7-12). The most common clinical presentation was painless lump presented from 4 months to 19 years before the final diagnosis. Most cases had isolated breast CE, few cases had synchronous localizations &ndash; femoral, thigh and lung, and previous liver CE. Most were active CL and CE1-2 cysts (72%). Ultrasound was used in 83%, followed by mammography (35%). Fine needle aspiration was reported in 27 cases with positive finding in 59%.Conclusions: In cases with cystic breast lesions from endemic regions we recommend the US as a gold standard. CT and MRT are more accurate but expensive tools without the potential to change the surgical tactic. In contrast to the other localizations of CE, complete excision of the cysts is the best diagnostic and treatment approach

Когнитивный стиль будущего специалиста ИТ-сферы в процессе организации командной работы

Introduction. Training future specialists in information technology to work in a team has a great potential both for solving educational problems in the higher education and for further development of graduates as professionals in the labour market. The efficiency of the teamwork is largely determined by the effectiveness of the distribution of roles in the team. The distribution of roles depends on the individual cognitive characteristics of each team member. Individual enlightening characteristics of the ways of perception and processing of information, the choice of ways to solve problems are associated with the cognitive style of the individual. Aim. The present research aims to analyse the nature of the influence of the cognitive style of the personality of each member of the team on the results of solving a practice-oriented task in the field of information and communication technologies. Methodology and research methods. The work used a systematic approach (N. A. Astashova, S. L. Melnikova, A. P. Tonkikh, L. N. Shilenkova, A. Burger, L. Naude, F. D. Fernandez, J. L. Arco-Tirado, M. Hervas-Torres); practice-oriented approach (E. F. Fefilova, D. Bednarek, M. Krulis, J. Yaghob); project approach (L. I. Savva, E. A. Gasanenko, K. E. Shakhmaeva); cognitive approach (J. B. Watson, G. A. Kimble, J. Anderson, B. M. Velichkovsky, J. Kelly, J. Bruner, J. J. Goodnow, G. A. Austin, M. A. Kholodnaya), in the frames of which general scientific and statistical methods were used. The works by M. A. Kholodnaya, J. Parker, J. D. Bain, H. A. Witkin, S. A. Moore, D. R. Goodenough, P. W. Cox constituted the theoretical and methodological basis of the study, on the basis of which the characteristics of students with different cognitive styles were studied. The analysis of the dependence of the success rate of solving practice-oriented tasks by a team of students on the cognitive style of each member of this team was carried out. The success rate was calculated as the sum of the normalised values for each type of work. 250 undergraduate students of Nizhny Tagil State Socio-Pedagogical Institute (branch) of Russian State Vocational Pedagogical University and Nizhny Tagil Institute of Technology (branch) of Ural Federal University took part in the study. The used research methods: questionnaires, testing, the method of expert assessments, ranking, scaling, rationing, content analysis of documents, methods of mathematical statistics in data processing, methods of analysis, synthesis, generalisation, comparison, abstraction when interpreting research results. The “Included Figures” test was used to determine the field dependence / field independence of the subjects. The main statistical calculations were performed using the nonparametric statistical method “Mann-Whitney U-test”. To confirm the reliable difference in the proportion of teams that successfully coped with the task, the Fisher criterion was applied. The data sources are open source databases (websites of international and Russian government bodies), regulatory documents regulating the basics of training IT specialists, research by leading scientists in the field of cognitive personality style, statistical information. Results. The authors developed the criteria to evaluate the results of solving a practiceoriented task by a team of future IT specialists and defined the concept of a success indicator. The authors demonstrated the importance of taking into account cognitive personality styles when forming a team of IT specialists. The dependence of the success rate of solving a practice-oriented task on the type of cognitive style of the participants of the task was revealed. It is established that the highest results of the success rate in solving a practice-oriented task were noted in those teams that included students with different cognitive personality styles of field dependence / field independence, with a predominant number of participants with a field-independent personality style. The findings indicate the need to take into account the cognitive styles of individuals when forming the composition of teams for IT projects. Scientific novelty. The results of the study expand the scientific facts that cognitive styles are predictors of students’ achievements in solving practical tasks in teamwork. Practical significance. The data obtained can be used to develop a strategy for training future IT specialists aimed at improving the effectiveness of teamwork in higher education institutions. The proposed calculations of the success rate of solving practice-oriented tasks can be employed to evaluate the results of educational practices and final qualifying works.Введение. Обучение будущих специалистов ИТ-сферы работе в команде имеет большой потенциал для решения образовательных задач в системе высшего образования, дальнейшего становления выпускников как специалистов на рынке труда. Результативность деятельности команды во многом определяется эффективностью распределения ролей, которое зависит от индивидуальных познавательных характеристиккаждого члена команды (способов восприятия и обработки информации, выбора способа решения проблем), связанных с когнитивным стилем личности. Цель статьи – анализ влияния когнитивного стиля личности каждого члена команды на результаты решения практико-ориентированной задачи в области информационно-коммуникационных технологий. Методология и методика исследования. В работе применялись системный подход (Н. А. Асташова, С. Л. Мельникова, А. П. Тонких, Л. Н. Шиленкова, A. Burger, L. Naude, F. D. Fernandez, J. L. Arco-Tirado, M. Hervas-Torres); практико-ориентированный подход (E. F. Fefilova, D. Bednarek, M. Krulis, J. Yaghob); проектный подход, (L. I. Savva, E. A. Gasanenko, K. E. Shakhmaeva); когнитивный подход (J. B. Watson, G. A. Kimble, J. Anderson, B. M. Velichkovsky, J. Kelly, J. Bruner, J. J. Goodnow, G. A. Austin, M. A. Kholodnaya), в рамках которых использовались общенаучные и статистические методы. Теоретико-методологическую основу исследования составили работы M. A. Kholodnaya, J. Parker, J. D. Bain, H. A. Witkin, С. A. Moore, D. R. Goodenough, P. W. Cox, на основе которых были изучены особенности студентов с разными когнитивными стилями личности. Проведен анализ зависимости показателя успешности решения практико-ориентированной задачи командой студентов от когнитивного стиля каждого члена этой команды. Показатель успешности рассчитывался как сумма нормированных значений за каждый вид работы. В исследовании приняли участие 250 студентов бакалавриата филиала Российского государственного профессионально-педагогического университета в г. Нижнем Тагиле и Нижнетагильского технологического института (филиала) Уральского федерального университета. Были использованы следующие методы исследования: анкетирование, тестирование, метод экспертных оценок, ранжирование, шкалирование, нормирование, контент-анализ документов, методы математической статистики при обработке данных, методы анализа, синтеза, обобщения, сравнения, абстрагирования при интерпретации результатов исследования. Для определения полезависимости/поленезависимости испытуемых применялся тест «Включенные фигуры». Основные статистические расчеты производились с помощью непараметрического статистического метода «U-критерий Манна – Уитни». Для подтверждения достоверного отличия в доле команд, которые успешно справились с поставленной задачей, применялся критерий Фишера. Источниками данных являются базы открытых источников (сайты международных и российских органов управления), нормативные документы, регламентирующие основы подготовки ИТ-специалистов, исследования ведущих ученых в области когнитивного стиля личности, информация статистического характера. Результаты исследования. Были разработаны критерии для оценки результатов решения практико-ориентированной задачи командой будущих специалистов ИТ-сферы, определено понятие показателя успешности. Продемонстрирована важность учета когнитивных стилей личности при формировании команды ИТ-специалистов. Выявлена зависимость показателя успешности решения практико-ориентированной задачи от типа когнитивного стиля каждого участника команды. Установлено, что наиболее высокие результаты коэффициента успешности в решении практико-ориентированной задачи отмечаются в тех командах, в состав которых входили студенты с разными когнитивными стилями личности с преобладающим количеством поленезависимых участников. Полученные выводы указывают на необходимость учета когнитивных стилей личностей при формировании состава команд для выполнения ИТ-проектов. Научная новизна. Результаты исследования расширяют научные факты о том, что когнитивные стили являются предикторами достижений студентов в решении практических задач в командной работе. Практическая значимость. Полученные данные могут быть использованы для разработки стратегии подготовки будущих ИТ-специалистов, целью которой является повышение эффективности командной работы в высших учебных заведениях. Предложенные расчеты показателя успешности решения практико-ориентированных задач могут применяться для оценки результатов учебных практик и выпускных квалификационных работ

