Divergent Synthesis of Quinolone Natural Products from Pseudonocardia\textit{Pseudonocardia} sp. CL38489

Two divergent synthetic routes are reported offering access to four quinolone natural products from $\textit{Pseudonocardia}$ sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald–Hartwig amination and a final acid-catalysed 1,3-allylic-alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported.The research leading to these results has received funding from the European Reserach Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007-2013) and ERC grant agreement number 279337/DOS. Research in the D. R. S. lab is also supported by the Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and BiologicalSciences Research Council (BBSRC), Medical Research Council (MRC), Cancer Research UK and the Wellcome Trust. Work in the M. W lab is supported by the BBSRC and MRC. J. T. H. was supported by Trinity College Cambridge

Identification of new quorum sensing autoinducer binding partners in Pseudomonas aeruginosa using photoaffinity probes.

Many bacterial species, including the human pathogen Pseudomonas aeruginosa, employ a mechanism of intercellular communication known as quorum sensing (QS), which is mediated by signalling molecules termed autoinducers. The Pseudomonas Quinolone Signal (PQS) and 2-Heptyl-3H-4-Quinolone (HHQ) are autoinducers in P. aeruginosa, and they are considered important factors in the progress of infections by this clinically relevant organism. Herein, we report the development of HHQ and PQS photoaffinity-based probes for chemical proteomic studies. Application of these probes led to the identification of previously unsuspected putative HHQ and PQS binders, thereby providing new insights into QS at a proteomic level and revealing potential new small molecule targets for virulence attenuation strategies. Notably, we found evidence that PQS binds RhlR, the cognate receptor in the Rhl QS sub-system of P. aeruginosa. This is the first indication of interaction between the Rhl and PQS systems at the protein/ligand level, which suggests that RhlR should be considered a highly attractive target for antivirulence strategies

Ubiquitin-dependent regulation of COPII coat size and function

Packaging of proteins from the ER into COPII-vesicles is essential for secretion. In cells, most COPII-vesicles are ~60-80nm in diameter, yet some must increase their size to accommodate 300-400nm procollagen fibers or chylomicrons. Impaired COPII function results in collagen deposition defects, cranio-lenticulo-sutural dysplasia, or chylomicron retention disease, but mechanisms to enlarge COPII-coats have remained elusive. Here, we have identified the ubiquitin ligase Cul3(Klhl12) as a regulator of COPII coat formation. Cul3(Klhl12) catalyzes the monoubiquitination of the COPII-component Sec31 and drives the assembly of large COPII coats. As a result, ubiquitination by Cul3(Klhl12) is essential for collagen export, yet less important for the transport of small cargo. We conclude that monoubiquitination controls the size and function of a vesicle coat

Aurora B kinase in Hodgkin lymphoma: immunohistochemical pattern of expression in neoplastic Hodgkin and Reed-Sternberg cells

Aurora B is a member of the chromosomal passenger complex, which is essential for proper completion of mitosis and cell division (cytokinesis). Inappropriate chromosomal segregation and cytokinesis due to deregulated expression of chromosome passenger proteins may lead to aneuploidy and cancer including lymphomas. According to our knowledge there are extremely limited studies investigating the immunohistochemical expression of Aurora B in tumor specimens of Hodgkin lymphoma. Our purpose was to characterize the expression of Aurora B in biopsies of Hodgkin lymphomas, and to evaluate the pattern of immunoreactivity in neoplastic Hodgkin and Reed-Sternberg cells (RS cells). We examined Aurora B immunoreactivity in paraffin sections of 15 samples of Hodgkin lymphomas, obtained from 15 patients, 8 men and 7 women. Ten were of nodular sclerosis type and five were of mixed cellularity. Our results showed immunoexpression of Aurora B in mononuclear lymphoid cells as well as in bi- and multinucleated RS cells. In addition, positive neoplastic cells in mitosis were observed, whereas a subpopulation without evidence of immunoreaction was also detected in each case. Taken together our results point to a possible association between Aurora B expression and mitotic deregulation in Hodgkin lymphoma, which may provide novel targets for treatment