Real Laboratories for Distance Education

Providing distance laboratory-based courses is becoming critical for distance technical education. In this work, we describe remote laboratories in digital system courses. While the hardware is based on widely used programmable logic, the Internet interfaces include those for remote development, testing and debugging as well as the cooperative work environment. Special attention has been paid to the objectivity of evaluating the remote cooperative work. The web tools for project progress evaluation, self- and group- assessment and the automated hardware support are being developed. Previous work consisted mainly of providing simulated environments or prefabricated circuits. The productivity and accessibility of these tools was greatly enhanced by using off-the-shelf hardware, software and networking elements

Estimating demographic contributions to effective population size in an age-structured wild population experiencing environmental and demographic stochasticity

We thank everyone who helped with fieldwork on Islay, in particular Sue Bignal and Pat Monaghan, as well as all land-owners and farmers who allowed access to nest sites. We thank Bernt-Erik Sӕther, Steinar Engen and Henrik Jensen for their generous help and discussions. AET was funded by the Natural Environment Research Council and Scottish Natural Heritage. JMR was supported by the European Research Council.Peer reviewedPostprin

Regulation of the androgen receptor by SET9-mediated methylation

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors that plays a critical role in regulating expression of genes involved in prostate development and transformation. Upon hormone binding, the AR associates with numerous co-regulator proteins that regulate the activation status of target genes via flux to the post-translational modification status of histones and the receptor. Here we show that the AR interacts with and is directly methylated by the histone methyltransferase enzyme SET9. Methylation of the AR on lysine 632 is necessary for enhancing transcriptional activity of the receptor by facilitating both inter-domain communication between the N- and C-termini and recruitment to androgen-target genes. We also show that SET9 is pro-proliferative and anti-apoptotic in prostate cancer cells and demonstrates up-regulated nuclear expression in prostate cancer tissue. In all, our date indicate a new mechanism of AR regulation that may be therapeutically exploitable for prostate cancer treatment

Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study

Abstract: Background: The clinical pathway to detect and diagnose prostate cancer has been revolutionised by the use of multiparametric MRI (mpMRI pre-biopsy). mpMRI however remains a resource-intensive test and is highly operator dependent with variable effectiveness with regard to its negative predictive value. Here we tested the use of the phi assay in standard clinical practice to pre-select men at the highest risk of harbouring significant cancer and hence refine the use of mpMRI and biopsies. Methods: A prospective five-centre study recruited men being investigated through an mpMRI-based prostate cancer diagnostic pathway. Test statistics for PSA, PSA density (PSAd) and phi were assessed for detecting significant cancers using 2 definitions: ≥ Grade Group (GG2) and ≥ Cambridge Prognostic Groups (CPG) 3. Cost modelling and decision curve analysis (DCA) was simultaneously performed. Results: A total of 545 men were recruited and studied with a median age, PSA and phi of 66 years, 8.0 ng/ml and 44 respectively. Overall, ≥ GG2 and ≥ CPG3 cancer detection rates were 64% (349/545), 47% (256/545) and 32% (174/545) respectively. There was no difference across centres for patient demographics or cancer detection rates. The overall area under the curve (AUC) for predicting ≥ GG2 cancers was 0.70 for PSA and 0.82 for phi. AUCs for ≥ CPG3 cancers were 0.81 and 0.87 for PSA and phi respectively. AUC values for phi did not differ between centres suggesting reliability of the test in different diagnostic settings. Pre-referral phi cut-offs between 20 and 30 had NPVs of 0.85–0.90 for ≥ GG2 cancers and 0.94–1.0 for ≥ CPG3 cancers. A strategy of mpMRI in all and biopsy only positive lesions reduced unnecessary biopsies by 35% but missed 9% of ≥ GG2 and 5% of ≥ CPG3 cancers. Using PH ≥ 30 to rule out referrals missed 8% and 5% of ≥ GG2 and ≥ CPG3 cancers (and reduced unnecessary biopsies by 40%). This was achieved however with 25% fewer mpMRI. Pathways incorporating PSAd missed fewer cancers but necessitated more unnecessary biopsies. The phi strategy had the lowest mean costs with DCA demonstrating net clinical benefit over a range of thresholds. Conclusion: phi as a triaging test may be an effective way to reduce mpMRI and biopsies without compromising detection of significant prostate cancers

Ubiquitin-specific protease 12 interacting partners Uaf-1 and WDR20 are potential therapeutic targets in prostate cancer

