Targeting the Wnt pathways for therapies

The Wnt/β-catenin signaling pathway is crucial in animal development from sponges to humans. Its activity in the adulthood is less general, with exceptions having huge medical importance. Namely, improper activation of this pathway is carcinogenic in many tissues, most notably in the colon, liver and the breast. On the other hand, the Wnt/β-catenin signaling must be re-activated in cases of tissue damage, and insufficient activation results in regeneration failure and degeneration. These both medically important implications are unified by the emerging importance of this signaling pathway in the control of proliferation of various types of stem cells, crucial for tissue regeneration and, in case of cancer stem cells - cancer progression and relapse. This article aims at briefly reviewing the current state of knowledge in the field of Wnt signaling, followed by a detailed discussion of current medical developments targeting distinct branches of the Wnt pathway for anti-cancer and pro-regeneration therapies

Calculated phonon spectra of paramagnetic iron at the alpha-gamma phase transition

We compute lattice dynamical properties of iron at the bcc-fcc phase transition using dynamical mean-field theory implemented with the frozen-phonon method. Electronic correlations are found to have a strong effect on the lattice stability of paramagnetic iron in the bcc phase. Our results for the structural phase stability and lattice dynamical properties of iron are in good agreement with experiment.Comment: 4 pages, 2 figure

First-principles Calculations of the Electronic Structure and Spectra of Strongly Correlated Systems: Dynamical Mean-field Theory

A recently developed dynamical mean-field theory in the iterated perturbation theory approximation was used as a basis for construction of the "first principles" calculation scheme for investigating electronic structure of strongly correlated electron systems. This scheme is based on Local Density Approximation (LDA) in the framework of the Linearized Muffin-Tin-Orbitals (LMTO) method. The classical example of the doped Mott-insulator La_{1-x}Sr_xTiO_3 was studied by the new method and the results showed qualitative improvement in agreement with experimental photoemission spectra.Comment: 11 pages, 3 Postscript figures, LaTeX, submit in Journal of Physics: Condensed Matte

Electronic correlations at the alpha-gamma structural phase transition in paramagnetic iron

We compute the equilibrium crystal structure and phase stability of iron at the alpha(bcc)-gamma(fcc) phase transition as a function of temperature, by employing a combination of ab initio methods for calculating electronic band structures and dynamical mean-field theory. The magnetic correlation energy is found to be an essential driving force behind the alpha-gamma structural phase transition in paramagnetic iron.Comment: 4 pages, 3 figure

Protecting the past for the public good: archaeology and Australian heritage law

Archaeological remains have long been recognised as fragile evidence of the past, which require protection. Legal protection for archaeological heritage has existed in Australia for more than thirty years but there has been little analysis of the aims and effectiveness of that legislation by the archaeological profession. Much Australian heritage legislation was developed in a period where the dominant paradigm in archaeological theory and practice held that archaeology was an objective science. Australian legislative frameworks continue to strongly reflect this scientific paradigm and contemporary archaeological heritage management practice is in turn driven by these legislative requirements. This thesis examines whether archaeological heritage legislation is fulfilling its original intent. Analysis of legislative development in this thesis reveals that legislators viewed archaeological heritage as having a wide societal value, not solely or principally for the archaeological community. Archaeological heritage protection is considered within the broader philosophy of environmental conservation. As an environmental issue, it is suggested that a ‘public good’ conservation paradigm is closer to the original intent of archaeological heritage legislation, rather than the “scientific” paradigm which underlies much Australian legislation. Through investigation of the developmental history of Australian heritage legislation it is possible to observe how current practice has diverged from the original intent of the legislation, with New South Wales and Victoria serving as case studies. Further analysis is undertaken of the limited number of Australian court cases which have involved substantial archaeological issues to determine the court’s attitude to archaeological heritage protection. Situating archaeological heritage protective legislation within the field of environmental law allows the examination of alternate modes of protecting archaeological heritage and creates opportunities for ‘public good’ conservation outcomes. This shift of focus to ‘public good’ conservation as an alternative to narrowly-conceived scientific outcomes better aligns with current public policy directions including the sustainability principles, as they have developed in Australia, as well as indigenous rights of self-determination. The thesis suggests areas for legal reforms which direct future archaeological heritage management practice to consider the ‘public good’ values for archaeological heritage protection

