A model of estrogen-related gene expression reveals non-linear effects in transcriptional response to tamoxifen

SynthSys is a Centre for Integrative Systems Biology (CISB) funded by BBSRC and EPSRC, reference BB/D019621/1.Background: Estrogen receptors alpha (ER) are implicated in many types of female cancers, and are the common target for anti-cancer therapy using selective estrogen receptor modulators (SERMs, such as tamoxifen). However, cell-type specific and patient-to-patient variability in response to SERMs (from suppression to stimulation of cancer growth), as well as frequent emergence of drug resistance, represents a serious problem. The molecular processes behind mixed effects of SERMs remain poorly understood, and this strongly motivates application of systems approaches. In this work, we aimed to establish a mathematical model of ER-dependent gene expression to explore potential mechanisms underlying the variable actions of SERMs. Results: We developed an equilibrium model of ER binding with 17 beta-estradiol, tamoxifen and DNA, and linked it to a simple ODE model of ER-induced gene expression. The model was parameterised on the broad range of literature available experimental data, and provided a plausible mechanistic explanation for the dual agonism/antagonism action of tamoxifen in the reference cell line used for model calibration. To extend our conclusions to other cell types we ran global sensitivity analysis and explored model behaviour in the wide range of biologically plausible parameter values, including those found in cancer cells. Our findings suggest that transcriptional response to tamoxifen is controlled in a complex non-linear way by several key parameters, including ER expression level, hormone concentration, amount of ER-responsive genes and the capacity of ER-tamoxifen complexes to stimulate transcription (e. g. by recruiting co-regulators of transcription). The model revealed non-monotonic dependence of ER-induced transcriptional response on the expression level of ER, that was confirmed experimentally in four variants of the MCF-7 breast cancer cell line. Conclusions: We established a minimal mechanistic model of ER-dependent gene expression, that predicts complex non-linear effects in transcriptional response to tamoxifen in the broad range of biologically plausible parameter values. Our findings suggest that the outcome of a SERM's action is defined by several key components of cellular micro-environment, that may contribute to cell-type-specific effects of SERMs and justify the need for the development of combinatorial biomarkers for more accurate prediction of the efficacy of SERMs in specific cell types.Publisher PDFPeer reviewe

Towards a Graphene-Based Quantum Impedance Standard

Precision measurements of the quantum Hall resistance with alternating current (ac) in the kHz range were performed on epitaxial graphene in order to assess its suitability as a quantum standard of impedance. The quantum Hall plateaus measured with alternating current were found to be flat within one part in 10^7. This is much better than for plain GaAs quantum Hall devices and shows that the magnetic-flux-dependent capacitive ac losses of the graphene device are less critical. The observed frequency dependence of about -8x10^-8/kHz is comparable in absolute value to the positive frequency dependence of plain GaAs devices, but the negative sign is attributed to stray capacitances which we believe can be minimized by a careful design of the graphene device. Further improvements thus may lead to a simpler and more user-friendly quantum standard for both resistance and impedance

