Genetics of amyotrophic lateral sclerosis and frontotemporal dementia and the potential for discovering new genes and pathways underlying these neurological disorders

Despite tremendous progress in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) genetic research over the last two decades, only 20% to 40% of the underlying genetic causes have been discovered. Several genes responsible for these two neurological disorders remain to be discovered. During my Ph.D., I utilized the current state-of-the-art exome and whole-genome sequencing technologies to discover new loci underlying ALS and FTD. This genetic knowledge helps to unravel the complex etiology of these disorders and paves the way for targeted therapies. Chapter 1 of this thesis talks about the evolution of genetic research in the past two decades. Chapter 2 introduces ALS and FTD, the two neurological disorders that are the focus of my thesis. Chapter 3 provides an overview of the genetics of ALS and FTD. Chapter 4 describes the discovery of the new gene linked to juvenile ALS, serine palmitoyltransferase long chain subunit 1 (SPTLC1), and proposes a treatment for the patients carrying mutations in this gene. Chapter 5 demonstrates that exome sequencing is a powerful technique for the analysis of rare hereditary conditions. I describe the discovery of gelsolin p.D187Y amino acid change, which was previously linked to hereditary amyloidosis type 4, in a large family in which multiple members were affected by bulbar neuropathy mimicking bulbar ALS. Chapter 6 discusses the role of the highly polymorphic locus replication factor C subunit 1 (RFC1) in ALS. Chapter 7 describes our whole-genome sequencing efforts in dementia and examines the data for the frequency of intermediate-size repeat expansions in genes previously linked to neurodegeneration

The Longitudinal Effects of STEM Identity and Gender on Flourishing and Achievement in College Physics

Background. Drawing on social identity theory and positive psychology, this study investigated women’s responses to the social environment of physics classrooms. It also investigated STEM identity and gender disparities on academic achievement and flourishing in an undergraduate introductory physics course for STEM majors. 160 undergraduate students enrolled in an introductory physics course were administered a baseline survey with self-report measures on course belonging, physics identification, flourishing, and demographics at the beginning of the course and a post-survey at the end of the academic term. Students also completed force concept inventories and physics course grades were obtained from the registrar. Results. Women reported less course belonging and less physics identification than men. Physics identification and grades evidenced a longitudinal bidirectional relationship for all students (regardless of gender) such that when controlling for baseline physics knowledge: (a) students with higher physics identification were more likely to earn higher grades; and (b) students with higher grades evidenced more physics identification at the end of the term. Men scored higher on the force concept inventory than women, although no gender disparities emerged for course grades. For women, higher physics (versus lower) identification was associated with more positive changes in flourishing over the course of the term. High-identifying men showed the opposite pattern: negative change in flourishing was more strongly associated with high identifiers than low identifiers. Conclusions. Overall, this study underlines gender disparities in physics both in terms of belonging and physics knowledge. It suggests that strong STEM identity may be associated with academic performance and flourishing in undergraduate physics courses at the end of the term, particularly for women. A number of avenues for future research are discussed

