Proteolysis targeting chimeras for the directed ubiquitination of the androgen receptor

Proteolysis targeting chimeras (PROTACs) are an emerging field of therapeutics and promising potential drug candidates. PROTACs consist of a target protein binder connected via a linker to an E3 ligase binder. PROTACs hijack the ubiquitin proteasome system to degrade the target protein in a cellular environment. This work focuses on the androgen receptor (AR) protein, a key nuclear receptor for healthy prostate development. Hence, AR inhibition and degradation are well-established strategies for treatment of prostate cancer. First, in this work stapled peptide PROTACs recruiting E3 ligase MDM2 for AR degradation were investigated. MDM2 has been underexploited as an E3 ligase for PROTACs, despite a beneficial ability to modulate the p53 protein, a vital tumour suppressor, in additional to inducing protein degradation. Using a two-component peptide stapling strategy, stapled peptide PROTACs were developed for AR degradation via recruitment of MDM2. Stapled peptides are commonly used to target challenging protein-protein interactions, such as MDM2-p53. Peptides are capable of emulating elements of protein structure, offering significant advantages over small molecule alternatives. Second, a series of small molecule MDM2 recruiting PROTACs were synthesised to establish a novel ligand capable of expanding the PROTAC toolbox. Finally, photoswitchable AR degrading PROTACs were synthesised. The photophysics and biological activity of the PROTACs were analysed. These PROTACs integrated ortho-fluoroazobenzene for light-induced conformational change. Incorporating photoswitchable moieties in pharmaceutical entities has been demonstrated to mitigate off-target toxicity, a promising strategy to reduce attrition rates in drug discovery. Improved selectivity, efficacy, and overall safety profiles could be delivered by dosing an inactive drug and using light to modulate its biological activity at the site of action

Assessment and Characterization of Microbial Communities in Salt Affected Soils on Galveston Island

After Hurricane Ike in 2008, Galveston Island was flooded with sea water that left the soil and groundwater of the island with elevated sodium concentrations. As part of a long-term study that aims to restore plant life to the island, various soil amelioration techniques are being evaluated. Samples from bedded and non- bedded plots treated with gypsum, mulch, or both were assessed for microbial populations. Samples collected in July and October 2016 were cultured on Tryptic Soy Agar (bacteria enumeration), Pseudomonas Agar, Actinomycete Agar, and Rose Bengal Agar (fungi enumeration). Bacteria populations ranged from 4.07 to 5.12 log CFU/gram and from 3.73 to 4.26, pseudomonads from 4.09 to 5.21 and from 3.76 to 4.28, actinomycetes from 4.14 to 5.22 and from 3.87 to 4.32, and fungi from 3.27 to 3.58 and from 3.09 to 3.71 in summer then fall, respectively. There were no consistent statistical differences in microbial populations among the treatments. Respiration measurements were also compared with no differences. Samples collected from control plots in January 2017 were cultured on Pseudomonas Agar amended with 0, 5, and 10 percent salt. No statistical differences were found. Sixteen isolates were characterized and preserved for future study. The study indicates no discernible effects on microbial populations in the soil from any of the soil amelioration techniques tested

A Rainy Day

Poe

Enhancing access to parenting services using digital technology supported practices

Background: Early parenting services (EPS) in Australia provide a range of expanding and rapidly changing services, including innovative digital technologies to improve service access for metropolitan and rural families. Aim: This research aims to provide comprehensive information required for the planning, implementation and evaluation of the use of digital technologies for service delivery with parenting/child and family services in Australia and New Zealand in metropolitan and rural settings. Methods: An interpretive descriptive approach was applied using semi-structured interviews from 23 EPS practitioners and managers in five sites. Findings: These are presented as five main themes – preparing the way, practitioner qualities, benefits of using technology, presenting challenges, and management and professional development requirements. The findings have provided recommendations for the ongoing work in this area, the recruitment of new employees, and ongoing professional development and planning of services using digital supported technologies. Conclusion: This study has explored the experiences of both practitioners and managers, with a positive response despite navigating the initial and ongoing challenges that can occur with technology and internet capabilities. The use of digital technologies has significant benefits for rural and remote families due to many not having easy access to parenting services locally

SeaWiFS Postlaunch Technical Report Series

The SeaWiFS Transfer Radiometer (SXR) was built for the Sea-viewing Wide Field-of-view Sensor (SeaWiFS) Project as part of an Interagency Agreement with the National Aeronautics and Space Administration (NASA). The SXR is a multichannel radiometer designed to verify and compare measurements of spectral radiance at six discrete wavelengths in the visible and near infrared for various calibration sources in the SeaWiFS Project. In addition, the SXR is used to compare these sources to standards of spectral radiance maintained at the National Institute of Standards and Technology (NIST). The SXR was designed, built, and thoroughly characterized in the Optical Technology Division at NIST. A unique optical design provides six independent optical paths, each equipped with a temperature stabilized interference filter and silicon photodiode. A separate beam path through the input lens is used to visually align the SXR. The entrance windows for each channel overlap at the source, with each channel sampling a unique solid angle within the field of view of the SXR; this allows for simultaneous sampling of all channels. The combined standard relative uncertainty of spectral radiance measurements with the SXR is estimated to be between 0.6% and 1.3%. This report describes the design and construction of the SXR in detail, and gives the results of the optical characterization and calibrations done at NIST. The SXR has been used for several intercomparisons which include several SeaWiFS Intercalibration Round-Robin Experiments (SIRREXs); those done at the Marine Optical Buoy (MOBY) laboratories in Honolulu, Hawaii; at the NEC Corporation in Yokohama, Japan; and Orbital Sciences Corporation (OSC) in Germantown, Maryland. Thorough optical characterization and calibration of the SXR was essential to the successful application of the radiometer for these measurements

Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice

<div><p>Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.</p></div