709 research outputs found
Design of a randomized controlled trial of Internet-based cognitive behavioral therapy for treatment-induced menopausal symptoms in breast cancer survivors
Design of a randomized controlled trial of Internet-based cognitive behavioral therapy for treatment-induced menopausal symptoms in breast cancer survivors
Cost-utility, cost-effectiveness, and budget impact of Internet-based cognitive behavioral therapy for breast cancer survivors with treatment-induced menopausal symptoms
Cost-utility, cost-effectiveness, and budget impact of Internet-based cognitive behavioral therapy for breast cancer survivors with treatment-induced menopausal symptoms
Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation
Loss of neurons in neurodegenerative diseases is usually preceded by the accumulation of protein deposits that contain components of the ubiquitin/proteasome system. Affected neurons in Alzheimer's disease often accumulate UBB+1, a mutant ubiquitin carrying a 19–amino acid C-terminal extension generated by a transcriptional dinucleotide deletion. Here we show that UBB+1 is a potent inhibitor of ubiquitin-dependent proteolysis in neuronal cells, and that this inhibitory activity correlates with induction of cell cycle arrest. Surprisingly, UBB+1 is recognized as a ubiquitin fusion degradation (UFD) proteasome substrate and ubiquitinated at Lys29 and Lys48. Full blockade of proteolysis requires both ubiquitination sites. Moreover, the inhibitory effect was enhanced by the introduction of multiple UFD signals. Our findings suggest that the inhibitory activity of UBB+1 may be an important determinant of neurotoxicity and contribute to an environment that favors the accumulation of misfolded proteins
Evaluation of asymmetric orthogonal cyanine fluorophores
Pentamethine cyanine (Cy5) fluomphores have proven to be versatile imaging agents (i.e., tracers) for a range of micro- and macroscopic imaging applications, including image-guided surgery. In this study the relationship between the structure of asymmetric Cy5 fluorophores and their photophysical properties was studied. To this end, seven Cy5 analogues, bearing orthogonal N-indole substituents (H, SC3-, or benzene), were synthesised and evaluated. In-depth analysis revealed that introduction of sulfonates enhanced the fluorescence brightness and photostability, while reducing the lipophilicity, serum binding and stacking tendency. The addition of benzene moieties induced a bathochromic shift of 10-20 nm, increased the lipophilicity (LogP = -1.56-1.23) and serum binding (67.3-93.8% bound), as well as negatively impacted the brightness (0.74-42.9 . 10(3) M-1 cm(-1)), photostability (24.4-90.6% remaining), and stacking tendency. Chemical stability was uninfluenced by the substitution pattern. Additionally, the generation of a c[RGDyK]-based hybrid tracer based on one of these fluomphores in combination with a diethylenetriaminepentaacetic acid (DTPA) chelate and an In-111-isotope was reported. This compound was evaluated in vitro using alpha(v)beta(3)-overexpressing Ge beta 3 cells and in vivo using a 4T1 mouse tumour model. Overall, the presented results imply that alterations of the asymmetrical orthogonal Cy5 fluomphore structure have impact on the (photo)physical properties. Furthermore, the orthogonal Cy5 fluorophore framework can readily be applied in tracer development.Radiolog
- …