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Mitotic spindle assembly during cell division is a highly regulated process. Ran-GTP produced around chromosomes controls the activity of a multitude of spindle assembly factors by releasing them from inhibitory interaction with importins. A major consequence of Ran-GTP regulation is the stimulation of local microtubule nucleation around chromosomes via augmin/HAUS-mediated branched microtubule nucleation, a process that is critically important for correct spindle assembly. However, augmin is not known to be a direct target of the Ran-GTP pathway, raising the question of how its activity is controlled. Here we present thein vitroreconstitution of Ran-GTP-regulated microtubule binding of the human HAUS complex. We demonstrate that importins directly bind to the HAUS complex, which prevents HAUS from binding to microtubules. Ran-GTP relieves this inhibition. Therefore, the HAUS complex is a direct target of the Ran-GTP pathway, suggesting that branching microtubule nucleation is directly regulated by the Ran-GTP gradient around chromosomes in dividing cells.

The FEBS journal 290(3), 821 - 836 (2022). doi:10.1111/febs.16616, Human histone deacetylase 6 (HDAC6) is a structurally unique, multido-main protein implicated in a variety of physiological processes includingcytoskeletal remodelling and the maintenance of cellular homeostasis. Ourcurrent understanding of the HDAC6 structure is limited to isolateddomains, and a holistic picture of the full-length protein structure, includ-ing possible domain interactions, is missing. Here, we used an integrativestructural biology approach to build a solution model of HDAC6 by com-bining experimental data from several orthogonal biophysical techniquescomplemented by molecular modelling. We show that HDAC6 is bestdescribed as a mosaic of folded and intrinsically disordered domains thatin-solution adopts an ensemble of conformations without any stable inter-actions between structured domains. Furthermore, HDAC6 forms dimers/higher oligomers in a concentration-dependent manner, and its oligomer-ization is mediated via the positively charged N-terminal microtubule-binding domain. Our findings provide the first insights into the structure offull-length human HDAC6 and can be used as a basis for further researchinto structure function and physiological studies of this unique deacetylase., Published by Wiley-Blackwell, Oxford [u.a.]

Socio-economic changes are accompanied by the growing complexity of labor and transformation of its content in the direction of innovative and creative aspects. The spread of such labor makes it necessary to search for new approaches to motivate employees to use their labor and creative potential effectively. Our study considers new forms of non-financial incentives such as taking part in participatory governance, creating management systems designed to ensure the involvement of talented and creative employees in innovation projects and promotion of their career advancement. The goal of our research is to study the impact of traditional (fair pay, good working conditions, etc.) and modern (creative approach, participation of employees in corporate management, etc.) motivation factors on the quality of labor potential and parameters of its implementation (in particular, productivity and wages). The novelty of our study consists in the fact that it tests methodological aspects that characterize the quality of labor potential and individual parameters of its implementation in the population groups that differ in their degree of satisfaction with motivation factors, taking into account the degree of their relevance. The difference between the approach we apply and the existing ones is that in our case it is not only possible to overcome the problem of judgment motives as objectified social facts, but also to justify a thesis according to which the role of modern motivation factors in the work of the population is underestimated. In particular, the latter is due to the fact that the results of the analysis have shown that the low importance of modern motivation factors is associated with a higher quality of labor potential, productivity and wages, while the high importance of traditional motivation factors can often lead to opposite results. Methodological provisions regarding the assessment of specific aspects of labor activity and daily life of the population concerning their satisfaction with them and their importance can be used as a tool to analyze the existing or emerging motivation systems at the organizational level

Histone deacetylase 6 (HDAC6) is a promising therapeutic target for the treatment of neurodegenerative disorders. SW-100 (1a), a phenylhydroxamate-based HDAC6 inhibitor (HDAC6i) bearing a tetrahydroquinoline (THQ) capping group, is a highly potent and selective HDAC6i that was shown to be effective in mouse models of Fragile X syndrome and Charcot-Marie-Tooth disease type 2A (CMT2A). In this study, we report the discovery of a new THQ-capped HDAC6i, termed SW-101 (1s), that possesses excellent HDAC6 potency and selectivity, together with markedly improved metabolic stability and druglike properties compared to SW-100 (1a). X-ray crystallography data reveal the molecular basis of HDAC6 inhibition by SW-101 (1s). Importantly, we demonstrate that SW-101 (1s) treatment elevates the impaired level of acetylated α-tubulin in the distal sciatic nerve, counteracts progressive motor dysfunction, and ameliorates neuropathic symptoms in a CMT2A mouse model bearing mutant MFN2. Taken together, these results bode well for the further development of SW-101 (1s) as a disease-modifying HDAC6i.

