Structure of the full-length TRPV2 channel by cryo-EM.

Transient receptor potential (TRP) proteins form a superfamily Ca(2+)-permeable cation channels regulated by a range of chemical and physical stimuli. Structural analysis of a 'minimal' TRP vanilloid subtype 1 (TRPV1) elucidated a mechanism of channel activation by agonists through changes in its outer pore region. Though homologous to TRPV1, other TRPV channels (TRPV2-6) are insensitive to TRPV1 activators including heat and vanilloids. To further understand the structural basis of TRPV channel function, we determined the structure of full-length TRPV2 at ∼5 Å resolution by cryo-electron microscopy. Like TRPV1, TRPV2 contains two constrictions, one each in the pore-forming upper and lower gates. The agonist-free full-length TRPV2 has wider upper and lower gates compared with closed and agonist-activated TRPV1. We propose these newly revealed TRPV2 structural features contribute to diversity of TRPV channels

Цифровая грамотность студентов вуза непрофильных направлений подготовки

Introduction. Forming and improving the readiness and ability of students in non-core (non-IT) areas of training to effectively, productively (safely) use digital devices, programs, technologies, apply digital competencies (knowledge, abilities and skills) to solve educational problems in the context of educational and professional activities is one of the important goals of educational standards in modern universities.Purpose setting. Purpose of the study is the analysis of the problems of the concept, structure and levels of digital literacy of university students in non-core areas of training.Methodology and methods of the study. Research methods are theoretical analysis and synthesis of research results on the definition, structural understanding and level typology of digital literacy of modern university students in non-core areas of training. The methodological basis of the study was the conceptual provisions and principles of the competency-based and personal-activity approaches.Results. Currently, there are theoretical tasks of developing an integrative model of digital literacy and practical tasks of increasing the digital literacy of students in non-core fields of study, including to the level where the student not only consumes digital competencies, but is able and ready to use them in the process independently or jointly with other students and teachers setting and solving educational and professional problems, including in the context of new professional specializations or even professions arising as a result of the digitalization of their work. The leading role in this process is played in the intrapersonal context by the cognitive components of literacy, and in the interpersonal context by communicative and moral-ethical ones.Conclusions. The author summarizes the results of studies on the formation and development of digital literacy among university students in non-core areas of training. The importance and promise of systematic, holistic work in the context of the formation and development of digital literacy of university students in non-core areas of training is noted. The prospects for theoretical and empirical study of this problem are connected precisely with the study of this component and its integrative role in the formation and development of digital literacy of university students in non-core fields.Введение. Формирование и совершенствование готовности и способности студентов непрофильных (не ИТ) направлений подготовки эффективно, продуктивно (безопасно) использовать цифровые устройства, программы, технологии, применять цифровые компетенции (знания, умения и навыки) для решения образовательных проблем в контексте учебно-профессиональной деятельности является одной из важных целей образовательных стандартов в современных вузах.Постановка задачи. Цель исследования – анализ проблем понятия, структуры и уровней сформированности цифровой грамотности студентов вуза непрофильных направлений подготовки.Методика и методология исследования. Методы исследования – теоретический анализ и синтез результатов исследований определения, структурного осмысления и уровневой типологизации цифровой грамотности современных студентов вуза не непрофильных направлений подготовки. Методологическую основу исследования составили концептуальные положения и принципы компетентностного и личностно-деятельностного подходов.Результаты. В настоящее время стоят теоретические задачи разработки интегративной модели цифровой грамотности и практические задачи повышения цифровой грамотности обучающихся непрофильных направлений подготовки, в том числе до уровня, когда студент не только потребляет цифровые компетенции, но и способен и готов использовать их в процессе самостоятельной или совместной с другими студентами и преподавателями постановки и решения образовательно-профессиональных задач, в том числе в контексте возникающих в результате цифровизации его труда новых профессиональных специализаций или даже профессий. Ведущую роль в этом процессе играют во внутриличностном контексте когнитивные компоненты грамотности, на межличностном – коммуникативные и нравственно-этические.Выводы. Автором суммируются результаты исследований формирования и развития цифровой грамотности студентов вуза непрофильных направлений подготовки. Отмечается важность и перспективность системной, целостной работы в контексте формирования и развития цифровой грамотности студентов вуза непрофильных направлений подготовки. Перспективы теоретического и эмпирического изучения этой проблемы связаны с изучением такого компонента и его интегративной роли в формировании и развитии цифровой грамотности студентов вузов непрофильных направлений

Problems of professional training in early adolescence

The article analyzes the peculiarities of psychological development in adolescence. The stages of professional adaptation in this period are considered. The main problems of adaptation at the stage of vocational training and training are analyzed on the example of the implementation of for mid-level training programsВ статье анализируются особенности психологического развития в юношеском возрасте. Рассматриваются этапы профессиональной адаптации в юношеском возрасте. Анализируются основные проблемы профессиональной адаптации на этапе профессиональной подготовки и обучения на примере реализации программ под-готовки специалистов среднего звен

Structural insights on TRPV5 gating by endogenous modulators.

TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and calmodulin (CaM) have been shown to directly bind to TRPV5 and activate or inactivate the channel, respectively. Using cryo-electron microscopy (cryo-EM), we determined TRPV5 structures in the presence of dioctanoyl PI(4,5)P2 and CaM. The PI(4,5)P2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P2 induce conformational rearrangements in the lower gate, opening the channel. The CaM structure reveals two TRPV5 C-terminal peptides anchoring a single CaM molecule and that calcium inhibition is mediated through a cation-π interaction between Lys116 on the C-lobe of calcium-activated CaM and Trp583 at the intracellular gate of TRPV5. Overall, this investigation provides insight into the endogenous modulation of TRPV5, which has the potential to guide drug discovery

Diagnosis and Treatment of Temporomandibular Arthrosis: a Clinical Case

Background. Complexity of anatomical structure, diversity of clinical pattern, lack of a unified theory of etiology, pathogenesis and treatment of this pathology, individual aspects of the course of the disease complicate the diagnosis and choice of relevant treatment for patients with various nosological forms of the temporomandibular joint diseases.Clinical case description. Patient P., 32 years-old, went to the clinic of orthopaedic dentistry with complaints of noise phenomena in the temporomandibular joint (clicks in the joint area have been registered for five years, the noise increased six months ago), dental crowding, absence of tooth 3.5. The patient underwent clinical examination with creating diagnostic models, electromyography of the masticatory muscles, axiography, computed tomography and MRI of the temporomandibular joint. Through computed magnetic resonance imaging of the temporomandibular joint, electromyography and axiography the patient was accurately diagnosed with deforming arthrosis of the temporomandibular joint complicated by dislocation of the intra-articular disc. A therapeutic-diagnostic plastic milled splint on the mandible was implemented. Dynamic observation during treatment was carried out. The effect of the treatment was observed after three months. The control cone-beam computed tomography of the temporomandibular joint showed positive dynamics in the form of an even expansion of all regions of the joint cavity on both sides, centered position of the heads of mandible in the mandibular fossa, but the cortical bone destruction of the upper contour of the mandibular head on the left was still present. After six months of treatment, electromyograms showed a decrease in bioelectrical activity at rest and an increase in bioelectrical activity during chewing on all the masticatory muscles within normal limits. The re-examination after six months revealed smoother vertical movements of the lower jaw, an increase in the amplitude of laterotrusion and protrusion, their symmetry, no “blockage” of lower jaw movements.Conclusion. An integrated application of radiologic imaging, electromyography and axiography in the diagnosis of temporomandibular joint diseases is crucial for objective analysis of the results, assessment of the quantitative and qualitative characteristics of the masticatory muscles and lower jaw movements, which ultimately determines the optimal patient surveillance and controlled treatment outcomes

Traditions in Industrial Training as a Tool for Shaping the Professional Culture of A Future Specialist

The article is devoted to the traditions in the field of professional education, which are organically combined with innovations. These traditions are one of the factors in the formation and development of professional culture and the competencies of a future specialist.Статья посвящена традициям в сфере профессионального образования, которые органически сочетаются с инновациями. Традиции являются одним из факторов формирования и развития профессиональной культуры и компетенций будущего специалиста

Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.

The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo. Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer

Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold

Transient receptor potential vanilloid type 1 (TRPV1) channel responds to a wide spectrum of physical and chemical stimuli. In doing so, it serves as a polymodal cellular sensor for temperature change and pain. Many chemicals are known to strongly potentiate TRPV1 activation, though how this is achieved remains unclear. In this study we investigated the molecular mechanism underlying the gating effects of divalent cations Mg and Ba. Using a combination of fluorescence imaging and patch-clamp analysis, we found that these cations potentiate TRPV1 gating by most likely promoting the heat activation process. Mg substantially lowers the activation threshold temperature; as a result, a significant fraction of channels are heat-activated at room temperature. Although Mg also potentiates capsaicin- and voltage-dependent activation, these processes were found either to be not required (in the case of capsaicin) or insufficient (in the case of voltage) to mediate the activating effect. In support of a selective effect on heat activation, Mg and Ba cause a Ca-independent desensitization that specifically prevents heat-induced channel activation but does not prevent capsaicin-induced activation. These results can be satisfactorily explained within an allosteric gating framework in which divalent cations strongly promote the heat-dependent conformational change or its coupling to channel activation, which is further coupled to the voltage- and capsaicin-dependent processes

Structural basis of purine nucleotide inhibition of human uncoupling protein 1

Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak of protons across the mitochondrial inner membrane, short-circuiting the mitochondrion to generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton leak by a molecular mechanism that is unclear. We present the cryo–electron microscopy structure of the GTP-inhibited state of UCP1, which is consistent with its nonconducting state. The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network. Our results provide a structural basis for understanding the specificity and pH dependency of the regulatory mechanism. UCP1 has retained all of the key functional and structural features required for a mitochondrial carrier–like transport mechanism. The analysis shows that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak