Clustering as a component of economic institutional reforms (on the example of Siberian region)

The article gives the definition of the local cluster as a spatial and sectoral concentration of interconnected companies, the end product or service that is exported outside of the local territorial entity. The cluster approach of solving the problems of economic development of the Siberian region is reflected in the "Strategy of socio-economic development of Siberia till 2020". It summarizes the experience of formation of high-tech clusters in Siberia. Marked economic perspective directions of clustering region. Tomsk region is marked as a regional with a great innovative potential in forming clusters and other innovative structures. The basic problems in the way of implementation of the cluster approach and related institutional changes in the economy are identified

Functional characterization of the TP53 mutome using CRISPR/Cas9 saturating mutagenesis

TP53 is an essential tumor suppressor gene which is inactivated in every second tumor. Most frequently TP53 is disabled by missense mutations which result in the expression of a mutant p53 protein. Mutant p53 protein is unable to prevent uncontrolled proliferation and can additionally increase cancer growth by dominant negative and gain of function effects. Mutations in TP53 are frequently associated with aggressive tumor growth, chemotherapy resistance and shortened survival. Therefore, the TP53 gene status has important clinical implication. Moreover, information about TP53 mutations will be essential for application of emerging p53-targeted therapeutics: Mdm2 inhibitors and p53 reactivators. Eight most frequent hotspot mutations account for nearly 30% of all missense TP53 variants found in tumors and are extensively studied. Hotspot TP53 mutations lead to production of a transcriptionally inactive loss of function protein. The rest 70% of TP53-mutated tumors contain one of >2000 distinct mutant p53 variants, most of which are uncharacterized. Such a broad spectrum of mutants makes prediction of their impact on disease outcome a very challenging task. Therefore, for advancing personalized cancer treatment it would be of utmost importance to study how the hundreds of individual p53 mutations influence a therapy response. Functional characterization of hundreds of mutations in a gene of interest is a tall order task which requires time-consuming in vitro and in vivo experiments. Thus, an experimental approach for a massive parallel phenotypic screening of mutations in TP53 gene would be of a great value. In the present work we took advantage of the CRISPR-Cas9 gene editing technology to develop the CSMS – CRISPR-based saturated mutagenesis screening of TP53 gene, an improved system for massive parallel functional screening of p53 mutants. We have established rapid and flexible protocol of targeting p53 mutations into endogenous TP53 locus using CRISPR-Cas9-induced homology-directed repair. We have validated CSMS by performing saturation mutagenesis of the short protein motif and demonstrated outstanding performance. We have scaled our protocol up to establish a high-throughput method that allows precise functional characterization of thousands of p53 variants. We have tested effects of p53 mutations on response to Mdm2 inhibitors and irradiation and revealed excellent correlation of screening results with known structural, functional and clinical data. Furthermore, we have demonstrated that CMSM is able to highlight even subtle functional difference between mutants and identify partially loss of function mutants. Manipulating the endogenous TP53 locus allowed us to study effects of mutation in non-coding regions, which was previously unachievable. A detailed comparison of our data with the previously published studies provided compelling evidence, that the procedure established in our study is significantly more accurate in categorization of pathogenic TP53 mutations. In summary, we have attested CSMS as a powerful tool to catalogue TP53 mutations. This tool can be used in the future to increase the utility of mutations in TP53 as clinical biomarkers

Exploring mutant p53 targeting strategies for cancer therapy

TP53 is an essential tumor suppressor gene. It is inactivated in 50% of tumors, most frequently by missense mutations that result in the expression of a mutant p53 protein (mutp53). Mutp53 loses the ability to activate tumor-suppressive target genes and acquires pro-tumorigenic gain-of-function properties. An emerging strategy for treatment of cancers with missense p53 mutations is pharmacological restoration of wild-type p53 activity. Initial evidence that p53 reactivation leads to tumor regression was obtained in mouse models where p53 loss was the initiating event. Many patient tumors, however, develop in the presence of wild-type p53 and inactivate it only at later stages of evolution. To bypass p53-dependent tumor suppression such tumors acquire alterations in the p53 pathway that, in principle, could render p53 reactivation inefficient. To test this, we have modeled late-stage p53 inactivation in mice. Surprisingly restoration of p53 in such late-inactivated tumors resulted in widespread apoptosis and superior survival of the animals. ARF gene alterations were identified as a cause of primary or acquired resistance that could be overcome by Mdm2 inhibitors. Together this study provided proof of concept that p53 reactivation is an effective therapy option for tumors with late-stage p53 inactivation and identified ARF as a predictive biomarker. Among the many different missense mutations, cooperativity mutations represent a mechanistically unique class that often results in a partial loss-of-function (pLOF). As pLOF is a characteristic of many non-hotspot p53 mutations, we have tested if residual functions of two distinct p53 cooperativity mutants (p53E177R “RR” and p53R178E “EE”) may be exploited to induce cell death. Using embryonic development as a model, we have shown that Mdm2-deficiency results in constitutive stabilization of p53 cooperativity mutants and triggers massive apoptosis and embryonic lethality. This indicated that the apoptosis deficiency, characteristic for p53 pLOF mutants, can be rescued by inhibition of Mdm2. Studies of p53 cooperativity mutant mice confirmed that stabilization of mutp53 by pharmacological or constitutive Mdm2 inhibition lowers the apoptotic threshold, sensitizes tumor cells to the pro-apoptotic activity of DNA damaging drugs, and generates a survival benefit under chemotherapy. This was even seen for the DNA binding-deficient cooperativity mutant EE, pointing at a critical role of non-transcriptional apoptotic functions in the context of chemotherapy. In parallel, p53EE was found to be incapable of suppressing tumor development, highlighting a differential role of p53’s non-transcriptional apoptotic functions in tumor suppression and cancer therapy. Collectively, our investigation of two cooperativity mutants suggests that non-hot-spot p53 variants retain residual wild-type activities, that can be harnessed for cancer therapy