Based on the survey of the employed population of the Vologda oblast for 2016, a regression model was constructed that reflects the relationship between job satisfaction and the parameters characterizing job stability, fairness of labor remuneration in relation to labor contribution, and availability of additional guarantees. The research results indicate that the main factor affecting job satisfaction is the material factor.

The article raises the issues of motivation in the context of individual approaches (Freudian, behavioral, cognitive-psychological, etc.) in the framework of theoretical-personal and theoretical-associative fields. The goals of the article are as follows: to structure the main existing approaches to the study of motivation, and to determine the provisions that can be used in the framework of the motivation for people’s creative labor activity. The study used general logical methods and techniques, such as system approach, generalization, analysis, and synthesis. We conclude that the main source of people’s activity is need-based tension, and the aim is to eliminate it using external incentive factors. We show that the nature of behavior will be determined by the degree of consistency between different groups of motives, correlation of motives and external goals, and in the absence of such coordination – by volitional mechanisms of regulation. We point out that scientific literature contains no unambiguous definition of motivational-stimulating mechanism; the paper provides its interpretation from the standpoint of behavioral approach and A.N. Leontiev’s theory of subjectified motivation. We focus our attention on the fact that the development of motivational-stimulating mechanism should take into account the specific nature of activity. We provide motives of creative activity, among which we highlight the cognitive and communicative motives, achievements, etc. We prove that the system-wide management of creative labor activity can be achieved by creating a motivational and stimulating mechanism, which would take into account direct and indirect methods of management, both external and internal factors that contribute to and hinder the development of subjectivity and have a different nature. Having reviewed the relevant literature, we conclude that most of the methods to promote people’s creative labor activity are empirical and arise mainly outside the study of scientific problems of creativity. So far, studies focus on cognitive aspects that provide creative thinking and behavior, while motivational aspects and those focused on overcoming negative effects of external stimuli are not given due attention. Theoretical aspects of our study can be used to develop a system of measures aimed to promote creative activity and motivational-stimulating mechanism

The paper summarizes and systematizes theoretical and methodological approaches to the study of the concept of “mentality”. The authors review historical-philosophical, cultural-anthropological, psychological, ethnographic, socio-cultural and sociological, socio-economic and interdisciplinary approaches. Special attention is paid to the system approach that considers how mental characteristics are manifested. The paper presents the structural approach that focuses on individual continents of mentality and an approach to the study from the standpoint of the “level of the nature of mentality” (conceptual-semantic, values-and-target, and behavioral levels). The authors substantiate the necessity of using an interdisciplinary approach to the determination of mentality. This is due to the fact that this scientific category is widely used in different sciences (sociology, psychology, the humanities), which requires unified conceptual analytical methods. The authors reveal distinctive features according to which mentality can be classified; they include: 1) the level of analysis (individual, professional, social mentality); 2) territorial feature (urban/rural (provincial)); 3) the level of historical development (primitive/modern (civilized)). The following features are also highlighted as the criteria: the nature of manifestation (preliterate, literate and media-mentality); the degree of relationship to the world (sensuous/ideational); focus on the structural elements of mentality: on psychological characteristics (conscious/unconscious), normative characteristics, etc. It is shown that when mentality is considered through the prism of various traditions (research schools), then the attention is focused on its various components: thinking (American school), historical traditions (German school), sensuous component, social aspects of interaction between people (French school). The authors reveal the relation between mentality and the resulting behavior of people. This relationship can be characterized in terms of “whole–part” and “object–manifestation of the object”. In the former case there are “behavioral components” of mentality such as: 1) consumption patterns (prestige, demonstrative behavior, on the one hand, or the psychology of the subsistence minimum on the other); 2) the norms of interaction between economic entities (equality/inequality in the interaction); 3) generally accepted stereotypes of relations between society and the individual (self-sufficiency or collective nature of dealing with problems)

Histone deacetylase 6 (HDAC6) is a multidomain cytosolic enzyme having tubulin deacetylase activity that has been unequivocally assigned to the second of the tandem catalytic domains. However, virtually no information exists on the contribution of other HDAC6 domains on tubulin recognition. Here, using recombinant protein expression, site-directed mutagenesis, fluorimetric and biochemical assays, microscale thermophoresis, and total internal reflection fluorescence microscopy, we identified the N-terminal, disordered region of HDAC6 as a microtubule-binding domain and functionally characterized it to the single-molecule level. We show that the microtubule-binding motif spans two positively charged patches comprising residues Lys-32 to Lys-58. We found that HDAC6-microtubule interactions are entirely independent of the catalytic domains and are mediated by ionic interactions with the negatively charged microtubule surface. Importantly, a crosstalk between the microtubule-binding domain and the deacetylase domain was critical for recognition and efficient deacetylation of free tubulin dimers both in vitro and in vivo. Overall, our results reveal that recognition of substrates by HDAC6 is more complex than previously appreciated and that domains outside the tandem catalytic core are essential for proficient substrate deacetylation.

