Can ionic concentration changes due to mechanical deformation be responsible for the neurostimulation caused by focused ultrasound? a simulation study

Objective Ultrasound stimulation is an emerging neuromodulation technique, for which the exact mechanism of action is still unknown. Despite the number of hypotheses such as mechanosensitive ion channels and intermembrane cavitation, they fail to explain all of the observed experimental effects. Here we are investigating the ionic concentration change as a prime mechanism for the neurostimulation by the ultrasound. Approach We derive the direct analytical relationship between the mechanical deformations in the tissue and the electric boundary conditions for the cable theory equations and solve them for two types of neuronal axon models: Hodgkin-Huxley and C-fibre. We detect the activation thresholds for a variety of ultrasound stimulation cases including continuous and pulsed ultrasound and estimate the mechanical deformations required for reaching the thresholds and generating action potentials. Main results We note that the proposed mechanism strongly depends on the mechanical properties of the neural tissues, which at the moment cannot be located in literature with the required certainty. We conclude that given certain common linear assumptions, this mechanism alone cannot cause significant effects and be responsible for neurostimulation. However, we also conclude that if the lower estimation of mechanical properties of neural tissues in literature is true, or if the normal cavitation occurs during the ultrasound stimulation, the proposed mechanism can be a prime cause for the generation of action potentials. Significance The approach allows prediction and modelling of most observed experimental effects, including the probabilistic ones, without the need for any extra physical effects or additional parameters

ОСОБЕННОСТИ ИСПОЛЬЗОВАНИЯ ДИСТАНЦИОННЫХ ОБРАЗОВАТЕЛЬНЫХ ТЕХНОЛОГИЙ ПРИ РЕАЛИЗАЦИИ ПРОГРАММ ДОПОЛНИТЕЛЬНОГО ПРОФЕССИОНАЛЬНОГО ОБРАЗОВАНИЯ

The article deals with the Russian universities and main objectives and tasks connected with distance educational technologies and e-learning in supplementary vocational programs.When implementing the program of further training it is necessary to take into account that students are already employed and work according to their profession. The educational process is carried out on the work-based basis. Due to this fact, the educational process meets additional requirements. These are training and methodological support of the students’ independent work, remote access to teaching materials that should be convenient for students, remote online and offline consulting and experienced professionals for conducting lessons. Application of distance learning technologies must be combined with the organization of workshops on the basis of the modern equipment and facilities.Following these factors, the educational process in RSACU is organized as a team work and individual work. The entire training period is divided into two parts: the period of self-study and laboratory exams (LES).Students’ independent work is controlled by means of LMS Moodle. It includes learning, posted training materials, controls, learning outcomes, as well as the interaction between the participants of the educational process. Distance learning is conducted on the individual basis. In addition to the resources of distance learning, the Russian State Agrarian Correspondence University created Interuniversity electronic library system (EBS) “AgriLib”, by combining teaching resources Agrotechnological profile of agricultural universities.В работе приведены основные цели и задачи, стоящие перед российскими вузами, связанные с использованием дистанционных образовательных технологий и электронного обучения при реализации дополнительных образовательных программ. При реализации программдополнительногопрофессионального образования необходимо учитывать, что, как правило, обучающиеся уже трудоустроены, работают по специальности. Образовательный процесс реализуется без отрыва (с минимальным отрывом) от производства.Как следствие, к образовательному процессу предъявляется ряд дополнительных требований, таких как необходимость разработки учебно-методического обеспечения самостоятельной работы слушателей, организации удаленного (дистанционного) доступа к учебно-методическим ресурсам в удобное для обучающегося время, организация удаленного консультирования в режимах онлайн и офлайн, привлечение к ведению занятий ведущих специалистов-практиков. При этом использование дистанционных образовательных технологийнеобходимо сочетать с организацией практических занятий на основе современного действующего оборудования, оснащения.С учетом указанных факторов учебный процесс в РГАЗУ организован с использованием как групповых, так и индивидуальных режимов работы, и реализуется следующим образом. Весь период обучения разделен на две части - период самостоятельного обучения и лабораторно-экзаменационная сессия (ЛЭС).Самостоятельная работа студентов управляется средствами СДО, реализованной на базе Moodle. В ней задается траектория обучения, размещаются учебно-методические материалы, средства контроля результатов обучения, а также происходит взаимодействие между участниками учебного процесса. Работа в системе дистанционного обучения проводится в индивидуальном режиме. В дополнение к ресурсам системы дистанционного обучения (СДО) в Российском государственном аграрном заочном университете создана межвузовская электронно-библиотечная система (ЭБС) AgriLibпутем объединения учебно-методических ресурсов агротехнологического профиля аграрных вузов

The Polycentric State: New Spaces of Empowerment and Engagement?

