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Configuring clinical linear accelerators (linacs) for ultra-high dose rate (UHDR) electron experiments typically requires invasive hardware manipulation and/or irreversible manufacturer modifications, limiting broader implementation. We present an independently developed UHDR electron configuration of a clinical TrueBeam linac that allows reversible switching between preclinical UHDR and conventional (CONV) modes using only non-invasive software settings. UHDR mode was achieved via service mode software with RF and beam current settings typical of a photon beam, the photon target and monitor chamber retracted, and a clinically unused low-energy scattering foil inserted. An external AC current transformer (ACCT) for beam monitoring, anatomy-specific collimator, and sample holder were mounted on the accessory tray, with external ion chamber in solid water for exit dose monitoring. Percent depth dose (PDD) was measured for UHDR and CONV beams. Dose-per-pulse (DPP) was varied by adjusting gun voltage and quantified with radiochromic film at different source-to-surface distances (SSD). Beam profiles assessed dose uniformity and usable field size. Dose calibration was established between film, ACCT, and ion chamber, and day-to-day reproducibility was tested. PDD confirmed similar energies for UHDR (12.8MeV) and CONV (11.9MeV) beams with matching profiles through mouse thickness. Maximum DPP exceeded 0.5Gy, reaching ~1.5Gy for collimated in vivo setups and ~0.7Gy at extended SSD for tissue culture. Field flatness and symmetry were maintained, supporting organ-specific irradiations and up to 5cm fields for culture. Calibration showed strong linearity across detectors, and output variation was <4%. We demonstrated accurate, reproducible UHDR delivery on a widely available clinical linac with no invasive hardware manipulation, enabling preclinical FLASH research on a clinical treatment machine.

Configuring clinical linear accelerators (linacs) for ultra-high dose rate (UHDR) electron experiments typically requires invasive hardware manipulation and/or irreversible manufacturer modifications, limiting broader implementation. We present an independently developed UHDR electron configuration of a clinical TrueBeam linac that allows reversible switching between preclinical UHDR and conventional (CONV) modes using only non-invasive software settings. UHDR mode was achieved via service mode software with RF and beam current settings typical of a photon beam, the photon target and monitor chamber retracted, and a clinically unused low-energy scattering foil inserted. An external AC current transformer (ACCT) for beam monitoring, anatomy-specific collimator, and sample holder were mounted on the accessory tray, with external ion chamber in solid water for exit dose monitoring. Percent depth dose (PDD) was measured for UHDR and CONV beams. Dose-per-pulse (DPP) was varied by adjusting gun voltage and quantified with radiochromic film at different source-to-surface distances (SSD). Beam profiles assessed dose uniformity and usable field size. Dose calibration was established between film, ACCT, and ion chamber, and day-to-day reproducibility was tested. PDD confirmed similar energies for UHDR (12.8MeV) and CONV (11.9MeV) beams with matching profiles through mouse thickness. Maximum DPP exceeded 0.5Gy, reaching ~1.5Gy for collimated in vivo setups and ~0.7Gy at extended SSD for tissue culture. Field flatness and symmetry were maintained, supporting organ-specific irradiations and up to 5cm fields for culture. Calibration showed strong linearity across detectors, and output variation was <4%. We demonstrated accurate, reproducible UHDR delivery on a widely available clinical linac with no invasive hardware manipulation, enabling preclinical FLASH research on a clinical treatment machine.

Configuring clinical linear accelerators (linacs) for ultra-high dose rate (UHDR) electron experiments typically requires invasive hardware manipulation and/or irreversible manufacturer modifications, limiting broader implementation. We present an independently developed UHDR electron configuration of a clinical TrueBeam linac that allows reversible switching between preclinical UHDR and conventional (CONV) modes using only non-invasive software settings. UHDR mode was achieved via service mode software with RF and beam current settings typical of a photon beam, the photon target and monitor chamber retracted, and a clinically unused low-energy scattering foil inserted. An external AC current transformer (ACCT) for beam monitoring, anatomy-specific collimator, and sample holder were mounted on the accessory tray, with external ion chamber in solid water for exit dose monitoring. Percent depth dose (PDD) was measured for UHDR and CONV beams. Dose-per-pulse (DPP) was varied by adjusting gun voltage and quantified with radiochromic film at different source-to-surface distances (SSD). Beam profiles assessed dose uniformity and usable field size. Dose calibration was established between film, ACCT, and ion chamber, and day-to-day reproducibility was tested. PDD confirmed similar energies for UHDR (12.8MeV) and CONV (11.9MeV) beams with matching profiles through mouse thickness. Maximum DPP exceeded 0.5Gy, reaching ~1.5Gy for collimated in vivo setups and ~0.7Gy at extended SSD for tissue culture. Field flatness and symmetry were maintained, supporting organ-specific irradiations and up to 5cm fields for culture. Calibration showed strong linearity across detectors, and output variation was <4%. We demonstrated accurate, reproducible UHDR delivery on a widely available clinical linac with no invasive hardware manipulation, enabling preclinical FLASH research on a clinical treatment machine.

