Zoe Feng

© 2016 Elsevier Ltd All rights reserved.Crystallographic studies of ligands bound to biological macromolecules represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank archive, ∼75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery and design, and the goodness-of-fit of ligand models to electron-density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide PDB/Cambridge Crystallographic Data Center/Drug Design Data Resource Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30-31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the PDB? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated.

The human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro- and anti-inflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1α and tumor necrosis factor-α, which are induced by lipopolysaccharides. The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase and mammalian target of rapamycin. The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions. © 2014 Elsevier Ltd.

Both SKP2 and transforming growth factor-β1 play important roles in cancer metastasis through different mechanisms: TGF-β1 via induction of epithelial-mesenchymal transition and SKP2 via downregulating p27kip1. Recent studies indicated that c-Myc and Akt1 were active players in metastasis. In this study we demonstrated a crosstalk between these pathways. Specifically, we found that TGF-β1 treatment increased SKP2 expression accompanied with increased phosphorylation of Akt1 and c-Myc protein accumulation during EMT. We demonstrated that Akt1 was required for TGF-β1-mediated SKP2 upregulation and that c-Myc transcription factor specifically bound to the promoter of SKP2 for its enhanced transcription. Analysis of 25 samples of normal human skin, nevi, and melanomas revealed a positive correlation between c-Myc and SKP2 accumulation. Furthermore, accumulation of SKP2 and c-Myc proteins was significantly higher in metastatic melanoma samples as compared with that in primary melanomas, which again was higher than that in normal skin or nevi. In summary, our results integrated TGF-β1 signals to SKP2 via Akt1 and c-Myc during EMT, and provided, to our knowledge, a previously unreported mechanistic molecular event for TGF-β1-induced metastasis in human melanoma. © 2014 The Society for Investigative Dermatology.

© 2015 Macmillan Publishers Limited. All rights reserved.One of the primary goals of nuclear physics is to understand the force between nucleons, which is a necessary step for understanding the structure of nuclei and how nuclei interact with each other. Rutherford discovered the atomic nucleus in 1911, and the large body of knowledge about the nuclear force that has since been acquired was derived from studies made on nucleons or nuclei. Although antinuclei up to antihelium-4 have been discovered and their masses measured, little is known directly about the nuclear force between antinucleons. Here, we study antiproton pair correlations among data collected by the STAR experiment at the Relativistic Heavy Ion Collider, where gold ions are collided with a centre-of-mass energy of 200 gigaelectronvolts per nucleon pair. Antiprotons are abundantly produced in such collisions, thus making it feasible to study details of the antiproton-antiproton interaction. By applying a technique similar to Hanbury Brown and Twiss intensity interferometry, we show that the force between two antiprotons is attractive. In addition, we report two key parameters that characterize the corresponding strong interaction: the scattering length and the effective range of the interaction. Our measured parameters are consistent within errors with the corresponding values for proton-proton interactions. Our results provide direct information on the interaction between two antiprotons, one of the simplest systems of antinucleons, and so are fundamental to understanding the structure of more-complex antinuclei and their properties.