Association of human papillomavirus 16 E2 with Rad50-interacting protein 1 enhances viral DNA replication

This work was supported by a Royal Society university research fellowship awarded to J.L.P. (UF110010). K.C.-L. is supported by a Medical Research Council research grant awarded to J.L.P. (MR/N023498/1).Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication.Publisher PDFPeer reviewe

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Investigations of G2/M decatenation checkpoint control, using the DNA topoisomerase II inhibitor ICRF-193

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

In vivo analysis of the cell cycle dependent association of the bovine papillomavirus E2 protein and ChlR1

AbstractIt has been shown that the genomes of episomally maintained DNA viruses are tethered to host cell chromosomes during cell division, facilitating maintenance in dividing cells. The papillomavirus E2 protein serves this mechanism of viral genome persistence by simultaneously associating with chromatin and the viral genome during mitosis. Several host cell proteins are reported to be necessary for the association of E2 with chromatin including the cohesion establishment factor ChlR1. Here we use fluorescence resonance energy transfer (FRET) technology to confirm the interaction between BPV-1 E2 and ChlR1. Furthermore, we use synchronised live cells to study the temporal nature of this dynamic protein interaction and show that ChlR1 and E2 interact during specific phases of the cell cycle. These data provide evidence that the association of E2 with ChlR1 contributes to a loading mechanism during DNA replication rather than direct tethering during mitotic division

Digital Palace Explorers: An On-site Storytelling Application for Families at the Tower of London

Our team adapted key elements of The Palace Explorers Program, an activity that combines online and on-site sessions to teach Key Stage 2 pupils about the Tower of London, to create an on-site, mobile digital application for families. We also provided the Education Department of Historic Royal Palaces a framework for our design process and a template for programming the application so that it could be modified and replicated at other sites overseen by Historic Royal Palaces

Digital Palace Explorers: An On-site Storytelling Application for Families at the Tower of London

Our team adapted key elements of The Palace Explorers Program, an activity that combines online and on-site sessions to teach Key Stage 2 pupils about the Tower of London, to create an on-site, mobile digital application for families. We also provided the Education Department of Historic Royal Palaces a framework for our design process and a template for programming the application so that it could be modified and replicated at other sites overseen by Historic Royal Palaces

Validity and Reliability of Surface Electromyography Measurements from a Wearable Athlete Performance System

The Athos ® wearable system integrates surface electromyography (sEMG ) electrodes into the construction of compression athletic apparel. The Athos system reduces the complexity and increases the portability of collecting EMG data and provides processed data to the end user. The objective of the study was to determine the reliability and validity of Athos as compared with a research grade sEMG system. Twelve healthy subjects performed 7 trials on separate days (1 baseline trial and 6 repeated trials). In each trial subjects wore the wearable sEMG system and had a research grade sEMG system’s electrodes placed just distal on the same muscle, as close as possible to the wearable system’s electrodes. The muscles tested were the vastus lateralis (VL), vastus medialis (VM), and biceps femoris (BF). All testing was done on an isokinetic dynamometer. Baseline testing involved performing isometric 1 repetition maximum tests for the knee extensors and flexors and three repetitions of concentric-concentric knee flexion and extension at MVC for each testing speed: 60, 180, and 300 deg/sec. Repeated trials 2-7 each comprised 9 sets where each set included three repetitions of concentric-concentric knee flexion-extension. Each repeated trial (2-7) comprised one set at each speed and percent MVC (50%, 75%, 100%) combination. The wearable system and research grade sEMG data were processed using the same methods and aligned in time. The amplitude metrics calculated from the sEMG for each repetition were the peak amplitude, sum of the linear envelope, and 95th percentile. Validity results comprise two main findings. First, there is not a significant effect of system (Athos or research grade system) on the repetition amplitude metrics (95%, peak, or sum). Second, the relationship between torque and sEMG is not significantly different between Athos and the research grade system. For reliability testing, the variation across trials and averaged across speeds was 0.8%, 7.3%, and 0.2% higher for Athos from BF, VL and VM, respectively. Also, using the standard deviation of the MVC normalized repetition amplitude, the research grade system showed 10.7% variability while Athos showed 12%. The wearable technology (Athos) provides sEMG measures that are consistent with controlled, research grade technologies and data collection procedures