Comparative research of empathy among Russian and Chinese students

The aim of this work is the study of the universal and specific characteristics of empathy of students from Russia and China.Methods. The methods involve the analysis and generalization of literature on the concept and structure of empathy, the influence of cultural factors on this phenomenon. The research is performed in line with the cross-cultural approach. Data are obtained using two methods: «Diagnostics of the level of poly-communications empathy» by I. M. Yusupov and «Diagnostics of the level of empathic abilities» by V. V. Boyko (in the modification of V. V. Boyko and O. A. Klitsenko).Results. The influence of cultural factor the formation of the components of empathy and the severity of the empathy towards various social objects are analyzed. Specific characteristics of empathy of students from Russia (generalization, association, high severity emotional component of empathy) and from China (differentiation and selective empathy) are detected. Two universal characteristics are founded: empathy to the parents to be stronger than for other social objects, and also equally expressed the cognitive component of empathy.Scientific novelty. The study has proved that it is not enough to examine only the level of development of empathy. It is necessary to study its emotional and cognitive components, as well as orientation towards various social objects.Practical significance. Recommendations for creation of more comfortable and safe educational environment in Russian Higher educational institutions for students from China are proposed.Целью публикации является изложение результатов исследования универсальных и специфических особенностей эмпатии у студентов из России и Китая. Методы. В работе использовались анализ и обобщение литературы о понятии и структуре эмпатии, влиянии культурного фактора на этот феномен. Исследование выполнено в русле кросс-культурного подхода. Данные были получены с помощью методик «Диагностика уровня поликоммуникативной эмпатии» И. М. Юсупова и «Диагностика уровня эмпатических способностей» В. В. Бойко (в модификации В. В. Бойко и О. А. Клиценко). Результаты. Проанализировано влияние культурного фактора на формирование компонентов эмпатии и ее выраженность по отношению к различным социальным объектам. Выявлены специфические особенности эмпатии студентов из России (генерализованность, интегрированность, высокая выраженность эмоционального компонента эмпатии) и Китая (дифференцированность и избирательность эмпатии). Также были обнаружены две универсальные особенности: эмпатия к родителям выражена у студентов обеих стран сильнее, чем к другим социальным объектам, а также одинаково представлен когнитивный компонент эмпатии. Научная новизна. Автор статьи доказывает, что недостаточно изучить только уровень развития эмпатии. Необходимо исследование ее эмоционального и когнитивного компонентов, а также направленности на различные социальные объекты. Практическая значимость. Сформулированы рекомендации для создания в российских высших учебных заведениях более комфортной и безопасной образовательной среды для студентов из Кита

Sentinel headache as a warning symptom of ischemic stroke

Background: There are no previous controlled studies of sentinel headache in ischemic stroke. The purpose of the present study was to evaluate the presence of such headache, its characteristics and possible risk factors as compared to a simultaneous control group. Methods: Eligible patients (n = 550) had first-ever acute ischemic stroke with presence of new infarction on magnetic resonance imaging with diffusion-weighted imaging (n = 469) or on computed tomography (n = 81). As a control group we studied in parallel patients (n = 192) who were admitted to the emergency room without acute neurological deficits or serious neurological or somatic disorders. Consecutive patients with stroke and a simultaneous control group were extensively interviewed soon after admission using validated neurologist conducted semi-structured interview forms. Based on our previous study of sentinel headache in transient ischemic attacks we defined sentinel headache as a new type of headache or a previous kind of headache with altered characteristics (severe intensity, increased frequency, absence of effect of drugs) within seven days before stroke. Results: Among 550 patients with stroke 94 patients (17.1%) had headache during seven days before stroke and 12 (6.2%) controls (p < 0.001; OR 3.9; 95% CI 1.7-5.8). Totally 81 patients (14.7%) had sentinel headache within the last week before stroke and one control. Attacks of arrythmia during seven days before stroke were significantly associated with sentinel headache (p = 0.04, OR 2.3; 95% CI 1.1-4.8). Conclusions: A new type of headache and a previous kind of headache with altered characteristics during one week before stroke are significantly more prevalent than in controls. These headaches represent sentinel headaches. Sudden onset of such headaches should alarm about stroke. © 2020 The Author(s)