PDZ domains are protein-protein interaction modules that recognize specific C-terminal sequences to assemble protein complexes in multicellular organisms. By scanning billions of random peptides, we accurately map binding specificity for approximately half of the over 330 PDZ domains in the human and Caenorhabditis elegans proteomes. The domains recognize features of the last seven ligand positions, and we find 16 distinct specificity classes conserved from worm to human, significantly extending the canonical two-class system based on position -2. Thus, most PDZ domains are not promiscuous, but rather are fine-tuned for specific interactions. Specificity profiling of 91 point mutants of a model PDZ domain reveals that the binding site is highly robust, as all mutants were able to recognize C-terminal peptides. However, many mutations altered specificity for ligand positions both close and far from the mutated position, suggesting that binding specificity can evolve rapidly under mutational pressure. Our specificity map enables the prediction and prioritization of natural protein interactions, which can be used to guide PDZ domain cell biology experiments. Using this approach, we predicted and validated several viral ligands for the PDZ domains of the SCRIB polarity protein. These findings indicate that many viruses produce PDZ ligands that disrupt host protein complexes for their own benefit, and that highly pathogenic strains target PDZ domains involved in cell polarity and growth.

External beam radiotherapy is used for radical treatment of organ-confined prostate cancer and to treat lesions in metastatic disease whereas molecular radiotherapy with labelled prostate-specific membrane antigen ligands and radium-223 (223Ra) is indicated for metastatic prostate cancer and has demonstrated substantial improvements in symptom control and overall survival compared with standard-of-care treatment. Prostate cancer is considered an immunologically cold tumour, so limited studies investigating the treatment-induced effects on the immune response have been completed. However, emerging data support the idea that radiotherapy induces an immune response in prostate cancer, but whether the response is an antitumour or pro-tumour response is dependent on the radiotherapy regime and is also cell-line dependent. In vitro data demonstrate that single-dose radiotherapy regimes induce a greater immune-suppressive profile than fractionated regimes; less is known about the immune response induced by molecular radiotherapy agents, but evidence suggests that these agents might induce an immune-suppressive systemic immune response, indicated by increased expression of inhibitory checkpoint molecules such as programmed cell death 1 ligand 1 and 2, and that these changes could be associated with clinical response. Different radiotherapy modalities can induce distinct immune profiles, which can either activate or suppress immune-mediated tumour killing and the current preclinical models used for prostate cancer research are not yet optimal for studying the complexity of the radiotherapy-induced immune response.This Review focusses on what is known about the interactions between conventional radiotherapy and the immune system. The authors discuss how this knowledge can be applied to investigate gaps regarding the immune interactions of molecular radiotherapies.

Aquifers provide integral freshwater resources and host ecosystems of largely uncharacterized, truncated endemic microorganisms. In recent history, many aquifers have become increasingly contaminated from various anthropogenic sources. To better understand the impacts of nitrogen contamination on native groundwater ecosystems, 16S rRNA sequencing of the groundwater microbial communities was carried out. Samples were taken from an aquifer known to be contaminated with nitrogen from multiple sources, including fertilizers and wastewater treatment plant effluents. In total, two primary contaminants were identified: NH4+ (<0.1–3.7–26 mg L−1 NH4+ min-median-max), and NO3− (<0.01–18–150 mg L−1 NO3− min-median-max). These contaminants were found to be associated with a decrease/increase in microbial species richness within affected groundwater for NH4+/NO3−, respectively. Important phyla were identified, including Proteobacteria, which had the highest abundance within samples unaffected by NH4+ (36–81% NH4+ unaffected, 4–33% NH4+ affected), and Planctomycetes (0.05–10% NH4+ unaffected, 43–72% NH4+ affected), which had the highest abundance within the NH4+ affected samples, likely due to its ability to perform anaerobic ammonia oxidation (ANAMMOX). Planctomycetes were identified as a potential indicator for the presence of NH4+ contamination. The analysis and characterization of sequencing data alongside physicochemical data showed potential to increase the depth of our understanding of contaminant behavior and fate within a contaminated aquifer using this type of data and analysis.

This article describes the radiation facilities and associated sample preparation, management, and analysis equipment currently in place at the Dalton Cumbrian Facility, a facility which opened in 2011 to support the UK’s nuclear industry. Examples of measurements performed using these facilities are presented to illustrate their versatility and the breadth of research they make possible. Results are presented from research which furthers our understanding of radiation damage to polymeric materials, radiolytic yield of gaseous products in situations relevant to nuclear materials, radiation chemistry in light water reactor cooling systems, material chemistry relevant to immobilization of nuclear waste, and radiation-induced corrosion of fuel cladding elements. Applications of radiation chemistry relevant to health care are also described. Research concerning the mechanisms of radioprotection by dietary carotenoids is reported. An ongoing open-labware project to develop a suite of modular sample handling components suited to radiation research is described, as is the development of a new neutron source able to provide directional beams of neutrons.

