ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation

Microcephaly and medulloblastoma may both result from mutations that compromise genomic stability. We report that ATR, which is mutated in the microcephalic disorder Seckel syndrome, sustains cerebellar growth by maintaining chromosomal integrity during postnatal neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis and cerebellar hypoplasia in mice. Co-deletions of either p53 or Bax and Bak prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. ATR-deficient CGNPs had impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to ATR-deficient proliferation was highly p53 dependent and markedly attenuated by p53 co-deletion. Acute ATR inhibition in vivo by nanoparticle-formulated VE-822 reproduced the developmental disruptions seen with Atr deletion. Genetic deletion of Atr blocked tumorigenesis in medulloblastoma-prone SmoM2 mice. Our data show that p53-driven apoptosis and cell cycle arrest – and, in the absence of p53, non-apoptotic cell death – redundantly limit growth in ATR-deficient progenitors. These mechanisms may be exploited for treatment of CGNP-derived medulloblastoma using ATR inhibition

Amine functionalization of cholecyst-derived extracellular matrix with generation 1 PAMAM dendrimer

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Biomacromolecules, copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/pdf/10.1021/bm701055k.A method to functionalize cholecyst-derived extracellular matrix (CEM) with free amine groups was established in an attempt to improve its potential for tethering of bioactive molecules. CEM was incorporated with Generation-1 polyamidoamine (G1 PAMAM) dendrimer by using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and N-hydroxysuccinimide cross-linking system. The nature of incorporation of PAMAM dendrimer was evaluated using shrink temperature measurements, Fourier transform infrared (FTIR) assessment, ninhydrin assay, and swellability. The effects of PAMAM incorporation on mechanical and degradation properties of CEM were evaluated using a uniaxial mechanical test and collagenase degradation assay, respectively. Ninhydrin assay and FTIR assessment confirmed the presence of increasing free amine groups with increasing quantity of PAMAM in dendrimer-incorporated CEM (DENCEM) scaffolds. The amount of dendrimer used was found to be critical in controlling scaffold degradation, shrink temperature, and free amine content. Cell culture studies showed that fibroblasts seeded on DENCEM maintained their metabolic activity and ability to proliferate in vitro. In addition, fluorescence cell staining and scanning electron microscopy analysis of cell-seeded DENCEM showed preservation of normal fibroblast morphology and phenotype

Интегративный подход как вектор персонализации образовательных практик в медицинском вузе

Introduction. The article discusses the formation of a model of a high quality educational process in a medical university in order to prepare a highly qualified specialist and a versatile educated person. Purpose setting. The objective of the study was to analyze the process of formation of clinical thinking, intellectual and communicative competencies in the process of preparing future specialists for professional activities in a medical university, based on the use of an integrative approach, assessment of the type of thinking and learning; constitutional features of the student and teacher; semantic differential method. Methodology and methods of the study. The methodology of the material presented in the article is based on the introduction of a systematic (holistic) approach to study the individual constitutional (mental and physical) characteristics of teachers and medical students in connection with training and further professional activities. Results. The article analyzes current trends and problematic issues of the educational process in pedagogy and andragogy, due to technological progress, the development of digital technologies, distance types and forms of education, the formation of the so-called «digital generation» of students, requiring the development and implementation of innovative methodological approaches and methods in the educational process training of specialists in medical universities. The necessity of forming not only intellectual and communicative competencies in the process of mastering a profession, but also conceptual and logical schemes of clinical thinking using the method of semantic differential is demonstrated. The role of the constitutional features of the teacher and student in the training of future specialists is shown. The relationship between the professional and personal qualities of a high school teacher and students is illustrated.Conclusion. The use of an integrative approach greatly contributes to improving the quality of the educational process in the professional training of a future medical specialist.Введение. Обсуждается формирование модели качественного образовательного процесса в медицинском вузе с целью подготовки высококвалифицированного специалиста и разносторонне образованной личности. Постановка задачи. Задача исследования – проанализировать процесс формирования клинического мышления, интеллектуальных и коммуникативных компетенций в процессе подготовки будущих специалистов к профессиональной деятельности в медицинском вузе на основе применения интегративного подхода, оценки типа мышления и обучения, конституциональных особенностей обучающегося и преподавателя, метода семантического дифференциала. Методика и методология исследования. Методология материала, представленного в статье, базируется на внедрении системного (целостного) подхода для изучения индивидуальных конституциональных (психических и физических) особенностей педагогов и студентов-медиков в связи с обучением и дальнейшей профессиональной деятельностью. Результаты. В статье проанализированы современные тенденции и проблемные вопросы образовательного процесса в педагогике и андрагогике, обусловленные технологическим прогрессом, развитием цифровых технологий, дистанционных видов и форм обучения, формированием так называемого «цифрового поколения» студентов, требующие разработки и внедрения инновационных методологических подходов и методов в образовательный процесс подготовки специалистов в медицинских вузах. Продемонстрирована необходимость формирования не только интеллектуальных и коммуникативных компетенций в процессе овладения профессией, но и понятийно-логических схем клинического мышления с использованием метода семантического дифференциала. Показана роль конституциональных особенностей преподавателя и студента в подготовке будущих специалистов. Проиллюстрирована зависимость между профессиональными и личными качествами преподавателя высшей школы и обучающихся. Выводы. Применение интегративного подхода в значительной степени способствует повышению качества образовательного процесса при профессиональной подготовке будущего специалиста медицинского профиля

