Browsing by Subject "INITIATION"

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  • Peret, Benjamin; Middleton, Alistair M.; French, Andrew P.; Larrieu, Antoine; Bishopp, Anthony; Njo, Maria; Wells, Darren M.; Porco, Silvana; Mellor, Nathan; Band, Leah R.; Casimiro, Ilda; Kleine-Vehn, Juergen; Vanneste, Steffen; Sairanen, Ilkka; Mallet, Romain; Sandberg, Goran; Ljung, Karin; Beeckman, Tom; Benkova, Eva; Friml, Jiri; Kramer, Eric; King, John R.; De Smet, Ive; Pridmore, Tony; Owen, Markus; Bennett, Malcolm J. (2013)
  • Ou, Hui-Ling; Kim, Christine S.; Uszkoreit, Simon; Wickström, Sara A.; Schumacher, Björn (2019)
    Genome integrity in primordial germ cells (PGCs) is a prerequisite for fertility and species maintenance. In C. elegans, PGCs require global-genome nucleotide excision repair (GG-NER) to remove UV-induced DNA lesions. Failure to remove the lesions leads to the activation of the C. elegans p53, CEP-1, resulting in mitotic arrest of the PGCs. We show that the eIF4E2 translation initiation factor IFE-4 in somatic gonad precursor (SGP) niche cells regulates the CEP-1/p53-mediated DNA damage response (DDR) in PGCs. We determine that the IFE-4 translation target EGL-15/FGFR regulates the non-cell-autonomous DDR that is mediated via FGF-like signaling. Using hair follicle stem cells as a paradigm, we demonstrate that the eIF4E2-mediated niche cell regulation of the p53 response in stem cells is highly conserved in mammals. We thus reveal that the somatic niche regulates the CEP-1/p53-mediated DNA damage checkpoint in PGCs. Our data suggest that the somatic niche impacts the stability of heritable genomes.
  • Mönttinen, Heli A. M.; Ravantti, Janne; Poranen, Minna (2019)
    Specific cleavage of proteins by proteases is essential for several cellular, physiological, and viral processes. Chymotrypsin-related proteases that form the PA clan in the MEROPS classification of proteases is one of the largest and most diverse group of proteases. The PA clan comprises serine proteases from bacteria, eukaryotes, archaea, and viruses and chymotrypsin-related cysteine proteases from positive-strand RNA viruses. Despite low amino acid sequence identity, all PA clan proteases share a conserved double beta-barrel structure. Using an automated structure-based hierarchical clustering method, we identified a common structural core of 72 amino acid residues for 143 PA clan proteases that represent 12 protein families and 11 subfamilies. The identified core is located around the catalytic site between the two beta-barrels and resembles the structures of the smallest PA clan proteases. We constructed a structure-based distance tree derived from the properties of the identified common core. Our structure-based analyses support the current classification of these proteases at the subfamily level and largely at the family level. Structural alignment and structure-based distance trees could thus be used for directing objective classification of PA clan proteases and to strengthen their higher order classification. Our results also indicate that the PA clan proteases of positive-strand RNA viruses are related to cellular heat-shock proteases, which suggests that the exchange of protease genes between viruses and cells might have occurred more than once.
  • Seifert, Mona; van Nies, Pauline; Stal Papini, Flavia; Arnold, Jamie; Poranen, Minna; Cameron, Craig E.; Depken, Martin; Dulin, David (2020)
    RNA virus survival depends on efficient viral genome replication, which is performed by the viral RNA dependent RNA polymerase (RdRp). The recent development of high throughput magnetic tweezers has enabled the simultaneous observation of dozens of viral RdRp elongation traces on kilobases long templates, and this has shown that RdRp nucleotide addition kinetics is stochastically interrupted by rare pauses of 1-1000 s duration, of which the short-lived ones (1-10 s) are the temporal signature of a low fidelity catalytic pathway. We present a simple and precise temperature controlled system for magnetic tweezers to characterize the replication kinetics temperature dependence between 25 degrees C and 45 degrees C of RdRps from three RNA viruses, i.e. the double-stranded RNA bacteriophage Phi 6, and the positive-sense single-stranded RNA poliovirus (PV) and human rhinovirus C (HRV-C). We found that Phi 6 RdRp is largely temperature insensitive, while PV and HRV-C RdRps replication kinetics are activated by temperature. Furthermore, the activation energies we measured for PV RdRp catalytic state corroborate previous estimations from ensemble pre-steady state kinetic studies, further confirming the catalytic origin of the short pauses and their link to temperature independent RdRp fidelity. This work will enable future temperature controlled study of biomolecular complex at the single molecule level.
