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Modern conditions of public administration are formed in the BANI world (Grabmeier, 2020), unstable, disturbing, uniquely technological and digital. How many of today's civil servants are capable of functioning in such a world through current training and professional development systems? This issue is particularly relevant for post-Soviet countries, as most of them belong to emerging economies that are still shaping their own unique public administration system. The article is aimed at studying the practice of professional development of civil servants within the framework of additional education in post-Soviet countries in the context of digitalisation. According to the study, it is clear that the Soviet model of supplementary education for civil servants is still valid, with minor differences in the countries studied. This model is characterised by a centralised organisation of training of civil servants within the framework of specially created structures (public service academies). With the transition to digital learning, countries are differentiated by the pace and level of transition to distance and e-learning for public servants.

William Sage,1 Rocío Fernández-Méndez,1 Anna Crofton,2 Michael J Gifford,3 Alexey Bannykh,3 Constantinos Chrysaphinis,4 Emma Tingley,4 Helen Bulbeck,5 Mita Brahmbhatt,1 John D Pickard,1 Fiona M Walter,6 Andrew Brodbelt,2 Stephen J Price,1 Alexis J Joannides1 1Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; 2Department of Neurosurgery, The Walton Centre, Liverpool, UK; 3Mountain Hare Consulting, London, UK; 4The Brain Tumour Charity, Farnborough, UK; 5Brainstrust, Cowes, Isle of Wight, UK; 6Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK Objective: The aim of this study was to determine the experience of patients with brain tumors and their carers across distinct parts of their treatment pathway and identify their views on potential service gaps in need of addressing.Methods: A structured survey was administered at patient workshops across the UK and online through a charity newsletter. Answers to closed questions were analyzed using descriptive statistics, and open questions were examined using techniques of inductive content analysis.Results: A total of 136 survey responses were received, representing patients with a variety of diagnoses and geographical locations (30 counties). There was a wide range of opinions on the provision of current neuro-oncology services. Key themes identified included a perceived lack of information provision, a gap in postdischarge psychological and neuropsychological supports, and an unmet willingness for involvement in research.Conclusion: This national survey enhances our knowledge of current patient and carer experience within neuro-oncology services. A number of areas of unmet clinical need are highlighted providing a basis for informing future patient-centered service improvements and research. Keywords: patient experience, brain cancer, brain tumors, neuro-oncology pathway

Digital transformation as a natural stage in the development of any organization in the context of new socio-economic conditions requires the development of general models for the course of this process, as well as systems for assessing the achievement of the main indicators of digital development. In the Russian Federation the President and the Government have set the goal of achieving "digital maturity" for the higher education system as a priority area in the "Strategy for the digital transformation of the science and higher education industry". Today, many Russian universities are already developing digital transformation programs, and this requires an analysis of the current situation, understanding and ranking problems, as well as constructing and forecasting possible risks and effects.The purpose of the research is to analyze foreign and domestic theoretical sources that reveal the concept, models and methods for assessing the "digital maturity" of higher education organizations. Qualitative method of document analysis has been used as a research method.The results. The terminology in the context of researching the "digital maturity" of a university is actively developing. In relation to the concept, different approaches have been formed: biological, psychological, process, the category is comprehended both as a result and as a prerequisite for the digital transformation of universities. In the Russian Federation there is also a normative definition that determines the strategic priorities of the digital development of the higher education system. At the moment, the concept has been tested on several models for assessing the digital maturity of foreign and domestic universities, but the results also do not allow us to speak about the formed concept of this phenomenon.

Heterotrimeric extracellular matrix proteins laminins are mostly deposited at basal membranes and are important in repair and neoplasia. Here, we localize laminin beta 2 (LAMB2) at the sites of blood–brain barrier (BBB). Microvasculature (MV) of normal brain is endowed with complete LAMB2 coverage. In contrast, its cognate protein laminin beta 1 (LAMB1) is absent in MV of normal brain but emerges at the sprouting tip of a growing vessels. Similarly, vascular proliferation in high-grade gliomas (HGG) is accompanied by marked overexpression of LAMB1, whereas LAMB2 shows deficient deposition. We find that many brain pathologies with presence of post-gadolinium enhancement (PGE) on magnetic resonance imaging (MRI) show disruption of LAMB2 vascular ensheathment. Inhibition of vascular endothelial growth factor signaling in HGG blocks angiogenesis, suppresses PGE in HGG, prevents expression of LAMB1, and restores LAMB2 vascular coverage. Analysis of single-cell RNA sequencing (scRNA-seq) databases shows that in quiescent brain LAMB2 is predominantly expressed by BBB-associated pericytes (PCs) and endothelial cells (ECs), whereas neither cell types produce LAMB1. In contrast, in HGG, both LAMB1 and 2 are overexpressed by endothelial precursor cells, a phenotypically unique immature group, specific to proliferating hyperplastic MV. [ABSTRACT FROM AUTHOR]

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.

