The Cellular Phenotype of Roberts Syndrome Fibroblasts as Revealed by Ectopic Expression of ESCO2

Cohesion between sister chromatids is essential for faithful chromosome segregation. In budding yeast, the acetyltransferase Eco1/Ctf7 establishes cohesion during DNA replication in S phase and in response to DNA double strand breaks in G2/M phase. In humans two Eco1 orthologs exist: ESCO1 and ESCO2. Both proteins are required for proper sister chromatid cohesion, but their exact function is unclear at present. Since ESCO2 has been identified as the gene defective in the rare autosomal recessive cohesinopathy Roberts syndrome (RBS), cells from RBS patients can be used to elucidate the role of ESCO2. We investigated for the first time RBS cells in comparison to isogenic controls that stably express V5- or GFP-tagged ESCO2. We show that the sister chromatid cohesion defect in the transfected cell lines is rescued and suggest that ESCO2 is regulated by proteasomal degradation in a cell cycle-dependent manner. In comparison to the corrected cells RBS cells were hypersensitive to the DNA-damaging agents mitomycin C, camptothecin and etoposide, while no particular sensitivity to UV, ionizing radiation, hydroxyurea or aphidicolin was found. The cohesion defect of RBS cells and their hypersensitivity to DNA-damaging agents were not corrected by a patient-derived ESCO2 acetyltransferase mutant (W539G), indicating that the acetyltransferase activity of ESCO2 is essential for its function. In contrast to a previous study on cells from patients with Cornelia de Lange syndrome, another cohesinopathy, RBS cells failed to exhibit excessive chromosome aberrations after irradiation in G2 phase of the cell cycle. Our results point at an S phase-specific role for ESCO2 in the maintenance of genome stability

The Vicious Circle of Post-Soviet Neopatrimonialism in Russia

Published online: 10 Aug 2015, journal issue (vol.32, N5) appeared in 2016Since the collapse of Communism, Russia and some other post-Soviet states have attempted to pursue socio-economic reforms while relying upon the political institutions of neopatrimonialism. This politico-economic order was established to serve the interests of ruling groups and establish the major features of states, political regimes, and market economies. It provided numerous negative incentives for governing the economy and the state due to the unconstrained rent seeking behavior of major actors. Policy reform programs discovered these institutions to be incompatible with the priorities of modernization, and efforts to resolve these contradictions through a number of partial and compromise solutions often worsened the situation vis-à-vis preservation of the status quo. The ruling groups lack incentives for institutional changes, which could undermine their political and economic dominance, and are caught in a vicious circle: reforms often result in minor returns or cause unintended and undesired consequences. What are the possible domestic and international incentives to reject the political institutions of neopatrimonialism in post-Soviet states and replace them with inclusive economic and political ones?Peer reviewe

Proteomic analysis of cell cycle progression in asynchronous cultures, including mitotic subphases, using PRIMMUS

AbstractThe temporal regulation of protein abundance and post-translational modifications is a key feature of cell division. Recently, we analysed gene expression and protein abundance changes during interphase under minimally perturbed conditions (Ly et al. 2014; Ly et al. 2015). Here we show that by using specific intracellular immunolabeling protocols, FACS separation of interphase and mitotic cells, including mitotic subphases, can be combined with proteomic analysis by mass spectrometry. Using this PRIMMUS (PRoteomic analysis of Intracellular iMMUnolabeled cell Subsets) approach, we now compare protein abundance and phosphorylation changes in interphase and mitotic fractions from asynchronously growing human cells. We identify a set of 115 phosphorylation sites increased during G2, which we term ‘early risers’. This set includes phosphorylation of S738 on TPX2, which we show is important for TPX2 function and mitotic progression. Further, we use PRIMMUS to provide a proteome-wide analysis of protein abundance remodeling between prophase, prometaphase and anaphase.</jats:p