Odic Versions of the ‘Social Contract’ in 18th-century Russia

The article was submitted on 12.04.2016.Теория общественного договора является одним из базовых социально-политических учений эпохи Просвещения в Европе и в России. Различные модели взаимоотношений власти и общества суть постоянно меняющийся идейный конструкт, негласное соглашение, создаваемое и проговариваемое в различных текстах культуры. Основное внимание в статье уделяется одической поэзии XVIII в., то есть той области литературной и политической культуры, где идеи взаимовыгодного соглашения сторон – монарха и подданных – получили образное общедоступное воплощение. Задача – выявить основные этапы и художественную специфику взаимоотношений между монархом и подданными, образно представленные в одической поэзии. Парадигма «общественного договора» в основных чертах сложилась уже в петровское время, когда были определены «должности» государя и подданных: монарх радеет о добре общем, а подданные повинуются и служат. Поэты Петровской эпохи (Карион Истомин, И. В. Паус, В. К. Тредиаковский) утверждают идеи просвещения «россов», вменяя в обязанности монарха защищать веру и отечество от врагов и долг верной службы народа царю. После смерти Петра ситуация меняется. На первый план в одах и надписях к иллюминациям и фейерверкам выдвигается фигура императрицы, идеальной правительницы и просвещенной государыни, деятельность которой направлена на достижение «блаженства» россов. Изменяются и эмоциональные мотивы «договора»: любовь объявляется движущей силой действий и монархини, и подданных; «за доброты и щедроты» императрицы подданные готовы жертвовать собой. Отечески-сыновняя модель отношений власти и граждан во время правления Елизаветы Петровны не превратилась в материнско-сыновнюю, и главными одическими «именами» императрицы остались «кровь Петрова» и «дщерь Петрова». В литературе конца 1770-х – 1790-х гг. блаженство подданных объявляется необходимым условиям блаженства правителя, а невозможность критики монарха инициирует критику вельмож, далеких от народных нужд и чаяний. К концу века торжественная ода становится нисходящим жанром, востребованным лишь в моменты восшествия на престол Павла I и Александра I. Начало 1800-х гг. можно считать условной границей, после которой в русском образованном обществе происходит крушение иллюзий в отношении «полюбовного соглашения» между монархом и подданными, что отразилось в литературных текстах.Social contract theory is one of the basic socio-political doctrines of the European and Russian Enlightenments. Various models of relationships between the authorities and society are reflected in the treatises of European and Russian enlighteners. However, the concept of the social contract is a constantly changing ideological construct, ‘a tacit agreement’ created, sought for, and pronounced in different cultural texts. The authors of the article mainly focus on the odic poetry of the 18th century, the sphere of Russian culture where the idea of a mutually beneficial agreement between a monarch and their subjects was most vividly, clearly, and comprehensively expressed. The article aims to identify the main stages in the history of development of the relationship between a monarch and their subjects as reflected in poetry. The ‘social contract’ paradigm was mostly formed during the reign of Peter the Great, when the ‘functions’ of a sovereign and his subjects were determined: a monarch took care of the commonweal and his subjects obeyed and served him. Some poets of the Petrine epoch (Karion Istomin, I. V. Paus, V. K. Trediakovsky) endorsed ideas of enlightening the Russ, the monarch’s duty to protect the faith and fatherland from foes, and subjects’ faithful service to their monarch. After Peter the Great’s death, the situation changed. The figure of the empress as an ideal ruler and an enlightened monarch who did everything possible to attain the ‘bliss’ of the Russ came to the fore in odes and verse inscriptions for fireworks and illuminations. The emotional motives of the ‘social contract’ were also modified: love was declared the driving force of the monarch and her subjects. Subjects should be willing to sacrifice themselves for the empress’s kindness and generosity. The paternal-filial model of the relationship between the authorities and citizens did not change into a maternal-filial one during Elizabeth’s reign. The names used to refer to the empress’s in odes names remained ‘Peter’s blood’ and ‘Peter’s daughter’. In the literary culture of the 1770s–1990s, subjects’ bliss was declared a necessary condition of the ruler’s bliss. That it was impossible to criticise the monarch provoked criticism from the nobles, who were unfamiliar with the common people’s needs and aspirations. By the end of the century, the genre of the solemn ode was in decline: it only returned to popularity during Paul I’s and Alexander I’s accessions to the throne. The beginning of the 1800s can be considered a borderline, after which illusions about the possibility of an ‘amicable agreement’ between a monarch and their subjects were destroyed

A systems description of the national well-being system. Version 1.0

Policymakers are confronted with hard-to-address questions, such as • What is the ultimate impact of very different policies on the well-being of citizens? • How to anticipate, which policies will promote well-being the most and which ones will lead to tough trade-offs? • How to focus scarce resources and maximize the positive impact on the well-being of citizens? Economic growth is ceasing down, and, moreover, in most of the developed countries additional growth does not promote the well-being of citizens as much as it used to. But what is well-being? According to a dictionary, well-being is a state of feeling happy, healthy or prosperous. In 1980s, a group of sociologists, philosophers and economists led by Amartya Sen and Martha Nussbaum suggested a framework to understand well-being beyond the economic indicators , such as the GDP. In fact, in the modern world, wellbeing itself becomes a prerequisite for economic growth and for social and economic stability. Governments begin to focus their attention directly on the multi-dimensional national well-being including and going beyond economic and material aspects. They look for new under-utilized resources that would raise the national well-being even despite weak economic growth. To discover effective and efficient solutions, one needs to maximize synergies and reduce losses from trade-offs . Systems analysis offers tools to do so. This challenge was presented to the International Institute for Applied Systems Analysis (IIASA) by the National Economic Council of Israel in 2018. In response, IIASA developed a pilot version of a systems description of the national well-being system that covers four major subsystems: economic subsystem, natural subsystem, human capacity subsystem, and social subsystem, each described by a set of indicators. This Working Paper presents the results of this pilot work. We rely on the OECD well-being framework as a basis to measure multi-dimensional well-being and work with 68 factors, of which 39 represent the OECD indicators. Based on evidence we collate from solid scientific literature, we connect these 68 factors by causal relationships and obtain a comprehensive systems map of the National Well-being System (NWS) (a causal loop diagram) comprising 208 directed links between factors. This systems map allows to trace all indirect effects and feedback loops between factors in a systematic fashion thus helping acquire a holistic understanding about the national well-being system. Empirical evidence clearly indicates that systems thinking is difficult to practice when causal interconnections become more complex, especially when it involves indirect effects and feedback loops. As a formal tool from qualitative systems analysis, our NWS map can assist policymakers to reveal trade-offs and synergies, reduce the problem’s “wickedness” and discipline a dialogue. This version 1.0 can and should be developed further. This includes expert validation and fine-tuning, as well as customizing it to particular national and policy contexts. Eventually, our ambition is to develop a policy simulation tool that enables comparison of different policy options and their ultimate impact on well-being. We invite interested parties to join us in this endeavour

Technology development of obtaining essential fatty acids from hydrobionts hydrolyzates

Articleɷ-3, 6-fatty acids from hydrobiontsare a minor component in the nutrition of European countries population. This causes a number of diseases, such as cardiovascular ones, cancer etc. There is a task of concentrating these acids in oil due to the fact that to meet their daily needs it is problematic to use large quantities of fish oil-from 15 to 20 g. Particularly rich in ɷ-3, 6-acids are wastes from the cutting of hydrobionts, containing muscle tissue and skin. Protein hydrolysates were obtained from rainbow trout (Oncorhynchusmykiss) and Atlantic herring (Clupeaharengus) wastes by the electrochemical method using electrolyzers of the original design which are allowed to be used in food industry. A technological scheme of separating of lipids from protein hydrolyzates has been developed and experimental batches of oil samples have been developed. To concentrate the fatty acids the cryoconcentration method was used. The phase transitions of the obtained lipids were studied after their cryoconcentration in the temperature range from + 15 °C to minus 40 °C in the environment of calcium chloride using a low-temperature refrigeration unit. To analyze phase transitions the plant was used, which is a container with a solution of calcium chloride cooled by a low-temperature refrigeration machine. The properties of 5 fractions of lipids formed at the time of lipid phase transitions have been identified and studied (the fractional composition, acid, iodine numbers, the content of polyunsaturated fatty acids (PUFAs), vitamin D3 and A). It was established that as cryoconcentration increases the concentration of PUFAs, reaching values close to 90%, which allows the resulting product to be attributed to biologically active food additives (BAA). By calculation, it was shown that to create functional food products on fish base from fish of the Gadidae family it is enough to inject 4 grams of BAA to 100 grams of the product. Organoleptic properties of food products from low-fat fish species were improved

Investigating RFC1 expansions in sporadic amyotrophic lateral sclerosis

A homozygous AAGGG repeat expansion within the RFC1 gene was recently described as a common cause of CANVAS syndrome. We examined 1069 sporadic ALS patients for the presence of this repeat expansion. We did not discover any carriers of the homozygous AAGGG expansion in our ALS cohort, indicating that this form of RFC1 repeat expansions is not a common cause of sporadic ALS. However, our study did identify a novel repeat conformation and further expanded on the highly polymorphic nature of the RFC1 locus

Obtention of omega-3-fatty acids cryoconcentrated fish oil from by-products of preserves industry

Received: February 24th, 2021 ; Accepted: May 2nd, 2021 ; Published: May 19th, 2021 ; Correspondence: [email protected] technology for obtaining and cryoconcentration of high-quality fish oil from collagen-containing wastes of slightly salted herring under gentle conditions using electrochemically obtained catholytes has been developed. Physicochemical analysis of raw materials was carried out and the yields of products from raw materials at all stages of processing were determined. Concentration of omega-3 fatty acids in oil was carried out using the cryo method. The main phase transitions in oil with decreasing temperature have been determined. The mass yields were determined and the biochemical composition of the cryoconcentrated fish oil fractions was investigated. It was defined the temperature of -14° С at which a phase transition is observed, providing an increase in the concentration of omega-3 fatty acids in oil by 3 times. The usage of cryoconcentrated fish oil allows to produce biologically active food supplement or raw materials for a functional food