Introduction. The modern period of development of higher education is directly related to the ongoing digital transformation of public relations. The changes that occur in universities, in their external interactions and functions, basic principles and value-normative foundations, require methodological analysis and research.Aim. The aim of the research is to analyse the theoretical approaches to disclosing the concept and essence of digital universities.Methodology and research methods. The mix-method was used as a research design: qualitative analysis (studying the content of theoretical sources and context, analysing the content of a concept) and quantitative analysis (scientometric analysis of publications and keywords in databases).Results. The study showed that in the methodological terms, there is a problem of defining the concept of “digital university”: there are several theoretical approaches based on different understanding of the phenomenon and its role in the digital development of the university. The methodological problem is complicated by the urgent need to systematise the practical activities of modern universities, which classify themselves in one way or another in the “digital” format; therefore, this is much more difficult to do without a coordinated approach to the concept itself.Scientific novelty lies in an attempt to systematise theoretical approaches to defining the concept of “digital university” and the problem of the absence of a holistic interdisciplinary approach has been identified.Practical significance of the study is associated with the need to develop a regulatory model of a digital university based on a holistic concept for the subsequent analysis of the activities of universities. The results of the analysis can be used in scientific discussion to further define the concept of “digital university” and develop a general model of a digital university.

Glioblastoma (GBM) is the most common malignant brain tumor. Less than 1% of patients survive longer than 10 years. A 77-year-old woman was diagnosed with MGMT-methylated GBM in 2009. The patient received cilengitide as part of the CENTRIC clinical trial in conjunction with standard radiation and chemotherapy. Though the study was halted in 2013, our patient received cilengitide until 2016 with no radiographic evidence of recurrence thus far. This is the oldest reported GBM patient with greater than 10-year survival. Her exceptional response may have been influenced by MGMT promoter methylation status and PTEN expression.

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.

In situ transgenesis methods such as viruses and electroporation can rapidly create somatic transgenic mice but lack control over copy number, zygosity, and locus specificity. Here we establish mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. We provide a toolkit of MADR elements for combination labeling, inducible and reversible transgene manipulation, VCre recombinase expression, and transgenesis of human cells. Further, we demonstrate the versatility of MADR by creating glioma models with mixed reporter-identified zygosity or with "personalized" driver mutations from pediatric glioma. MADR is extensible to thousands of existing mouse lines, providing a flexible platform to democratize the generation of somatic mosaic mice. VIDEO ABSTRACT.

There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix, including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers, including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. We also showed that depletion of laminin-411 α4 and β1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice and significantly increased survival of host animals compared with mice with untreated cells. Inhibition of laminin-411 suppressed Notch pathway in normal and malignant human brain cell types. A nanobioconjugate potentially suitable for clinical use and capable of crossing blood-brain barrier was designed to block laminin-411 expression. Nanobioconjugate treatment of mice carrying intracranial GBM significantly increased animal survival and inhibited multiple CSC markers, including the Notch axis. This study describes an efficient strategy for GBM treatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma.Significance: Laminin-411 expression in the glioma microenvironment correlates with Notch and other cancer stem cell markers and can be targeted by a novel, clinically translatable nanobioconjugate to inhibit glioma growth.

Astroblastoma is a rare and controversial glioma with variable clinical behavior. The diagnosis currently rests on histologic findings of a circumscribed glioma with astroblastomatous pseudorosettes and vascular hyalinization. Immunohistochemical studies have suggested different oncogenic drivers, such as BRAF p.V600E, but very few cases have been studied using genome-wide methodologies. Recent genomic profiling identified a subset of CNS embryonal tumors with astroblastoma-like morphology that harbored MN1 gene fusions, termed "CNS high-grade neuroepithelial tumors with MN1 alteration" (CNS-HGNET-MN1). To further characterize the genetic alterations that drive astroblastomas, we performed targeted next-generation sequencing (NGS) of 500 cancer-associated genes in a series of eight cases. We correlated these findings with break-apart fluorescence in situ hybridization (FISH) analysis of the MN1 locus and genome-wide DNA methylation profiling. Four cases showed MN1 alteration by FISH, including two pediatric cases that lacked other pathogenic alterations, and two adult cases that harbored other cancer-associated gene mutations or copy number alterations (eg, CDKN2A/B homozygous deletion, TP53, ATM and TERT promoter mutations). Three of these cases grouped with the CNS-HGNET-MN1 entity by methylation profiling. Two of four MN1 intact cases by FISH showed genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH-wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS and TERT promoter mutations) and these cases had an aggressive clinical course. Two clinically indolent cases remained unclassifiable despite multimodal molecular analysis. We conclude that astroblastoma histology is not specific for any entity including CNS-HGNET-MN1, and that additional genetic characterization should be considered for astroblastomas, as a number of these tumors likely contain a methylation profile or genetic alterations that suggest classification as other tumor entities. Our heterogeneous molecular findings help to explain the clinical unpredictability of astroblastoma.