Carrageenan-based hydrogels for the controlled delivery of PDGF-BB in bone tissue engineering applications

One of the major drawbacks found in most bone tissue engineering approaches developed so far consists in the lack of strategies to promote vascularisation. Some studies have addressed different issues that may enhance vascularisation in tissue engineered constructs, most of them involving the use of growth factors (GFs) that are involved in the restitution of the vascularity in a damaged zone. The use of sustained delivery systems might also play an important role in the re-establishment of angiogenesis. In this study, !-carrageenan, a naturally occurring polymer, was used to develop hydrogel beads with the ability to incorporate GFs with the purpose of establishing an effective angiogenesis mechanism. Some processing parameters were studied and their influence on the final bead properties was evaluated. Platelet derived growth factor (PDGF-BB) was selected as the angiogenic factor to incorporate in the developed beads, and the results demonstrate the achievement of an efficient encapsulation and controlled release profile matching those usually required for the development of a fully functional vascular network. In general, the obtained results demonstrate the potential of these systems for bone tissue engineering applications.This work was supported by the European NoE EXPERTISSUES (NMP3-CT-2004-500283), the European STREP HIPPOCRATES (NMP3-CT-2003-505758), and by the Portuguese Foundation for Science and Technology (FCT) through the project PTDC/FIS/68517/2006 and through the V. Espirito Santo's Ph.D. grant (SFRH/BD/39486/2007)

Mathematical modeling of an effect of refractory metal nanopowders on the strength of concrete

The quality of concrete and the reliability of its exploitation in structures and structures are largely determined by such characteristic as strength. Additives increasing the strength can significantly improve the quality of concrete. The aim of this work is mathematical modeling of the effect of refractory metal nanopowders on the strength of concrete. Regression equations of the first and second orders are constructed, which adequately find the dependence of the compressive strength of concrete on the input parameters. For presented model the optimal values of the concentrations of refractory metal nanopowders have been calculated

Structural characterization of self-organized mono- and multilayers of partly fluorinated polydialkoxyphosphazenes at the air/water interface

We report studies of the collapse of monolayers of mesomorphic poly[bis-(2,2,3,3,4,4,5,5-octafluo-ropentoxy)phosphazene] and poly[bis-(2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptoxy)phosphazene]. The structure of the films has been examined at different stages of the collapse process by synchrotron grazing incidence X-ray diffraction. Surface pressure–surface area isotherms show that these films undergo a stepwise collapse with formation of multilayers. Grazing incidence X-ray diffraction reveals only one diffraction peak for the monolayer as well as for multilayers of the two polymers studied, which corresponds to an in-plane interchain spacing d = 15.2±0.1°Å and 17.6±0.5°Å, respectively. The in-plane correlation length ξxy reaches ca. 500 Å for PFP-C5 (33 macromolecules) and ca. 400 Å for PFP-C7 (23 macromolecules), implying a certain mesoscale order similar to a quasi-long-range one