Nitrogen contamination is ubiquitous across the globe; as a result of this, the need to understand and predict the extent and effects of nitrogen contamination on microbial ecosystems is increasingly important. This paper utilises a dataset that provides a rare opportunity to observe varying contamination conditions in a single aquifer and understand the differences between potential background bores and two different types of contamination spread across the other bores. Using physicochemical and microbiological community analysis, this paper aims to determine the impacts of the two contaminants, nitrate and ammonia, on the microbial communities and the differences between polluted and physicochemical background bores. Total nitrogen (N) varied by a factor of over 2000 between bores, ranging from 0.07 to 155 mg L−1. Nitrate (NO3−) concentrations ranged from 150 to <0.01 mg L−1; ammonium (NH4+) concentrations ranged from 26 to <0.1 mg L−1. MANOVA analysis confirmed an overall significant relationship (p = 0.0052) between N variables and the physicochemical data (or status) of the three areas of contamination dubbed ‘contamination zones’. The contamination zones were defined by no known presence of contamination in the uncontaminated bores, the presence of NO3− contamination and the presence of NO3− and NH4+ contamination. PERMANOVA analysis confirmed that there was an overall significant difference in the microbial communities between the three contamination zones (p = 0.0002); however, the presence of NH4+ had a significant effect (p = 0.0012). In general, the nitrate-contaminated bores showed a decrease in the abundance of individual OTUs. We further confirmed that NH4+ contamination had a significant relationship with an increased percentage of abundance occupied by the Planctomycetota phylum (specifically the Candidatus Brocadia genus). It was found that one of the two background bores (BS-004) was likely also representative of natural microbial background, and another (BS-002) showed characteristics that may be representative of past or intermittent contamination. This paper demonstrates a possible way to determine the microbial background and discusses the potential uses for this information.

Background Rapid fluid delivery from ingested beverages is the goal of oral rehydration solutions (ORS) and sports drinks. Objective The aim of the present study was to investigate the effects of increasing carbohydrate and sodium content upon fluid delivery using a deuterium oxide (D 2 O) tracer. Design Twenty healthy male subjects were divided into two groups of 10, the first group was a carbohydrate group (CHO) and the second a sodium group (Na). The CHO group ingested four different drinks with a stepped increase of 3% glucose from 0% to 9% while sodium concentration was 20 mmol/L. The Na group ingested four drinks with a stepped increase of 20 mmol/L from 0 mmol/L to 60 mmol/l while glucose concentration was 6%. All beverages contained 3 g of D 2 O. Subjects remained seated for two hours after ingestion of the experimental beverage, with blood taken every 5 min in the first hour and every 10 min in the second hour. Results Including 3% glucose in the beverage led to a significantly greater AUC 60 min (19640 ± 1252 δ‰ vs. VSMOW.60 min) than all trials. No carbohydrate (18381 ± 1198 δ‰ vs. VSMOW.60 min) had a greater AUC 60 min than a 6% (16088 ± 1359 δ‰ vs. VSMOW.60 min) and 9% beverage (13134 ± 1115 δ‰ vs. VSMOW.60 min); the 6% beverage had a significantly greater AUC 60 min than the 9% beverage. There was no difference in fluid delivery between the different sodium beverages. Conclusion In conclusion the present study showed that when carbohydrate concentration in an ingested beverage was increased above 6% fluid delivery was compromised. However, increasing the amount of sodium (0–60 mmol/L) in a 6% glucose beverage did not lead to increases in fluid delivery.

The following roundtable was commissioned as a set of brief oral presentations delivered at the joint annual conferences of the British and Irish Associations for American Studies (affectionately referred to here as \"IBAAS\"), hosted by Queen's University Belfast, on 9 April 2016. We, the associate editors of the Journal of American Studies, envisaged the roundtable as an opportunity for early-career scholars to get together and discuss the importance of the \"second project.\" In such a competitive job market, simply seeing your PhD through to publication is often not enough to land that elusive academic position; having a clearly articulated \"second project\" is important for securing a postdoctoral fellowship and/or full-time, permanent lecturing appointment. With this mind, we invited five early-career scholars (four of whom are represented here) to reflect on both the intellectual and the logistical challenges of conceptualizing a second project, especially given the precarious circumstances in which many early-career scholars teach and research once the PhD is complete and/or funding has run out. The event elicited much discussion by audience members and, in this print version of the roundtable, we include three responses by established scholars who attended the session and whom we invited to comment on the roundtable. We are deeply grateful to our ECR participants and respondents for reflecting so passionately and eloquently on changing iterations of the second project, its challenges and rewards, and on the responsibilities of established academics vis-a-vis those who have recently entered the profession.