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Infrared-to-visible upconversion emission intensities are investigated in Li+ and Er3+ codoped ZnO nanocrystals. Li+ ions doped in ZnO/Er3+ nanocrystals can greatly enhance the upconversion emission intensity of Er3+ ions. The extended X-ray absorption fine structure spectroscopy data show that both the Er−O bond length and coordination number of the Er−Er bond have been altered by introducing Li+ ions in the ZnO/Er3+ nanocrystals. The variation of Er−O bond length leads to the change in the local asymmetry around Er3+ ions. Meanwhile, the greater coordination number of the Er−Er bond causes stronger interaction between neighboring Er3+ ions and, hence, strengthens the reaction Er3+ (4F7/2) + Er3+ (4I11/2) → 2Er3+ (4F9/2). In this process, the 4F9/2 state is a metastable state that could be excited to the 2H9/2 state by absorbing one photon at high excitation power. Li+ ions also can reduce the OH groups in specimen, which is the other reason for enhancing the upconversion emission intensities.

Mutations in LRRK2 (leucine-rich repeat kinase 2) have been identified as major genetic determinants of Parkinson's disease (PD). The most prevalent mutation, G2019S, increases LRRK2's kinase activity, therefore understanding the sites and substrates that LRRK2 phosphorylates is critical to understanding its role in disease aetiology. Since the physiological substrates of this kinase are unknown, we set out to reveal potential targets of LRRK2 G2019S by identifying its favored phosphorylation motif. A non-biased screen of an oriented peptide library elucidated F/Y-x-T-x-R/K as the core dependent substrate sequence. Bioinformatic analysis of the consensus phosphorylation motif identified several novel candidate substrates that potentially function in neuronal pathophysiology. Peptides corresponding to the most PD relevant proteins were efficiently phosphorylated by LRRK2 in vitro. Interestingly, the phosphomotif was also identified within LRRK2 itself. Autophosphorylation was detected by mass spectrometry and biochemical means at the only F-x-T-x-R site (Thr 1410) within LRRK2. The relevance of this site was assessed by measuring effects of mutations on autophosphorylation, kinase activity, GTP binding, GTP hydrolysis, and LRRK2 multimerization. These studies indicate that modification of Thr1410 subtly regulates GTP hydrolysis by LRRK2, but with minimal effects on other parameters measured. Together the identification of LRRK2's phosphorylation consensus motif, and the functional consequences of its phosphorylation, provide insights into downstream LRRK2-signaling pathways.

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Androgen signaling through the androgen receptor (AR), a ligand-dependent transcription factor within the steroid receptor superfamily, plays an important role in the development and maintenance of many tissues. In muscle, androgens act as anabolic agents that increase both muscle mass and strength; however, a key unanswered question is the mechanism through which AR-mediated gene expression leads to these effects. To gain further insight into the mechanism of AR action in muscle, we identified AR-binding sites in primary human muscle cells using ChIP-on-Chip (chromatin immunoprecipitation coupled with tiling microarray detection of genomic fragments). Through this analysis, we identified 32,518 potential AR-binding sites throughout the genome that were enriched upon androgen treatment. Sequence analysis of these regions indicated that approximately 90% possess a consensus androgen response element or half-site. Among the identified AR-binding sites are genes known to be directly regulated by AR, confirming the validity of our methodology. Additionally, we identified a number of novel AR targets, including genes and micro-RNAs implicated in muscle differentiation and function, suggesting a direct role for AR-mediated transcription in muscle development. Intriguingly, binding sequences for the Mef2 family of transcription factors were enriched in the AR-bound regions, and we show that several Mef2c-dependent genes are direct targets of AR, suggesting a functional interaction between Mef2c and AR in skeletal muscle. Our results provide new insights into the mechanisms by which androgens promote muscle growth and validate AR as a potential therapeutic target for sarcopenia, muscle wasting, and other androgen-related muscle disorders.

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