Regulation of SUMO Modification

The small ubiquitin related modifier SUMO is a posttranslational modifier that functions in a wide range of cellular processes like intracellular transport, cell cycle regulation, DNA repair and regulation of transcription. SUMO is an 11 kDa protein and is ligated to its target proteins using a mechanism involving three regulated enzymatic steps that are catalyzed by an E1, E2 and an E3 enzyme. Since many crucial biological processes are regulated by SUMO modification, it is evident that the SUMO pathway can play a role in disease as well. In fact, a role for SUMO modification has been implicated in cancer, neurodegenerative diseases and viral infection. The work in this thesis provides insight into the molecular mechanism of sumoylation by analysis of SUMO modification using a combination of biochemistry and structural biology. The E2 enzyme is a central player in the sumoylation cascade since it accepts SUMO from the E1 enzyme and transfers it to the target. Surprisingly, we found that the SUMO protein itself can regulate the function of the E2 enzyme, Ubc9, in two different ways. The noncovalent interaction of SUMO with Ubc9 is important for the formation of SUMO chains possibly through a mechanism that is also used in K63-linked ubiquitin chain formation. The covalent complex of SUMO and Ubc9 is structurally and functionally different and is involved in target discrimination, some targets are enhanced in SUMO modification while others are inhibited in modification. Generally, an E3 enzyme is required for enhancement of sumoylation, one of these SUMO E3 enzymes is the nucleoporin RanBP2. We have studied the catalytic mechanism of RanPB2, and shown that it accelerates SUMO transfer by an allosteric mechanism. Finally we have studied the consequences of sumoylation of a newly identified SUMO target, the ubiquitin conjugating enzyme E2-25K. Here sumoylation inhibits the basic enzymatic activity of the E2. Even though the ubiquitin E2 enzyme E2-25K is similar to the SUMO E2 Ubc9, the effect of their sumoylation is completely different. In this thesis we describe various aspects of both regulation by sumoylation as well as the regulation of the process of sumoylation itself. We found how SUMO can regulate the process of sumoylation and determined the function of sumoylation of two distinct targets

Мифологема книги в романе Т. Толстой «Кысь»

Рассматривается функционирование мифологемы Книги в романе Т.Толстой "Кысь", представленной как главная ценность эстетического порядка, способная "спасти мир". Осмысливаются уровни ее реализации, равно как и функционирование других арехетипических позитивных образов (огонь, культура) в антиутопической парадигме произведения. Ключевые слова: книга, культура, антиутопия, деконструкция.Розглядається функціонування міфологеми Книги в романі Т.Толстой "Кись", що представлена як головна цінність естетичного ґатунку, здатна "врятувати світ". Осмислюються рівні її реалізації, функціонування інших архетипових позитивних образів (вогонь, культура) в антиутопічній парадигмі твору.The article investigates the functioning of the myth of Book in the novel of T.Tolstaya "Kees", presented as a highest value, which can "save the world". Focus on the levels of its realizations as well as functioning of other archetypical positive images (fire, culture) in the dystopian paradigm of the novel

Escape loneliness by going digital: A quantitative and qualitative evaluation of a Dutch experiment in using ECT to overcome loneliness among other adults

Background: This study evaluates the outcomes of an Internet-at-home intervention experiment that intended to decrease loneliness among chronically ill and physically handicapped older adults through introducing them to the use of an electronic communication facility. Method: To determine the effectiveness of the experiment in terms of reducing loneliness, 15 older adults were interviewed three times: shortly before the start, two years later and immediately after termination of the experiment, while their loneliness scores at zero and post-measurement were compared with those of a control group. Results: Both the participants and the control persons experienced a reduction in loneliness over time. However, the reduction was only significant for the intervention participants. Moreover, the changes in loneliness were significantly greater among the participants compared to the control persons. When looking more in detail, the effect of the experiment was only significant regarding emotional loneliness and among the highest educated. Findings of the qualitative research enabled us to understand the mechanisms through which the intervention helped alleviate loneliness. E-mail was found to facilitate social contact. Furthermore, the computer and Internet were often used to pass the time, taking people's minds off their loneliness. Unexpectedly, the intervention also improved people's self-confidence. Conclusion: The decline in loneliness is likely to be greater if persons under more favorable circumstances are selected and if more social functions of the Internet are used. © 2007 Taylor & Francis