Non-stoichiometric oxide and metal interfaces and reactions

We have employed a combination of experimental surface science techniques and density functional calculations to study the reduction of TiO2(110) surfaces through the doping with submonolayer transition metals. We concentrate on the role of Ti adatoms in self doping of rutile and contrast the behaviour to that of Cr. DFT+U calculations enable identification of probable adsorption structures and their spectroscopic characteristics. Adsorption of both metals leads to a broken symmetry and an asymmetric charge transfer localised around the defect site of a mixed localised/delocalised character. Charge transfer creates defect states with Ti 3d character in the band gap at similar to 1-eV binding energy. Cr adsorption, however, leads to a very large shift in the valence-band edge to higher binding energy and the creation of Cr 3d states at 2.8-eV binding energy. Low-temperature oxidation lifts the Ti-derived band-gap states and modifies the intensity of the Cr features, indicative of a change of oxidation state from Cr3+ to Cr4+. Higher temperature processing leads to a loss of Cr from the surface region, indicative of its substitution into the bulk

Cluster Dynamical Mean-field calculations for TiOCl

Based on a combination of cluster dynamical mean field theory (DMFT) and density functional calculations, we calculated the angle-integrated spectral density in the layered $s=1/2$ quantum magnet TiOCl. The agreement with recent photoemission and oxygen K-edge X-ray absorption spectroscopy experiments is found to be good. Th e improvement achieved with this calculation with respect to previous single-site DMFT calculations is an indication of the correlated nature and low-dimensionality of TiOCl.Comment: 9 pages, 3 figures, improved version as publishe

An experience of scaling and intensifying the industrial production of the Gam-COVID-Vac vector adenovirus vaccine in the limiting conditions of the pandemic

The COVID-19 pandemic has presented a global challenge to the health system. More than 200 years of world epidemiological experience since the first mass use of vaccines have convincingly shown that effective vaccines are the key tools in the fight against dangerous infectious diseases, especially epidemic and pandemic ones. In the context of a rapidly spreading pandemic of a new infectious agent, it is crucial not only to develop fundamentally new vaccines, but also to be able to quickly organise their large-scale production. In the Russian Federation, in 2020, a team of the National Research Centre for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya developed an innovative vector vaccine, Gam-COVID-Vaс, for the prevention of coronavirus disease caused by the SARS-CoV-2 virus. A number of pharmaceutical companies faced the challenge of producing the vaccine. The aim of the study was to optimise the production technology of Gam-COVID-Vac for scaling and increasing the production capacity. In the course of the work, the authors established critical quality attributes of the product, optimised analytical methods for their control, identified poorly scalable technological stages, streamlined the technological process before its transfer to production, and modified non-scalable and technologically unfeasible stages. The work resulted in the launch of industrial-scale production of active pharmaceutical ingredients for both components of Gam-COVID-Vac, which made it possible not only to meet the critical need for COVID-19 immunoprophylaxis in the Russian Federation, but also to supply this vaccine to a number of foreign countries

Перспективы использования технологической платформы ELISPOT в системе противоэпидемических мероприятий против новой коронавирусной инфекции COVID-19