New Labour claims to have radically reformed territorial governance structures in the UK by devolving political power to the Celtic nations and London, begetting the most enduring legacy of the first Blair government. More recently it has sought to extend its devolution agenda by embracing city-regionalism and the new localism, ostensibly to create new spaces of empowerment and engagement. But devolution is not the whole story of New Labour’s attitude to power. On the contrary, this article argues that New Labour is a modern Janus because its commitment to devolving power, so clear in principle, is more equivocal in practice. Drawing on these three devolution narratives, the article concludes by assessing the implications for the current debate about relational versus territorial readings of place politics

IMMUNOBIOLOGY OF ACUTE GRAFT-VERSUS-HOST DISEASE

Transplantation of allogeneic hematopoietic stem cells is the only curative option for a number of diseases of hematopoietic system. It is intended to replace the hematopoietic system of the recipient withthe donor’s. However, when mature T cells contained in the graft enter the recipient organism, it may lead to a severe post-transplant complication, the “graft versus host” disease (GVHD). It occurs due to the fact that the donor immune system contains T cell clones specific to recipient alloantigens. These cell clones are activated upon encountering their antigens, thus causing systemic damage to healthy tissues. Development of the alloreactive clones is caused by genetic differences between donor and recipient. The most importantfactors determining successful transplantation concern the compatibility for the genes coding for Major Histocompatibility Complex (MHC), that are expressed in all nucleated cells and are responsible for antigen presentation to the immune cells. Currently established extensive donor banks allow for majority of patients to choose a compatible donor. However, this does not provide complete prevention of the GVHD development, because in addition to the MHC genes the donor and recipient may differ in so-called minor histocompatibility antigens. Minor antigens may be caused by genetic polymorphisms in all of the genome coding regions. Pre-transplantation conditioning of the patient, which is necessary for engraftment represent an additional factor contributing to the GVHDdevelopment, since as its side effect it leads to formation of a pro-inflammatory environment in the organism of recipient. Severe GVHD develops in approximately 40% of MHC-matched patients, while in cases of partial compatibility this proportion is even higher. GVHD causes mortality comparable to other causes of posttransplantdeath, such as viral infections or relapse of underlying disease. Thus, the development of severe GVHD is a significant limitation for clinical applications of stem cell transplantation. Severe immunesuppression or depletion of mature donor T cells from the transplant leads to increased probability of relapse and weakens anti-infectious immunity. Hence, further search for alternative, more specific ways to prevent GVHD is required. This review will focus on the mechanisms of alloreactive T lymphocyte clone development and key pathogenetic stages of acute “graft versus host” disease

Inhibition of nicotinic acetylcholine receptors, a novel facet in the pleiotropic activities of snake venom phospholipases A2.

Phospholipases A2 represent the most abundant family of snake venom proteins. They manifest an array of biological activities, which is constantly expanding. We have recently shown that a protein bitanarin, isolated from the venom of the puff adder Bitis arietans and possessing high phospholipolytic activity, interacts with different types of nicotinic acetylcholine receptors and with the acetylcholine-binding protein. To check if this property is characteristic to all venom phospholipases A2, we have studied the capability of these enzymes from other snakes to block the responses of Lymnaea stagnalis neurons to acetylcholine or cytisine and to inhibit α-bungarotoxin binding to nicotinic acetylcholine receptors and acetylcholine-binding proteins. Here we present the evidence that phospholipases A2 from venoms of vipers Vipera ursinii and V. nikolskii, cobra Naja kaouthia, and krait Bungarus fasciatus from different snake families suppress the acetylcholine- or cytisine-elicited currents in L. stagnalis neurons and compete with α-bungarotoxin for binding to muscle- and neuronal α7-types of nicotinic acetylcholine receptor, as well as to acetylcholine-binding proteins. As the phospholipase A2 content in venoms is quite high, under some conditions the activity found may contribute to the deleterious venom effects. The results obtained suggest that the ability to interact with nicotinic acetylcholine receptors may be a general property of snake venom phospholipases A2, which add a new target to the numerous activities of these enzymes

A Split-Marker System for CRISPR-Cas9 Genome Editing in Methylotrophic Yeasts

Methylotrophic yeasts such as Ogataea polymorpha and Komagataella phaffii (sin. Hansenula polymorpha and Pichia pastoris, respectively) are commonly used in basic research and biotechnological applications, frequently those requiring genome modifications. However, the CRISPR-Cas9 genome editing approaches reported for these species so far are relatively complex and laborious. In this work we present an improved plasmid vector set for CRISPR-Cas9 genome editing in methylotrophic yeasts. This includes a plasmid encoding Cas9 with a nuclear localization signal and plasmids with a scaffold for the single guide RNA (sgRNA). Construction of a sgRNA gene for a particular target sequence requires only the insertion of a 24 bp oligonucleotide duplex into the scaffold. Prior to yeast transformation, each plasmid is cleaved at two sites, one of which is located within the selectable marker, so that the functional marker can be restored only via recombination of the Cas9-containing fragment with the sgRNA gene-containing fragment. This recombination leads to the formation of an autonomously replicating plasmid, which can be lost from yeast clones after acquisition of the required genome modification. The vector set allows the use of G418-resistance and LEU2 auxotrophic selectable markers. The functionality of this setup has been demonstrated in O. polymorpha, O. parapolymorpha, O. haglerorum and Komagataella phaffii