Noise Management by Molecular Networks

Fluctuations in the copy number of key regulatory macromolecules (“noise”) may cause physiological heterogeneity in populations of (isogenic) cells. The kinetics of processes and their wiring in molecular networks can modulate this molecular noise. Here we present a theoretical framework to study the principles of noise management by the molecular networks in living cells. The theory makes use of the natural, hierarchical organization of those networks and makes their noise management more understandable in terms of network structure. Principles governing noise management by ultrasensitive systems, signaling cascades, gene networks and feedback circuitry are discovered using this approach. For a few frequently occurring network motifs we show how they manage noise. We derive simple and intuitive equations for noise in molecule copy numbers as a determinant of physiological heterogeneity. We show how noise levels and signal sensitivity can be set independently in molecular networks, but often changes in signal sensitivity affect noise propagation. Using theory and simulations, we show that negative feedback can both enhance and reduce noise. We identify a trade-off; noise reduction in one molecular intermediate by negative feedback is at the expense of increased noise in the levels of other molecules along the feedback loop. The reactants of the processes that are strongly (cooperatively) regulated, so as to allow for negative feedback with a high strength, will display enhanced noise

The Mismanaged Integration of Zaporizhzhya with the World Economy: Implications for Regional Development in Peripheral Regions

VAN ZON H. (1998) The mismanaged integration of Zaporizhzhya with the world economy: implications for regional development in peripheral regions, Reg. Studies 32, 607-618. In Soviet times, Zaporizhzhya, a major industrial town in South Eastern Ukraine, developed in almost complete isolation from the world economy and world society. After the independence of Ukraine in 1991, Zaporizhzhya endured rapid industrial decline. The internationalization that has taken place was mostly confined to markets rather than to productive structures. The export base became very weak mainly based on the export of subsidized steel and aluminium. This paper analyses the modalities of the integration of Zaporizhzhya into the world economy and the impact this had upon endogenous development potential. In particular the institutional barriers, such as the lack of 'social capital', to Zaporizhzhya's beneficial integration into the world economy are considered. VAN ZON H. (1998) L'integration mal dirigee de Zaporizhzhya dans l'economie mondiale: des consequences eventuelles pour l'amenagement des regions periphe �riques, Reg. Studies 32, 607-618. A l'epoque sovietique, Zaporizhzhya, une importante ville industrielle situee dans l'Ukraine du Sud-Est, s'est developpee presque a l'ecart de l'economie et de la societe mondiales. Au lendemain de l'independance de l'Ukraine en 1991, Zaporizhzhya a subi un declin economique rapide. L'internationalisation qui a eu lieu a concerne dans une large mesure les marches plutot que les structures productives. La base des exportations, surtout l'exportation de l'acier et de l'aluminium subventionne �s, s'est affaiblie. Cet article cherche a analyser les modalites de l'integration de Zaporizhzhya dans l'economie mondiale et les consequences pour le potentiel de developpement endogene. En particulier on considere les barrieres institutionnelles, telles que le manque de capital social, a l'integration avantageuse de Zaporizhzhya dans l'economie mondiale. VAN ZON H. (1998) Die fehlgeschlagene Eingliederung Zaporizhzhyas in die Weltwirtschaft: Implikationen fur regionale Entwicklung in Randgebieten, Reg. Studies 32, 607-618. Zu Zeiten der Sowjetunion entwickelte sich im Su �dosten der Ukraine in Zaporizhzhya eine bedeutende Industriestadt in fast volliger Abgeschiedenheit von der Weltwirtschaft und Weltgesellschaft. Nach der Unabha �ngigkeit der Ukraine im Jahre 1991 erlitt Zaporizhzhya einen raschen industriellen Niedergang. Die Internationalisierung, die stattgefunden hatte, beschrankte sich meist mehr auf Markte als auf Produktionsstrukturen. Die Exportgrundlage war sehr geschwacht worden, da sie hauptsachlich auf der Ausfuhr von subventioniertem Stahl und Aluminium beruht hatte. Dieser Aufsatz analysiert die Modalitaten der Eingliederung Zaporizhzhyas in die Weltwirtschaft und auf die Wirkung, die sie auf das endogene Entwicklungspotential ausubte. Es werden vorallem die institutionellen Hindernisse - wie der Mangel an Sozialkapital - fur Zaporizhzhyas vorteilhafte Eingliederung in die Weltwirtschaft behandelt.Transitional Economies, Eastern Europe, Ukraine, Regional Developments, Internationalization,