In this work we adapt rare-earth-ion-doped NaYF4 nanoparticles coated with a silicon oxide shell (NaYF4:20%Yb,0.2%Tm@SiO2) for biological and medical applications (for example, imaging of cancer cells and therapy at the nano level). The wide upconversion emission range under 980 nm excitation allows one to use the nanoparticles for cancer cell (4T1) photodynamic therapy (PDT) without a photosensitizer. The reactive oxygen species (ROS) are generated by Tm/Yb ion upconversion emission (blue and UV light). The in vitro PDT was tested on 4T1 cells incubated with NaYF4:20%Yb,0.2%Tm@SiO2 nanoparticles and irradiated with NIR light. After 24 h, cell viability decreased to below 10%, demonstrating very good treatment efficiency. High modification susceptibility of the SiO2 shell allows for attachment of biological molecules (specific antibodies). In this work we attached the anti-human IgG antibody to silane-PEG-NHS-modified NaYF4:20%Yb,0.2%Tm@SiO2 nanoparticles and a specifically marked membrane model by bio-conjugation. Thus, it was possible to perform a selective search (a high-quality optical method with a very low-level organic background) and eventually damage the targeted cancer cells. The study focuses on therapeutic properties of NaYF4:20%Yb,0.2%Tm@SiO2 nanoparticles and demonstrates, upon biological functionalization, their potential for targeted therapy.
The circadian oscillator is a molecular feedback circuit whose orchestration involves posttranslational control of the activity and protein levels of its components. Although controlled proteolysis of circadian proteins is critical for oscillator function, our understanding of the underlying mechanisms remains incomplete. Here, we report that JmjC domain–containing protein 5 (JMJD5) interacts with CRYPTOCHROME 1 (CRY1) in an F-box/leucine-rich repeat protein 3 (FBXL3)-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. We also report that in the absence of JMJD5, AMP-regulated protein kinase (AMPK)-induced CRY1 degradation is impaired, establishing JMJD5 as a key player in this mechanism. JMJD5 cooperates with CRY1 to repress circadian locomotor output cycles protein kaput (CLOCK)–brain and muscle ARNT-like protein 1 (BMAL1), thus linking CRY1 destabilization to repressive function. Finally, we find that ablation of JMJD5 impacts FBXL3- and CRY1-related functions beyond the oscillator.
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