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Radiosensitization of Epidermal Growth Factor Receptor/HER2-Positive Pancreatic Cancer Is Mediated by Inhibition of Akt Independent of Ras Mutational Status

Epidermal growth factor receptor family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors

Strategies to induce p53 activation in wtp53-retaining tumors carry high potential in cancer therapy. Nutlin, a potent highly selective MDM2 inhibitor, induces non-genotoxic p53 activation. Although Nutlin shows promise in promoting cell death in hematopoietic malignancies, a major roadblock is that most solid cancers do not undergo apoptosis but merely reversible growth arrest. p53 inhibition by unopposed MDMX is one major cause for apoptosis resistance to Nutlin. The Hsp90 chaperone is ubiquitously activated in cancer cells and supports oncogenic survival pathways, many of which antagonize p53. The Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) is known to induce p53-dependent apoptosis. We show here that in multiple difficult-to-kill solid tumor cells 17AAG modulates several critical components that synergize with Nutlin-activated p53 signaling to convert Nutlin's transient cytostatic response into a cytotoxic killing response in vitro and in xenografts. Combined with Nutlin, 17AAG destabilizes MDMX, reduces MDM2, induces PUMA and inhibits oncogenic survival pathways, such as PI3K/AKT, which counteract p53 signaling at multiple levels. Mechanistically, 17AAG interferes with the repressive MDMX–p53 axis by inducing robust MDMX degradation, thereby markedly increasing p53 transcription compared with Nutlin alone. To our knowledge Nutlin+17AAG represents the first effective pharmacologic knockdown of MDMX. Our study identifies 17AAG as a promising synthetic lethal partner for a more efficient Nutlin-based therapy