Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia

Human iPSC lines represent a powerful translational model of tauopathies. We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the MAPT 10+16 splice-site mutation. This mutation leads to the increased splicing of 4R tau isoforms. However, the role of different isoforms of tau protein in initiating neuronal dementia-related dysfunction, and the causality between the MAPT 10+16 mutation and altered neuronal activity have remained unclear. Here, we employed genetically engineered cells, in which the IVS10+16 mutation was introduced into healthy donor iPSCs to increase the expression of 4R tau isoform in exon 10, aiming to explore key physiological traits of iPSC-derived MAPT IVS10+16 neurons using patch-clamp electrophysiology and multiphoton fluorescent imaging techniques. We found that during late in vitro neurogenesis (from ~180 to 230 days) iPSC-derived cortical neurons of the control group (parental wild-type tau) exhibited membrane properties compatible with "mature" neurons. In contrast, MAPT IVS10+16 neurons displayed impaired excitability, as reflected by a depolarized resting membrane potential, an increased input resistance, and reduced voltage-gated Na+- and K+-channel-mediated currents. The mutation changed the channel properties of fast-inactivating Nav and decreased the Nav1.6 protein level. MAPT IVS10+16 neurons exhibited reduced firing accompanied by a changed action potential waveform and severely disturbed intracellular Ca2+ dynamics, both in the soma and dendrites, upon neuronal depolarization. These results unveil a causal link between the MAPT 10+16 mutation, hence overproduction of 4R tau, and a dysfunction of human cells, identifying a biophysical basis of changed neuronal activity in 4R tau-triggered dementia. Our study lends further support to using iPSC lines as a suitable platform for modelling tau-induced human neuropathology in vitro

Study successful development programming courses of the first-year students

The paper addresses the issue of training of students of IT-specialty and the impact on the success of training factors such as the results of the Unified State Exam, professional motivation and social and psychological adaptation of the first-year studentsВ работе рассматривается вопрос об обучении программированию студентов ИТ-специальности и влиянии на успешность обучения таких факторов как результаты Единого Государственного Экзамена, профессиональной мотивации и социально-психологической адаптации студентов-первокурснико

The String Theory Approach to Generalized 2D Yang-Mills Theory

We calculate the partition function of the $SU(N)$ ( and $U(N)$) generalized $YM_2$ theory defined on an arbitrary Riemann surface. The result which is expressed as a sum over irreducible representations generalizes the Rusakov formula for ordinary YM_2 theory. A diagrammatic expansion of the formula enables us to derive a Gross-Taylor like stringy description of the model. A sum of 2D string maps is shown to reproduce the gauge theory results. Maps with branch points of degree higher than one, as well as ``microscopic surfaces'' play an important role in the sum. We discuss the underlying string theory.Comment: TAUP-2182-94, 53 pages of LaTeX and 5 uuencoded eps figure

Non-Douglas-Kazakov phase transition of two-dimensional generalized Yang-Mills theories

In two-dimensional Yang-Mills and generalized Yang-Mills theories for large gauge groups, there is a dominant representation determining the thermodynamic limit of the system. This representation is characterized by a density the value of which should everywhere be between zero and one. This density itself is determined through a saddle-point analysis. For some values of the parameter space, this density exceeds one in some places. So one should modify it to obtain an acceptable density. This leads to the well-known Douglas-Kazakov phase transition. In generalized Yang-Mills theories, there are also regions in the parameter space where somewhere this density becomes negative. Here too, one should modify the density so that it remains nonnegative. This leads to another phase transition, different from the Douglas-Kazakov one. Here the general structure of this phase transition is studied, and it is shown that the order of this transition is typically three. Using carefully-chosen parameters, however, it is possible to construct models with phase-transition orders not equal to three. A class of these non-typical models are also studied.Comment: 11 pages, accepted for publication in Eur. Phys. J.

Summing Over Inequivalent Maps in the String Theory Interpretation of Two Dimensional QCD

Following some recent work by Gross, we consider the partition function for QCD on a two dimensional torus and study its stringiness. We present strong evidence that the free energy corresponds to a sum over branched surfaces with small handles mapped into the target space. The sum is modded out by all diffeomorphisms on the world-sheet. This leaves a sum over disconnected classes of maps. We prove that the free energy gives a consistent result for all smooth maps of the torus into the torus which cover the target space $p$ times, where $p$ is prime, and conjecture that this is true for all coverings. Each class can also contain integrations over the positions of branch points and small handles which act as ``moduli'' on the surface. We show that the free energy is consistent for any number of handles and that the first few leading terms are consistent with contributions from maps with branch points.Comment: 17 pages, 5 eps figures contained in a uuencoded file, UVA-HET-92-1

Effective gauge theories on domain walls via bulk confinement?

