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| 2. |
- Geny, Sylvain, et al.
(författare)
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Next-generation bis-locked nucleic acids with stacking linker and 2 '-glycylamino-LNA show enhanced DNA invasion into supercoiled duplexes
- 2016
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 44:5, s. 2007-2019
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Tidskriftsartikel (refereegranskat)abstract
- Targeting and invading double-stranded DNA with synthetic oligonucleotides under physiological conditions remain a challenge. Bis-locked nucleic acids (bisLNAs) are clamp-forming oligonucleotides able to invade into supercoiled DNA via combined Hoogsteen and Watson-Crick binding. To improve the bisLNA design, we investigated its mechanism of binding. Our results suggest that bisLNAs bind via Hoogsteen-arm first, followed by Watson-Crick arm invasion, initiated at the tail. Based on this proposed hybridization mechanism, we designed next-generation bisLNAs with a novel linker able to stack to adjacent nucleobases, a new strategy previously not applied for any type of clamp-constructs. Although the Hoogsteen-arm limits the invasion, upon incorporation of the stacking linker, bisLNA invasion is significantly more efficient than for non-clamp, or nucleotide-linker containing LNA-constructs. Further improvements were obtained by substituting LNA with 2'-glycylamino-LNA, contributing a positive charge. For regular bisLNAs a 14-nt tail significantly enhances invasion. However, when two stacking linkers were incorporated, tail-less bisLNAs were able to efficiently invade. Finally, successful targeting of plasmids inside bacteria clearly demonstrates that strand invasion can take place in a biologically relevant context.
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| 3. |
- Stickley, Andrew, et al.
(författare)
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Loneliness and its association with psychological and somatic health problems among Czech, Russian and U.S. adolescents
- 2016
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Ingår i: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Loneliness is common in adolescence and has been linked to various negative outcomes. Until now, however, there has been little cross-country research on this phenomenon. The aim of the present study was to examine which factors are associated with adolescent loneliness in three countries that differ historically and culturally-the Czech Republic, Russia and the United States, and to determine whether adolescent loneliness is associated with poorer psychological and somatic health. Methods: Data from a school survey, the Social and Health Assessment (SAHA), were used to examine these relations among 2205 Czech, 1995 Russian, and 2050 U.S. male and female adolescents aged 13 to 15 years old. Logistic regression analysis was performed to examine if specific demographic, parenting, personal or school-based factors were linked to feeling lonely and whether lonely adolescents were more likely to report psychological (depression and anxiety) or somatic symptoms (e.g. headaches, pain). Results: Inconsistent parenting, shyness, and peer victimisation were associated with higher odds for loneliness in at least 4 of the 6 country- and sex-wise subgroups (i.e. Czech, Russian, U.S. boys and girls). Parental warmth was a protective factor against feeling lonely among Czech and U.S. girls. Adolescents who were lonely had higher odds for reporting headaches, anxiety and depressive symptoms across all subgroups. Loneliness was associated with other somatic symptoms in at least half of the adolescent subgroups. Conclusion: Loneliness is associated with worse adolescent health across countries. The finding that variables from different domains are important for loneliness highlights the necessity of interventions in different settings in order to reduce loneliness and its detrimental effects on adolescent health. © 2016 Stickley et al.
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- Rogers, Kathryn, et al.
(författare)
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Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice.
- 2012
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: A hallmark of Alzheimer’s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer’s disease. Results: Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM) and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. Conclusions: EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer’s disease.
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