Notch/Delta signaling constrains reengineering of pro-T cells by PU.1

PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through β-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo β-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment

Predicting Adaptive Behavior in the Environment from Central Nervous System Dynamics

To generate adaptive behavior, the nervous system is coupled to the environment. The coupling constrains the dynamical properties that the nervous system and the environment must have relative to each other if adaptive behavior is to be produced. In previous computational studies, such constraints have been used to evolve controllers or artificial agents to perform a behavioral task in a given environment. Often, however, we already know the controller, the real nervous system, and its dynamics. Here we propose that the constraints can also be used to solve the inverse problem—to predict from the dynamics of the nervous system the environment to which they are adapted, and so reconstruct the production of the adaptive behavior by the entire coupled system. We illustrate how this can be done in the feeding system of the sea slug Aplysia. At the core of this system is a central pattern generator (CPG) that, with dynamics on both fast and slow time scales, integrates incoming sensory stimuli to produce ingestive and egestive motor programs. We run models embodying these CPG dynamics—in effect, autonomous Aplysia agents—in various feeding environments and analyze the performance of the entire system in a realistic feeding task. We find that the dynamics of the system are tuned for optimal performance in a narrow range of environments that correspond well to those that Aplysia encounter in the wild. In these environments, the slow CPG dynamics implement efficient ingestion of edible seaweed strips with minimal sensory information about them. The fast dynamics then implement a switch to a different behavioral mode in which the system ignores the sensory information completely and follows an internal “goal,” emergent from the dynamics, to egest again a strip that proves to be inedible. Key predictions of this reconstruction are confirmed in real feeding animals

Hormonal basis of sex differences in anesthetic sensitivity

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females

Inclusive educational process at the university: Theoretical and experimental model of teachers' psychological readiness

Introduction. The institutionalisation of inclusion in higher education determines new requirements for university teachers, what is also found in the field of psychological readiness for the implementation of the educational process with the participation of students with disabilities. Aim. The present research was aimed to develop theoretical framework and experimental verification of the model of psychological readiness of academic teaching staff for the implementation of an inclusive educational process. Methodology and research methods. Methodologically, the research was based on the idea that the true implementation of inclusive higher education is conditioned by the formation of an inclusive culture of university teachers, which serves as the foundation for the implementation of inclusive practices and policies and one of the immanent attributes of which is psychological readiness to implement the educational process with the participation of disabled students. In the diagnostic and methodological terms, the current study relied on the authors' questionnaire containing the blocks of questions built using a 5-point Likert scale and characterising the severity of the various components of such readiness among university teachers in relation to working with disabled students of diverse nosological groups. The survey results were analysed qualitatively and quantitatively using the Cronbach Alpha coefficient, Shapiro-Wilk, Kolmogorov-Smirnov, Mann-Whitney tests, and the median test applying the Pearson test. To check the consistency of the proposed theoretical model of the psychological readiness of university teachers to implement an inclusive educational process, structural equation modelling (or SEM - the method of asymptotically non-parametric assessment) was employed. For statistical calculations, the program IBM SPSS Statistics ver.23 and the AMOS module were used. Results. The integrative model of the psychological readiness of faculty for the implementation of an inclusive educational process has been theoretically substantiated and experimentally confirmed. This model includes a motivational-value component (the acceptance of the values of an inclusive culture, beliefs and attitudes of the teacher regarding inclusive education), an affective component (the emotional acceptance of the situation of inclusive education and its subjects) and an operational component (the teacher's assessment of own skills in using the tools of inclusive education). In the presented model, the teacher's methodical preparedness for teaching students with disabilities acts as a cognitive component, and the resulting component is the implementation of inclusive practice based on the willingness and ability to interact with students with disabilities. It was found that, to the greatest extent, university teachers have formed a motivational readiness to implement inclusive education, but they experience a deficit of operational skills, when working with students with disabilities. At the same time, the level of psychological readiness to implement an inclusive educational process significantly differs depending on the subject specialisation of teachers and the presence / absence of previous experience of interaction with people with disabilities. Scientific novelty. The model of the psychological readiness of teachers for the implementation of inclusive education in Russia was developed and empirically confirmed. Practical significance. The findings of this research highlight the significance of the stages of the formation of university teachers' psychological readiness for inclusive education. The following stages are determined: from providing basic methodological readiness in the framework of professional development through the creation of internal conditions for readiness for inclusive education, examining the experiences and psychological difficulties in interacting with people with disabilities, and, finally, to accompanying the actual inclusive teaching practice.Введение. Институционализация инклюзии в высшей школе детерминирует новые требования к вузовским педагогам, обнаруживающиеся и в сфере психологической готовности к реализации образовательного процесса с участием студентов-инвалидов. Цель исследования, материалы которого представлены в статье, заключалась в теоретическом обосновании и экспериментальной проверке модели психологической готовности профессорско-преподавательского состава вузов к реализации инклюзивного образовательного процесса. Методология и методики исследования. В методологическом плане исследование основывалось на представлении о том, что подлинная имплементация инклюзивного высшего образования обусловливается формированием инклюзивной культуры вузовских преподавателей, которая служит фундаментом реализации инклюзивной практики и политики и одним из имманентных атрибутов которой является психологическая готовность к осуществлению образовательного процесса с участием студентов-инвалидов. диагностико-методическом плане исследование опиралось на авторский опросник, содержащий блоки вопросов, построенных с использованием 5-пунктовой шкалы Лайкерта и характеризующих выраженность у вузовских педагогов различных компонентов такой готовности применительно к работе со студентами-инвалидами разных нозологических групп. Результаты опроса подвергались качественному и количественному анализу с использованием коэффициента альфа Кронбаха, критериев Шапиро - Уилка, Колмогорова -Смирнова, Манна - Уитни, а также медианного теста с использованием критерия Пирсона. Для проверки состоятельности предложенной теоретической модели психологической готовности вузовских преподавателей к реализации инклюзивного образовательного процесса применялся метод моделирования структурными уравнениями (метод асимптотически непараметрической оценки). Для статистических расчетов использовались программа IBM SPSS Statistics ver.23 и модуль AMOS. Результаты. Теоретически обоснована и экспериментально подтверждена интегративная модель психологической готовности вузовского преподавателя к реализации инклюзивного образовательного процесса, которая включает в себя мотивационно-ценностный компонент (принятие ценностей инклюзивной культуры, убеждения и установки преподавателя, касающиеся инклюзивного образования), аффективный компонент (эмоциональное принятие ситуации инклюзивного образования и ее субъектов) и операциональный компонент (оценка преподавателем своих навыков в использовании инструментов инклюзивного образования) и в которой в качестве когнитивного компонента выступает методическая подготовленность преподавателя к обучению студентов с инвалидностью, а результирующим компонентом является реализация инклюзивной практики, основанная на готовности и способности взаимодействовать со студентами-инвалидами. Установлено, что в наибольшей степени у вузовских преподавателей сформирована мотивационная готовность к реализации инклюзивного образования, но они испытывают дефицит операциональных навыков при работе со студентами с инвалидностью. При этом уровень психологической готовности к реализации инклюзивного образовательного процесса достоверно различается в зависимости от предметной специализации преподавателей и наличия/отсутствия у них предшествующего опыта взаимодействия с инвалидами. Научная новизна результатов исследования определяется тем, что была разработана и эмпирически подтверждена модель психологической готовности преподавателей к реализации инклюзивного образования в России. Практическая значимость исследования связана с тем, что в свете его результатов определяются этапы формирования психологической готовности вузовских преподавателей к инклюзивному образованию: от обеспечения базовой методической подготовленности в рамках повышения профессиональной квалификации - через создание внутренних условий готовности к инклюзивному образованию, с проработкой переживаний и психологических затруднений во взаимодействии с людьми с инвалидностью - к сопровождению собственно инклюзивной преподавательской практики