"A Naked Person” and “the Unbearable World”: Exodus Variants (Based on Early Works by A. I. Solzhenitsyn)

This paper analyses the motif of “the naked person” in Alexander Solzhenitsyn’s early work. Epic tales which belong to the so called “labour camp prose”, such as One Day in the Life of Ivan Denisovich (1959) and The Cancer Ward (1968), stand out in the context of this motif. Moreover, the “unbearable world” and the “naked person” have been structurally significant for the “labour camp prose” since Fyodor Dostoevsky and Anton Chekhov. All of them imply that these elements bring the reader closer to understanding the ontology of a person who is forbidden to wear a cross on his chest and thus seek protection from God and cultural myths. The paper examines historical developments of the “naked person” imagery in Russian literature from the seventeenth century to the Avantgarde and postmodernism by analysing relations between reality and the “unbearable world” (the space of labour camps) in which nakedness and misery are deemed to be charisma, gifts from God. The Cancer Ward is still one of Solzhenitsyn’s most widely read works in Europe and America. Unlike the peasants in the story, Kostoglotov, an intellectual, reflects on the value of freedom, prospects of choice and the nature of evil – something which Ivan Denisovich touches upon only vaguely. The author is interested in mechanisms of self-identity in horrendous living conditions. Solzhenitsyn’s The Cancer Ward is a variation of the classic “non-finito” narrative. The protagonist, who has endured hardship and overcome limits of the “unbearable world”, moves towards the house-ark as his life is just beginning. In fact, by employing terrible history, a labour camp and the hospital ward of the doomed, Solzhenitsyn’s text explores the driving forces behind a person’s self-identity, the most important of which are moral elevation, will, mercy and belief in life

Business-State Relations and the Role of Corporate Social Responsibility in Russia's Regions

In Russia's regions, companies closely collaborate with state administrations in the field of corporate social responsibility (CSR). Different forms of interaction have emerged, including the so-called "socio-economic cooperation agreements" (SECAs). These greements between business actors and governors define mutual responsibilities with regard to regional development and regulate the companies' social and ecological investments in their territories of presence. In addition, business and state actors collaborate in joint investment projects, public-private partnerships, working groups and charity activities. Business-state collaboration is characterized by interdependence: companies need licenses and administrative support for business operations, while state actors seek additional financing for welfare provision and regional infrastructure. For companies, CSR has become an important tool to institutionalize their charity activities and determine their social obligations towards the state

The Traditionalist Discourse of Contemporary Russian Literature: From Neo-traditionalism to “New Realism”

The article analyses modern traditionalism and its main directions (classical traditionalism, neo-traditionalism and new realism). This analysis encompasses the reasons for a returning interest to the realistic principles of writing, and the dialogues between traditionalism and the avant-garde and the cosmos and chaos as key to the development of culture as a whole. It highlights the ways in which current literary studies and criticism reflect the shift of the cultural paradigm and the transition from the poetics of postmodernism to the realistic principles of writing, while preserving elements of postmodern aesthetics. Particular attention is paid to the increasingly controversial direction of “new realism”, which is represented by two key areas: patriotic and naturalistic. The “new realism” authors actively form their own mythology, participating in politics, and trying to reconcile Soviet and anti-Soviet discourses. They search for “avant-gardism in conservatism”, where conservatism is a treasury of Russian classic images, and avantgardism is the innovations that reflect the current public realia. The article provides a detailed analysis of the literary work of Siberian author Mikhail Tarkovsky. Tarkovsky’s work combines elements of the poetics of “classical traditionalism” and “new realism” to present an original geopolitical project and a cultural character capable of bringing the country to a new level of civilisation

Synchronising internal and external information: a commentary on Meyer, Sun & Martin (2020)

Published online: 19 Mar 2020AKG was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No 798971. NM was supported by the Spanish Ministry of Science, Innovation and Universities (grant RTI2018-096311-B-I00), the Agencia Estatal de Investigación (AEI), the Fondo Europeo de Desarrollo Regional (FEDER). The authors acknowledge financial support from the “Severo Ochoa” Programme for Center/Unit of Excellence in R&D (SEV-2015-490) and by the Basque Government through the BERC 2018–2021 programme

Formal contracting and state–business relations in Russia. A case study from Khanty-Mansi Autonomous Okrug

The Russian state requires companies to invest in welfare provision and to conclude socio-economic cooperation agreements (SECAs) with regional administrations. Based on empirical evidence from Khanty–Mansi Autonomous Okrug, this article analyses state-business interactions at the subnational level. We show that state and business actors have formalised their resource exchange in the SECAs. Because of the agreements' adaptive nature, both parties are able to manage their respective obligations and risks within an authoritarian and highly volatile environment. We identify four patterns of contractual relations, depending on the companies' production capacities and their commitment to providing social investments in the region