Determination of T-cell immune response to SARS-CoV-2 is important both for diagnosis of the disease in symptomatic patients, and for determination of the total number of people who have had the disease, including its asymptomatic form. In addition, these assays are efficient for assessing the immune response after vaccination, as well as immunity levels in risk groups and in convalescent patients. The most promising method of T-cell immune response assessment is an ELISPOT-based assay measuring the release of interferon-gamma (IGRA) after stimulation with coronavirus-specific antigens. The present review analyses the prospects for using the ELISPOT technological platform in the clinical laboratory setting when dealing with the new coronavirus infection COVID-19, given specific aspects of the immune response. The review summarises data from articles published in peer-reviewed journals, preprints of articles available at arXiv resources, and information that some leading immunologists shared with the authors during private discussions. It has been shown that the introduction of B- and T-cell ELISPOT assays will make it possible to monitor the immunological status of patients, select a treatment strategy, identify the most vulnerable populations, carry out comprehensive assessment of vaccines during the development, clinical trials and implementation stages. The paper discusses the issues of maintaining T-cell immunity in the blood of people who have had HCoV, SARS, MERS, and COVID-19 coronavirus infections. It also discusses the advantages of the T-cell ELISPOT assay over serological tests as regards epidemiological assessment of the prevalence of the new coronavirus infection, and clinical trials of COVID-19 vaccines. Biotechnology companies have a ready-made technological platform for the development and industrial-scale production of ELISPOT kits, and this platform is easily adaptable to specific types of assays and pathogens. The paper supports the need to develop vaccines that would stimulate both cellular and humoral immune responses, and raises the question of the protective potential of cross-immunity acquired before the COVID-19 pandemic.Определение наличия Т-клеточного иммунного ответа к вирусу SARS-CoV-2 актуально как для диагностики заболевания у пациентов с наличием симптомов, так и для определения общего количества людей, перенесших данное заболевание, в том числе бессимптомно. Кроме того, данные тесты эффективны для оценки иммунного ответа после проведения вакцинации, а также оценки напряженности специфического иммунитета в группах риска и ранее переболевших. При этом среди методов оценки Т-клеточного иммунного ответа наиболее перспективным является тест ELISPOT на выброс интерферона гамма (IGRA) под действием специфических вирусных антигенов. В обзоре рассмотрены перспективы использования технологической платформы ELISPOT в клинико-лабораторной практике при работе с новой коронавирусной инфекцией COVID-19 с учетом особенностей иммунного ответа при данном заболевании. В качестве источников литературы использовались статьи, опубликованные в реферируемых журналах, препринты статей, размещенные на ресурсах arXiv, кроме того, использовались личные коммуникации авторов с ведущими иммунологами. Показано, что внедрение В- и Т-клеточного ELISPOT-тестов позволит осуществлять мониторинг иммунологического статуса пациентов и выбор тактики лечения, выявлять наиболее уязвимые группы населения, осуществлять комплексную оценку вакцинных препаратов на этапах разработки, клинических исследований и внедрения в практику. Обсуждаются вопросы сохранения Т-клеточного иммунитета в крови переболевших коронавирусными инфекциями HCoV, SARS, MERS, COVID-19 и преимущества Т-клеточного ELISPOT-теста перед серологическими тестами для эпидемиологической оценки распространенности новой коронавирусной инфекции и в клинических исследованиях вакцин против COVID-19. Биотехнологические компании имеют готовую технологическую платформу, легко адаптируемую под конкретный вид анализа и патогена, для разработки и промышленного производства наборов ELISPOT. Подтверждена необходимость разработки вакцин, стимулирующих как клеточный, так и гуморальный иммунные ответы, поднят вопрос о защитном потенциале перекрестного иммунитета, приобретенного до пандемии COVID-19

Ultrafast evolution and transient phases of a prototype out-of-equilibrium Mott-Hubbard material

The study of photoexcited strongly correlated materials is attracting growing interest since their rich phase diagram often translates into an equally rich out-of-equilibrium behaviour. With femtosecond optical pulses, electronic and lattice degrees of freedom can be transiently decoupled, giving the opportunity of stabilizing new states inaccessible by quasi-adiabatic pathways. Here we show that the prototype Mott-Hubbard material V2O3 presents a transient non-thermal phase developing immediately after ultrafast photoexcitation and lasting few picoseconds. For both the insulating and the metallic phase, the formation of the transient configuration is triggered by the excitation of electrons into the bonding a1g orbital, and is then stabilized by a lattice distortion characterized by a hardening of the A1g coherent phonon, in stark contrast with the softening observed upon heating. Our results show the importance of selective electron-lattice interplay for the ultrafast control of material parameters, and are relevant for the optical manipulation of strongly correlated systems. \ua9 The Author(s) 2017