Bad expression influences time to androgen escape in prostate cancer

&lt;b&gt;OBJECTIVE&lt;/b&gt;: To assess the role of selected downstream Bcl-2 family members (Bad, Bax, Bcl-2 and Bcl-xL) in the development of androgen-independent prostate cancer (AIPC), as androgen-deprivation therapy is the treatment of choice in advanced prostate cancer, yet patients generally relapse and progress to an AI state within 18–24 months. &lt;b&gt;PATIENTS, MATERIALS AND METHODS&lt;/b&gt;: The patient cohort was established by retrospectively selecting patients with prostate cancer who had an initial response to androgen-deprivation therapy, but subsequently relapsed with AIPC. In all, 58 patients with prostate cancer were included with matched androgen-dependent (AD) and AI prostate tumours available for immunohistochemical analysis; two independent observers using a weighted-histoscore method scored the staining. Changes in Bad, Bax, Bcl-2 and Bcl-xL expression during transition to AIPC were evaluated and then correlated to known clinical variables. &lt;b&gt;RESULTS&lt;/b&gt;: High Bad expression in AD tumours was associated with an increased time to biochemical relapse (&lt;i&gt;P&lt;/i&gt; = 0.007) and a trend towards improved overall survival (&lt;i&gt;P&lt;/i&gt; = 0.053). There were also trends towards a decrease in Bad (&lt;i&gt;P&lt;/i&gt; = 0.068) and Bax (&lt;i&gt;P&lt;/i&gt; = 0.055) expression with progression to AIPC. There were no significant results for Bcl-2 or Bcl-xL. &lt;b&gt;CONCLUSION&lt;/b&gt;: There is evidence to suggest that Bad expression levels at diagnosis influence time to biochemical relapse and overall survival, and that levels of pro-apoptotic proteins Bad and Bax fall during AIPC development. Bad might therefore represent a possible positive prognostic marker and potential therapeutic target for AIPC in the future

The Yekaterinburg headache initiative: an interventional project, within the Global Campaign against Headache, to reduce the burden of headache in Russia.

BACKGROUND: As major causes of global public ill-health and disability, headache disorders are paradoxically ignored in health policy and in planning, resourcing and implementing health services. This is true worldwide. Russia, where the prevalence of headache disorders and levels of attributed disability are well in excess of the global and European averages, is no exception, while arcane diagnoses and treatment preferences are an aggravating factor. Urgent remedial action, with political support, is called for. METHODS: Yekaterinburg, in Sverdlovsk Oblast, is the chosen centre for a demonstrational interventional project in Russia, undertaken within the Global Campaign against Headache. The initiative proposes three actions: 1) raise awareness of need for improvement; 2) design and implement a three-tier model (from primary care to a single highly specialized centre with academic affiliation) for efficient and equitable delivery of headache-related health care; 3) develop a range of educational initiatives aimed at primary-care physicians, non-specialist neurologists, pharmacists and the general public to support the second action. RESULTS AND CONCLUSION: We set these proposals in a context of a health-care needs assessment, and as a model for all Russia. We present and discuss early progress of the initiative, justify the investment of resources required for implementation and call for the political support that full implementation requires. The more that the Yekaterinburg headache initiative can achieve, the more likely it is that this support will be forthcoming

The characteristics of reflexivity of younger and middle adolescents

The article is devoted to the problem of development of reflection in the adolescence at the age 11–12 and 13–14. It is shown that there are differences in development of reflexivity of younger and middle adolescents. The structure of relations between reflexivity and locus of control and empathy is investigated by means of factor analysis. The specific of reflexivity of younger and middle adolescents is analyzed. Data are given is used for adaptation of program aimed for development of younger and middle adolescents’ reflexivity by means of debate technology.В статье рассматривается проблема развития рефлексии у подростков 11–12 и 13–14 лет. Выявлены различия в развитии рефлексивности у младших и средних подростков. Посредством факторного анализа и учена структура связей рефлексивности с локусом контроля и эмпатией, проанализирована специфика рефлексивности младших и средних подростков. Полученные результаты используются для адаптации программы по развитию рефлексивности у данных возрастных групп с помощью технологии «Дебаты»

The occurrence of extreme monthly temparatures and precipitation in two global regions

There has been a lot of focus on the occurrence of extreme weather events and a possible connection to climate change and variability. Much of this work has been related to individual events, rather than for long periods of time. This work will examine the occurrence of extreme conditions in the monthly temperature and precipitation for two geographically disparate regions of the Northern Hemispher

Long-term changes in the equatorial Pacific trade winds [abstract]

EXTRACT (SEE PDF FOR FULL ABSTRACT): Past work has shown that surface zonal equatorial wind stress, zonally integrated from one side of the Pacific to the other, is the key variable for estimating long-term El Niño behavior in the eastern Pacific. ... We used detrended COADS pressure in the eastern and western equatorial Pacific and post-1960 detrended Florida State University equatorial wind stress zonally averaged across the Pacific to verify this relationship