We study with lattice techniques the localisation of gauge fields on domain wall defects in 2+1 dimensions, following a scenario originally proposed by Dvali and Shifman for 3+1 dimensions, based on confining dynamics in the bulk. We find that a localised gauge zero-mode does exist, if the domain wall is wide enough compared with the confinement scale in the bulk. The range of applicability of the corresponding low-energy effective theory is determined by the mass gap to the higher modes. For a wide domain wall, this mass gap is set by ``Kaluza--Klein modes'' as determined by the width. It is pointed out that in this regime the dynamical energy scales generated by the interactions of the localised zero-modes are in fact higher than the mass gap. Therefore, at least in 2+1 dimensions, the zero-modes alone do not form a low-energy effective gauge theory of a traditional type. Finally, we discuss how the situation is expected to change in going to 3+1 dimensions.Comment: 24 pages. v2: published versio

A Posteriori Assessment of the Labor Intensity of Training Tasks Within the Scoring System

В работе описывается методика оценки трудоёмкости (сложности) учебных заданий на основе статистического анализа результатов, показанных учебной группой в предыдущем учебном цикле и зафиксированных в рамках модульной балльно-рейтинговой системы. В качестве меры трудоемкости задания служит средний балл набранный за его выполнение всей учебной группой. Производится сравнение средних баллов для всех учебных заданий в рамках конкретной дисциплины, позволяющее выделить из них более сложные или наоборот, вызвавшие наименьшие затруднения у студентов. В качестве примера рассматриваются результаты освоения конкретной учебной дисциплины.The paper describes a methodology for assessing the labor intensity (complexity) of training tasks based on a statistical analysis of the results shown by the training group in the previous training cycle and recorded within the framework of a modular scoring system. As a measure of the complexity of the task, the average score scored for it by the group is used. Comparison of average scores for all educational tasks within a particular discipline is made, which allows to single out more complex ones from them or vice versa, which caused the least difficulties for students. As an example, the results of mastering a specific academic discipline are considered

Planning of Time Costs of Students’s Educational Activities Within the Framework of the Score-Rating System

The paper describes a methodology for assessing the planned labor costs of students when assessing their current knowledge using a pointrating system. This takes into account that each academic discipline is divided into modules, assessed separately. The real educational process of the Perm State National Research University is considered as an example.Описана методика оценивания планируемых трудозатрат студентов при оценке их текущих знаний с помощью балльно-рейтинговой системы с учетом того, что каждая учебная дисциплина делится на модули, оцениваемые отдельно. В качестве примера рассмотрен реальный учебный процесс Пермского государственного национального исследовательского университета

The H1 Forward Proton Spectrometer at HERA

The forward proton spectrometer is part of the H1 detector at the HERA collider. Protons with energies above 500 GeV and polar angles below 1 mrad can be detected by this spectrometer. The main detector components are scintillating fiber detectors read out by position-sensitive photo-multipliers. These detectors are housed in so-called Roman Pots which allow them to be moved close to the circulating proton beam. Four Roman Pot stations are located at distances between 60 m and 90 m from the interaction point.Comment: 20 pages, 10 figures, submitted to Nucl.Instr.and Method

Serotonin 5-HT4 receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin

Activity-dependent remodeling of excitatory connections underpins memory formation in the brain. Serotonin receptors are known to contribute to such remodeling, yet the underlying molecular machinery remains poorly understood. Here, we employ high-resolution time-lapse FRET imaging in neuroblastoma cells and neuronal dendrites to establish that activation of serotonin receptor 5-HT4 (5-HT4R) rapidly triggers spatially-restricted RhoA activity and G13-mediated phosphorylation of cofilin, thus locally boosting the filamentous actin fraction. In neuroblastoma cells, this leads to cell rounding and neurite retraction. In hippocampal neurons in situ, 5-HT4R-mediated RhoA activation triggers maturation of dendritic spines. This is paralleled by RhoA-dependent, transient alterations in cell excitability, as reflected by increased spontaneous synaptic activity, apparent shunting of evoked synaptic responses, and enhanced long-term potentiation of excitatory transmission. The 5-HT4R/G13/RhoA signaling thus emerges as a previously unrecognized molecular pathway underpinning use-dependent functional remodeling of excitatory synaptic connections