History-Dependent Excitability as a Single-Cell Substrate of Transient Memory for Information Discrimination

Neurons react differently to incoming stimuli depending upon their previous history of stimulation. This property can be considered as a single-cell substrate for transient memory, or context-dependent information processing: depending upon the current context that the neuron “sees” through the subset of the network impinging on it in the immediate past, the same synaptic event can evoke a postsynaptic spike or just a subthreshold depolarization. We propose a formal definition of History-Dependent Excitability (HDE) as a measure of the propensity to firing in any moment in time, linking the subthreshold history-dependent dynamics with spike generation. This definition allows the quantitative assessment of the intrinsic memory for different single-neuron dynamics and input statistics. We illustrate the concept of HDE by considering two general dynamical mechanisms: the passive behavior of an Integrate and Fire (IF) neuron, and the inductive behavior of a Generalized Integrate and Fire (GIF) neuron with subthreshold damped oscillations. This framework allows us to characterize the sensitivity of different model neurons to the detailed temporal structure of incoming stimuli. While a neuron with intrinsic oscillations discriminates equally well between input trains with the same or different frequency, a passive neuron discriminates better between inputs with different frequencies. This suggests that passive neurons are better suited to rate-based computation, while neurons with subthreshold oscillations are advantageous in a temporal coding scheme. We also address the influence of intrinsic properties in single-cell processing as a function of input statistics, and show that intrinsic oscillations enhance discrimination sensitivity at high input rates. Finally, we discuss how the recognition of these cell-specific discrimination properties might further our understanding of neuronal network computations and their relationships to the distribution and functional connectivity of different neuronal types

Connected consciousness after tracheal intubation in young adults: an international multicentre cohort study

Background: Connected consciousness, assessed by response to command, occurs in at least 5% of general anaesthetic procedures and perhaps more often in young people. Our primary objective was to establish the incidence of connected consciousness after tracheal intubation in young people aged 18e40 yr. The secondary objectives were to assess the nature of these responses, identify relevant risk factors, and determine their relationship to postoperative outcomes. Methods: This was an international, multicentre prospective cohort study using the isolated forearm technique to assess connected consciousness shortly after tracheal intubation. Results: Of 344 enrolled subjects, 338 completed the study (mean age, 30 [standard deviation, 6.3] yr; 232 [69%] female). Responses after intubation occurred in 37/338 subjects (11%). Females (13%, 31/232) responded more often than males (6%, 6/106). In logistic regression, the risk of responsiveness was increased with female sex (odds ratio [OR adjusted ]¼2.7; 95% confidence interval [CI], 1.1e7.6; P¼0.022) and was decreased with continuous anaesthesia before laryngoscopy (OR adjusted ¼0.43; 95% CI, 0.20e0.96; P¼0.041). Responses were more likely to occur after a command to respond (and not to nonsense, 13 subjects) than after a nonsense statement (and not to command, four subjects, P¼0.049). Conclusions: Connected consciousness occured after intubation in 11% of young adults, with females at increased risk. Continuous exposure to anaesthesia between induction of anaesthesia and tracheal intubation should be considered t