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

The article deals with the sociological assessment of the skills level and identification of its influence on some aspects of labour activity: the realization of labour potential, choice of the scope of activity, position and occupation. It suggests an approach based on the subjective evaluation of the population as an instrument of the skills level assessment. The received results are compared with the indirect estimates allowing to characterize some particular components of labour potential which are similar to the considered skills. A specific feature of the research is not only the determination of the professional sphere, occupation and position on the skills level, but also the accounting of the reverse effect. The methodological tools including the methods for the assessment of skills level, labour potential and extent of its implementation in a labour activity have been approved in the Vologda region. The study revealed that, at the present time, the most developed skills are the teamwork, communication and mutual understanding while the least developed ones are the initiative and creativity as well as ability to be retrained and readiness to increase the professional level. It shows that the employees of socially oriented spheres and also the representatives of state structures have more developed skills. At the same time, the development of innovative skills not only leads to the growth of labour potential, but also creates conditions for the employment in workplaces with higher skills requirements. The paper shows that higher skills level along with higher skills requirements leads to more complete implementation of cumulative potential in the labour activity. The received results can be used by regional authorities for the development of the analytical system of labour market, the development of labour force and the labour potential of the population.

Human histone deacetylase 6 (HDAC6) is the major deacetylase responsible for removing the acetyl group from Lys40 of α-tubulin (αK40), which is located lumenally in polymerized microtubules. Here, we provide a detailed kinetic analysis of tubulin deacetylation and HDAC6/microtubule interactions using individual purified components. Our data unequivocally show that free tubulin dimers represent the preferred HDAC6 substrate, with a K M value of 0.23 µM and a deacetylation rate over 1,500-fold higher than that of assembled microtubules. We attribute the lower deacetylation rate of microtubules to both longitudinal and lateral lattice interactions within tubulin polymers. Using TIRF microscopy, we directly visualized stochastic binding of HDAC6 to assembled microtubules without any detectable preferential binding to microtubule tips. Likewise, indirect immunofluorescence microscopy revealed that microtubule deacetylation by HDAC6 is carried out stochastically along the whole microtubule length, rather than from the open extremities. Our data thus complement prior studies on tubulin acetylation and further strengthen the rationale for the correlation between tubulin acetylation and microtubule age.

This paper presents various approaches to the definition of the innovative activity of the population based on the results of a study performed by the Institute of Socioeconomic Development of Territories, Russian Academy of Sciences, in Vologda oblast in November 2012 by using econometric methods (probit models) for the assessment of the population’s creativity in relation to various social, demographic, and economic characteristics of respondents.

Professional education is the main part of personnel training and it serves as the driver of modernization process. “Knowledge workers” are carriers of knowledge provided by the professional training system. Professional activity of “knowledge workers” is strategically important in the economy under transformation. The paper reviews domestic and foreign experience and defines criteria for identifying people as “knowledge workers”: educational level, employment in “intellectually demanding” industries. The study identifies specific characteristics of “knowledge workers”, represents their typological classification depending on their employment affiliation (professional managers, new workers, certified technicians, scientists, innovator specialists). The paper focuses on determining the level of implementation of employment potential of qualified specialists in the context of economic modernization. The authors define the dependence of the level of regions’ modernization on the employment of workers that have vocational education. At the same time, the paper points out that the modernization of the territory is influenced not so much by the training of “knowledge workers” as the fulfilment of their potential in the labor market. This thesis is confirmed by the results of correlation analysis, which evidence the lack of direct connection between the number of college and university students and the level of modernization. From the position of effective implementation of the potential accumulated, the study shows the importance of integrating the graduates of educational organizations into the labor market in accordance with the specialty they obtained. The paper also identifies problems that hamper job placement within the specialty obtained. The study shows that the slowdown in modernization processes is due mainly to the economic and cognitive aspects. In particular, the imbalances in the components of the secondary modernization index stem from an insufficient number of scientists and engineers, people who file patent applications, and from the small amount of allocations to research and development in GRP. The paper reveals that one of the ways to improve human capital is to increase innovative activity of the youth; the authors substantiate the thesis about the direct positive impact of the development of competencies on participation in research and scientific developments. The results of the study can be used to work out strategic plans for the development of innovation industries and social entrepreneurship in Russia’s regions