  • Vogt, Tobias; van Raalte, Alyson; Grigoriev, Pavel; Myrskyla, Mikko (2017)
    Before the fall of the Berlin Wall, mortality was considerably higher in the former East Germany than in West Germany. The gap narrowed rapidly after German reunification. The convergence was particularly strong for women, to the point that Eastern women aged 50-69 now have lower mortality despite lower incomes and worse overall living conditions. Prior research has shown that lower smoking rates among East German female cohorts born in the 1940s and 1950s were a major contributor to this crossover. However, after 1990, smoking behavior changed dramatically, with higher smoking intensity observed among women in the eastern part of Germany. We forecast the impact of this changing smoking behavior on East-West mortality differences and find that the higher smoking rates among younger East German cohorts will reverse their contemporary mortality advantage. Mortality forecasting methods that do not account for smoking would, perhaps misleadingly, forecast a growing mortality advantage for East German women. Experience from other countries shows that smoking can be effectively reduced by strict anti-smoking policies. Instead, East Germany is becoming an example warning of the consequences of weakening anti-smoking policies and changing behavioral norms.
  • Alhede, Christina; Lauridsen, Trine K.; Johannessen, Arne; Dixen, Ulrik; Jensen, Jan S.; Raatikainen, Pekka; Hindricks, Gerhard; Walfridsson, Haakan; Kongstadf, Ole; Pehrson, Steen; Englund, Anders; Hartikainen, Juha; Hansen, Peter S.; Nielsen, Jens C.; Jons, Christian (2018)
    Introduction: Supraventricular ectopic complexes (SVEC) are known risk factors of recurrent atrial fibrillation (AF). However, the impact of SVEC in different age groups is unknown. We aimed to investigate the risk of AF recurrence with higher SVEC burden in patients +/- 57 years, respectively, after treatment with antiarrhythmic medication (AAD) or catheter ablation (CA). Methods: In total, 260 patients with LVEF >40% and age 195 SVEC/day. AF recurrence was defined as AF >= 1 min, AF-related cardioversion or hospitalization. Results: Age >57 years were significantly associated with higher AF recurrence rate after CA (58% vs 36%, p = 0.02). After CA, we observed a higher SVEC burden during follow-up in patients >57 years which was not observed in the younger age group treatedwith CA (p = 0.006). High SVEC burden at 3 months after CA was associated with AF recurrence in older patients but not in younger patients (>57 years: HR 3.4 [1.4-7.9], p = 0.005). We did not find any age-related differences after AAD. Conclusion: We found that younger and older patients respond differently to CA and that SVEC burden was only associated with AF recurrence in older patients. (C) 2017 Elsevier B.V. All rights reserved.
  • Ojala, Kaisu; Meretoja, Tuomo J.; Mattson, Johanna; Salminen-Peltola, Paivi; Leutola, Suvi; Berggren, Marianne; Leidenius, Marjut H. K. (2016)
    Background and objectives: This study aims to clarify quality of breast cancer surgery in population-based setting. We aim to elucidate factors influencing waiting periods, and to evaluate the effect of hospital volume on surgical treatment policies. Special interest was given to diagnostic and surgical processes and their impact on waiting times. Methods: All 1307 patients having primary breast cancer surgery at the Helsinki and Uusimaa Hospital District during 2010 were included in this retrospective study. Results: Median waiting time for primary surgery was 24 days and significantly affected by additional imaging and diagnostic biopsies as well as hospital volume. Final rate of breast conserving surgery was surprisingly low, 51%, not affected by hospital volume, p = 0.781. Oncoplastic resection and immediate breast reconstruction (IBR) were performed more often in high volume units, p <0.001. Quality of axillary surgery varied with unit size. Multiple operations, IBR and high volume unit were factors prolonging initiation of adjuvant treatment. Conclusion: Quality of preoperative diagnostics play a crucial role in minimizing the need of repeated imaging and biopsies as well as multiple operations. Positive impact of high-volume hospitals becomes evident when analyzing procedures requiring advanced surgical techniques. High-volume hospitals achieved better quality in axillary surgery. (C) 2016 Elsevier Ltd. All rights reserved.