Background. The problem of parallel use of a set of statistical criteria aimed at testing one or another statistical hypothesis is considered. As a rule, on small samples of 16 experiments, statistical tests give a high value of the probabilities of errors of the first and second kind. Materials and methods. However, if we build an equivalent artificial neuron for each of the statistical criteria and combine them into a large network of artificial neurons, then we will get a long code with high redundancy. The reduction of the redundancy of such codes makes it possible to correct the errors of some statistical tests. The paper presents functional dependencies and thresholds used in the software implementation of 11 new criteria and artificial neurons equivalent to them. Several techniques for modifying classical statistical criteria are identified, which allow reducing the values of their probabilities of errors of the first and second kind by up to nine times. Results and conclusions. Presumably, the use of new statistical criteria can make it possible to make decisions with a confidence probability of 0,99 when using 25 artificial neurons equivalent to them.

Pyridoxal hydrochloride, a vitamin B6 vitamer, was synthetically converted to a series of diverse redox‐active benzoyl pyridinium salts. Cyclic voltammetry studies demonstrated redox reversibility under basic conditions, and two of the most promising salts were subjected to laboratory‐scale flow battery tests involving galvanostatic cycling at 10 mM in 0.1 M NaOH. In these tests, the battery was charged completely, corresponding to the transfer of two electrons to the electrolyte, but no discharge was observed. Both CV analysis and electrochemical simulations confirmed that the redox wave observed in the experimental voltammograms corresponds to a two‐electron process. To explain the irreversibility in the battery tests, we conducted bulk electrolysis with the benzoyl pyridinium salts, affording the corresponding benzylic secondary alcohols. Computational studies suggest that the reduction proceeds in three consecutive steps: first electron transfer (ET), then proton‐coupled electron transfer (PCET) and finally proton transfer (PT) to give the secondary alcohol. 1H NMR deuterium exchange studies indicated that the last PT step is not reversible in 0.1 M NaOH, rendering the entire redox process irreversible. The apparent reversibility observed in CV at the basic media likely arises from the slow rate of the PT step at the timescale of the measurement. [ABSTRACT FROM AUTHOR]

Background. The problem of parallel use of a set of statistical criteria aimed at testing one or another statistical hypothesis is considered. Materials and methods. As a rule, on small samples of 16 experiments, statistical tests give a high value of the probabilities of errors of the first and second kind. However, if we build an equivalent artificial neuron for each of the statistical criteria and combine them into a large network of artificial neurons, then we will get a long code with high redundancy. The reduction of the redundancy of such codes makes it possible to correct the errors of some statistical tests. Results. The paper presents functional dependencies and thresholds used in the software implementation of 9 basic criteria or artificial neurons equivalent to them. Conclusions. On the logarithmic scale of the probabilities of errors of the first and second kind for each criterion and on the logarithmic scale of the number of criteria generalized by the neural network, the self-correcting error correction code “by voting on the majority of bit states” is well described by a linear function.

The continuing fertility decline in Russia encourages the study of socio-economic factors influencing it as well as the relations between these factors. The contradicting results of international and Russian research do not allow unambiguous conclusions in this field. The paper aims to analyse the influence of socio-economic factors on the total fertility rate, as well as on fertility rates by birth order (first, second, third, and fourth with subsequent children). We hypothesise that the birth rate of the first and subsequent children is affected by various socio-economic factors. Using panel data econometric analysis, we examined the information on 85 constituent entities of the Russian Federation for the period from 2005 to 2017. We applied fifteen main and three additional explanatory variables (regressors), which reflect demographic, economic and social (infrastructural) factors of fertility. The analysis includes the development of models with fixed effects for the total fertility rate and fertility rates by birth order, and examination of the interdependence of certain factors. As a result of the analysis, we revealed the differences in the influence of individual variables on the dynamics of fertility rates for the first child and subsequent children. For example, the influence of real monetary income on the birth order rates is gradually decreasing, while the influence of the unemployment rate, reserves-to-production ratio, and marriage rate is multidirectional. Additionally, in some cases, we discovered a negative relationship between the birth rate and number of regressors (the number of abortions, the share of the urban and working-age population, the pre-school enrolment). The research results can be considered by public authorities when developing the state demographic and social policy at the federal and local levels.

Abstract The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.