The androgen receptor (AR) is a key transcription factor in the initiation and progression of prostate cancer (PC) and is a major therapeutic target for the treatment of advanced disease. Unfortunately, current therapies are not curative for castration resistant PC and a better understanding of AR regulation could identify novel therapeutic targets and biomarkers to aid treatment of this disease. The AR is known to be regulated by a number of post-translational modifications and we have recently identified the deubiquitinating enzyme Usp12 as a positive regulator of AR. We determined that Usp12 deubiquitinates the AR resulting in elevated receptor stability and activity. Furthermore, Usp12 silencing was shown to reduce proliferation of PC cells. Usp12 is known to require the co-factors Uaf-1 and WDR20 for catalytic activity. In this report we focus further on the role of Uaf-1 and WDR20 in Usp12 regulation and investigate if these co-factors are also required for controlling AR activity. Firstly, we confirm the presence of the Usp12/Uaf-1/WDR20 complex in PC cells and demonstrate the importance of Uaf-1 and WDR20 for Usp12 stabilisation. Consequently, we show that individual silencing of either Uaf-1 or WDR20 is sufficient to abrogate the activity of the Usp12 complex and down-regulate AR-mediated transcription via receptor destabilisation resulting in increased apoptosis and decreased colony forming ability of PC cells. Moreover, expression of both Uaf-1 and WDR20 is higher in PC tissue compared to benign controls. Overall these results highlight the potential importance of the Usp12/Uaf-1/WDR20 complex in AR regulation and PC progression. Androgen receptor is a key transcriptional regulator in prostate cancer. Usp12/Uaf-1/WDR20 complex plays a crucial role in androgen receptor stability and activity. Destabilising an individual Usp12/Uaf-1/WDR20 complex member reduces the protein levels of the whole complex and diminishes androgen receptor activity. Protein levels of all members of the Usp12/Uaf-1/WDR20 complex are significantly increased in PC

Evaluation of Outcomes following Focal Ablative Therapy for Treatment of Localised Clinically Significant Prostate Cancer in Patients >70 Years: A Multi-institute, Multi-energy 15-year Experience

PURPOSE: In older patients who do not wish to undergo watchful waiting, focal therapy could be an alternative to the more morbid radical treatment. We evaluated the role of focal therapy (FT) in patients 70 years and older as an alternative management modality. MATERIALS AND METHODS: 649 patients across 11 UK sites receiving focal high intensity focused ultrasound (HIFU) or cryotherapy between June 2006 - July 2020 reported within the UK based HIFU Evaluation and Assessment of Treatment and the International Cryotherapy Evaluation (ICE) registries were evaluated. Primary outcome was failure free survival (FFS) defined by need for more than 1 focal re-ablation, progression onto radical treatment, development of metastases, need for systemic treatment or prostate cancer specific death. This was compared to the FFS in patients undergoing radical treatment via a propensity score weighted analysis. RESULTS: Median age was 74 years (IQR: 72, 77) and median follow-up 24 months (IQR: 12, 41). 60% had intermediate risk disease and 35% high risk disease. 113 patients (17%) required further treatment. 16 had radical treatment and 44 required systemic treatment. FFS was 82% (95% CI: 76-87%) at 5 years. Comparing patients who had radical therapy to those who had focal therapy, 5-year FFS was 96%, (95% CI: 93-100%) and 82% (95% CI: 75-91%) respectively, P < .001. 93% of those in the radical treatment arm had received Radiotherapy as their primary treatment with its associated use of Androgen Deprivation Therapy (ADT) thereby leading to potential over estimation of treatment success in the radical treatment arm, especially given the similar metastases free and overall survival rates seen. CONCLUSIONS: We propose FT to be an effective management option for the older or comorbid patient who is unsuitable for or not willing to undergo radical treatment

The opto-mechanical design of the GMT-Consortium Large Earth Finder (G-CLEF)

The GMT-Consortium Large Earth Finder (G-CLEF) will be part of the first generation instrumentation suite for the Giant Magellan Telescope (GMT). G-CLEF is a general purpose echelle spectrograph operating in the optical passband with precision radial velocity (PRV) capability. The measurement precision goal of G-CLEF is 10 cm/sec; necessary for the detection of Earth analogues. This goal imposes challenging stability requirements on the optical mounts and spectrograph support structures especially when considering the instrument's operational environment. G-CLEF's accuracy will be influenced by changes in temperature and ambient air pressure, vibration, and micro gravity-vector variations caused by normal telescope motions. For these reasons we have chosen to enclose G-CLEF's spectrograph in a wellinsulated, vibration-isolated vacuum chamber in a gravity invariant location on GMT's azimuth platform. Additional design constraints posed by the GMT telescope include; a limited space envelope, a thermal leakage ceiling, and a maximum weight allowance. Other factors, such as manufacturability, serviceability, available technology, and budget are also significant design drivers. G-CLEF will complete its Critical Design phase in mid-2018. In this paper, we discuss the design of GCLEF's optical mounts and support structures including the choice of a low-CTE carbon-fiber optical bench. We discuss the vacuum chamber and vacuum systems. We discuss the design of G-CLEF's insulated enclosure and thermal control systems which simultaneously maintain the spectrograph at milli-Kelvin level stability and limit thermal leakage into the telescope dome. Also discussed are micro gravity-vector variations caused by normal telescope slewing, their uncorrected influence on image motion, and how they are dealt with in the design. We discuss G-CLEF's front-end assembly and fiber-feed system as well as other interface, integration and servicing challenges presented by the telescope, enclosure, and neighboring instrumentation. This work has been supported by the GMTO Corporation, a non-profit organization operated on behalf of an international consortium of universities and institutions: Arizona State University, Astronomy Australia Ltd, the Australian National University, the Carnegie Institution for Science, Harvard University, the Korea Astronomy and Space Science Institute, the São Paulo Research Foundation, the Smithsonian Institution, the University of Texas at Austin, Texas AM University, the University of Arizona, and the University of Chicago

Real-time imaging of cotranscriptional splicing reveals a kinetic model that reduces noise: implications for alternative splicing regulation

A combination of several rate-limiting steps allows for efficient control of alternative splicing