Allosteric regulation of MDM2 protein

The diverse functions of the MDM2 oncoprotein in growth control and tumourigenesis are managed through coordinated regulation of its discrete domains induced by both extrinsic and intrinsic stimuli. A picture of MDM2 is immerging where structurally discrete but interdependent functional domains are linked through changes in conformation. However compelling insights into how this process is carried out have been hindered by inadequate information on the structure and conformation of the full-length protein. The data presented indicates that the C-terminal RING domain of MDM2, primarily responsible of the E3 ubiquitin ligase activity of the protein, has other intriguing functions. The binding of ATP within the RING domain, triggers conformational changes of MDM2 and its main interaction partner – p53. This in effect promotes efficient binding of the p53 tumour suppressor to specific DNA promoter sequences. Moreover, results presented in this thesis demonstrate a novel role for the RING domain of MDM2 in determining the conformation and activity of its N-terminal hydrophobic cleft, the key target of anticancer drugs designed to activate the function of p53 tumour suppressor protein. Specific modulations within the RING domain, affecting Zinc coordination are synonymous with increased binding affinity of the hydrophobic pocket to the transactivation domain of p53 resulting in a gain of MDM2 transrepressor function thus leading to a decrease in p53-dependant gene expression. ThermoFluor measurements and size exclusion chromatography show that changes in the RING motif lack an effect on the overall integrity of the MDM2 protein. The intrinsic fluorescence measurements manifest that these changes generate long range conformational transitions that are transmitted through the core/central acidic domain of MDM2 resulting in allosteric regulation of the N-terminal hydrophobic pocket. Such RING generated conformational changes result in the relaxation of the hydrophobic pocket. Additionally, it is shown that the cooperation between the RING and the hydrophobic cleft in MDM2 has implications in the efficiency of binding of anticancer drugs such as Nutlin by MDM2. Cooperation between the RING and hydrophobic domain of MDM2 to regulate function demonstrates an allosteric relationship and highlights the need to study MDM2 in a native conformation. In essence the presented data demonstrates that the complex relationship between different domains of MDM2 can impact on the efficacy of anticancer drugs directed towards its hydrophobic pocket

Nauczyciel partycypującym liderem. TZI jako model nauczania i wychowania według Ruth C. Cohn

In the Theme-Centred Interaction, special attention is given to the management of group processes, which are present in the school environment. TCI differs not only from all forms of educational activities that are devoid of group leadership, or merely moderated, but also from the learning programs with predetermined methods and media. What is specific for group leadership within TCI is the encouragement to learn and communicate. The teachers who lead a group of students according to TCI are expected to get involved in the group interaction process together with the students. They consciously and actively take part in the processes that they direct. Participative leadership also means that in the course of directing a group, leaders reveal their opinions and viewpoints.Participative leadership in TCI groups occurs when a teacher constantly moves along the border between his existential involvement in the subject and the group processes, but at the same time he clearly understands his own function of a leader, which is understood not as a status but as a commitment to the group. Participative leadership according to TCI requires long practice and, if possible, professional training. The task of a group leader, amongst others, is to watch over “the dynamic equilibrium” (dynamische Balance in German) between all the factors that are still used in live group processes and that join one another. Participative leadership on the methodical and scientific level opens up the way for investigation of participation, which should be further developed

Determinants of the social and economic development of Żórawina commune. Selected aspects

In today’s global economy, the local level is an important recipient of the effects of the processes and changes taking place. The goal of the article is to define the basic determinants of the social and economic development of Żórawina commune located in the region of Wrocław. In the first part of the article, the author points to the numerous different approaches to defining social and economic development; they also focus on the understanding of development at local level and determine the conditions constituting the basis for development. Then the general characteristics of the analysed commune are presented. The authors focused their considerations on selected conditions of the social and economic development of the studied area in order to create a detailed analysis of this space in the indicated scope. In the study, research conducted on the basis of literature and documents as well as simple statistical and descriptive methods were used

Influence of toxins in food on a little child's speech development - overview

Environmental toxicology is a well-known theme, but not every food toxicology „common” man had to deal with. Hearing the definition of „toxicology” we think that this is an area of medicine, but do not really know what it does and to what extent. Toxicology is the study of toxins, harmful effects on the impact on the health and life of a living organism. In these times it should be erected on a pedestal of medical science. The environment in which we live and lives is contaminated. Toxins are both in the inhaled by human air, of drinking water, food consumption, taking medication, inhaled (even by accident) the substances. There are many types of toxins. In this hearing, the importance will be those present in the food as: product additive, chemical, pesticide residues, mycotoxins, aflatoxins chloroprapanoli, amines, heavy metals, fungi, molds (manufactured improperly stored food or in bad conditions), and other xenoestrogens. The impact of toxins on children's development, and their speech to the 36th of the month is hypothesized to be relatively large. Children up to this moment (theoretically healthy, with normal development) are not subjected to specialist diagnosis, so they do not always small problems are seriously taken into account. It happens that parents or teachers of children (nursery, kindergarten) do not notice the difficulties, there are also often aware of them. The presence of toxins in the environment parents (before becoming pregnant women), prenatally and after birth to 36 months of age has a negative impact on child development

Diagnosis and neurologopedic therapy in a child with sensory-motor alalia

Introduction: Alalia sensory-motor mechanism is a disorder of understanding speech, words expressing thoughts, auditory perception, shaped on the basis of physical hearing, as well as mechanisms for creating movements and create their accuracy. Alalia is dysfunction, which reveals the source of difficulty for up to 2 years of age. The reason is usually damage to the structure of the cerebral cortex, which may take place during fetal life and perinatal time. Most often alalii sensory-motor are confused with autism spectrum disorders, of both are in fact similar. Objective: The aim of the study was to develop and apply individual therapy neurologopedic alalia a child with sensory-motor and the answer to the question whether such therapy can improve speech perception and the ability of the child. Material and methods: The research method of work is an individual case study. Diagnosis was obtained from intelligence, surveillance, indicative speech testing and research neurologopedic. The result has been supplemented with the child's medical records. Results: Therapy neurologopedic brought the desired results. Results achieved in the field of manual and motor skills and eye-hand coordination. Improved memory and perception of auditory-visual and extended the time attention. Significantly enriched vocabulary. Developed the ability to play, a desire to follow suit. Improved ability to eat independently and function of organs oral-facial area. The patient became me sensitive to stimulus, more stabile, the central muscle tone has been reinforced

Edith Stein’s Thought and Stance as the Inspiration for the Educational Dialogue Culture

Poszukując inspiracji do budowania edukacyjnej kultury dialogu, zwracamy się ku Edycie Stein. Jej antropologia filozoficzna i teologiczna jest podstawą dzieła wychowania. Wypracowana przez nią koncepcja „wczucia” otwiera szerokie możliwości konstruowania prawdziwych relacji międzyludzkich opartych na godności człowieka, dla którego źródłem dialogu jest Bóg. Święta Teresa Benedykta od Krzyża wskazuje światło na drodze wychowania przez refleksję naukową oraz osobiste świadectwo życia.Searching for the inspiration to create an educational dialogue culture we turn to Edith Stein. Her philosophical and theological anthropology is the base for educational work. Her concept of empathy, “putting ourselves in the situation of others” opens up a wide range of possibilities for building true interpersonal relations based on the dignity of human for whom God is the source of dialogue. St. Teresa Benedicta of the Cross shows the light on the educational path that is scientific reflection and personal testimony of life