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Abstract Generative AI has prompted educators to reevaluate traditional teaching and assessment methods. This study examines AI’s ability to write essays analysing Old English poetry; human markers assessed and attempted to distinguish them from authentic analyses of poetry by first-year undergraduate students in English at the University of Oxford. Using the standard UK University grading system, AI-written essays averaged a score of 60.46, whilst human essays achieved 63.57, a margin of difference not statistically significant (p = 0.10). Notably, student submissions applied a nuanced understanding of cultural context and secondary criticism to their close reading, while AI essays often described rather than analysed, lacking depth in the evaluation of poetic features, and sometimes failing to properly recognise key aspects of passages. Distinguishing features of human essays included detailed and sustained analysis of poetic style, as well as spelling errors and lack of structural cohesion. AI essays, on the other hand, exhibited a more formal structure and tone but sometimes fell short in incisive critique of poetic form and effect. Human markers correctly identified the origin of essays 79.41% of the time. Additionally, we compare three purported AI detectors, finding that the best, ‘Quillbot’, correctly identified the origin of essays 95.59% of the time. However, given the high threshold for academic misconduct, conclusively determining origin remains challenging. The research also highlights the potential benefits of generative AI’s ability to advise on structuring essays and suggesting avenues for research. We advocate for transparency regarding AI’s capabilities and limitations, and this study underscores the importance of human critical engagement in teaching and learning in Higher Education. As AI’s proficiency grows, educators must reevaluate what authentic assessment is, and consider implementing dynamic, holistic methods to ensure academic integrity.

L-arginine metabolism through arginases and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of Chagas disease. Infection with Trypanosoma cruzi can cause a wide spectrum of disease, ranging from acute forms contained by the host immune response to chronic ones, such as the chronic chagasic cardiomyopathy. Here, we analyzed, in an in vitro model, the ability of two T. cruzi isolates, with different degrees of virulence, to regulate the metabolism of L-arginine through arginase 1 (Arg-1) and NOS2 in macrophages and through arginase 2 (Arg-2) and NOS2 in cardiomyocytes. Stimulation of bone marrow-derived macrophages (BMMΦ), obtained from CD1 mice, with TNF-α + IFN-γ induced their polarization into classically activated macrophages (CAMΦ), which expressed functional NOS2, while stimulation with IL-4 induced their polarization into alternatively activated macrophages (AAMΦ), which expressed functional Arg-1. Interestingly, stimulation of cardiomyocytes, obtained from hearts of CD1 neonatal mice, with TNF-α + IFN-γ or IL-4 also resulted in functional NOS2 and arginase expression, as observed in CAMΦ and AAMΦ, but Arg-2 was the arginase isoform expressed instead of Arg-1. We observed that infection of BMMΦ with the more virulent T. cruzi isolate (QRO) importantly diminished NOS2 expression and nitric oxide (NO) production in CAMΦ, allowing parasite survival, while infection with the less virulent isolate (CI2) did not diminish NOS2 activity and NO production in CAMΦ to a great extent, which resulted in parasite killing. Regarding Arg-1, infection of BMMΦ with the QRO isolate significantly induced Arg-1 expression and activity in AAMΦ, which resulted in a higher parasite load than the one in the unstimulated BMMΦ. Even though infection with CI2 isolate did not increase Arg-1 expression and activity in AAMΦ, the parasite load was higher than the one in the unstimulated BMMΦ but at a lesser magnitude than that observed during infection with the QRO isolate. On the other hand, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with TNF-α + IFN-γ inhibited NOS2 expression and NO production, leading to amelioration of infection. Surprisingly, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with IL-4 strongly inhibited Arg-2 expression and function, which resulted in parasite loads similar to those observed in unstimulated cardiomyocytes. Our results suggest that T. cruzi isolates that exhibit variable virulence or pathogenicity degrees differentially regulate L-arginine metabolism through Arg-1/2 and NOS2 in macrophages and cardiomyocytes.

The Ptolemaic era (305–30 BCE) is an important period of Ancient Egyptian history known for its material and scientific advances, but also intermittent political and social unrest in the form of (sometimes widespread) revolts against the Ptolemaic elites. While the role of environmental pressures has long been overlooked in this period of Egyptian history, ice-core-based volcanic histories have identified the period as experiencing multiple notable eruptions, and a repeated temporal association between explosive volcanism and revolt has recently been noted. Here we analyze the global and regional (Nile River basin) hydroclimatic response to a unique historical sequence of four large and closely timed volcanic eruptions (first a tropical one, followed by three extratropical northern hemispheric events) between 168 and 158 BCE, a particularly troubled period in Ptolemaic history for which we now provide a more detailed hydroclimatic context. The NASA (National Aeronautics and Space Administration) GISS (Goddard Institute for Space Studies) ModelE2.1 Earth system model simulates a strong radiative response with a radiative forcing (top of atmosphere) of −7.5 W m−2 (following the first eruption) and −2.5 W m−2 (after each of the three remaining eruptions) at a global scale. Associated with this, we observe a global surface cooling of the order of 1.5 ∘C following the first (tropical) eruption, with the following three extratropical eruptions extending the cooling period for more than 15 years. Consequently, this series of eruptions is observed to constrain the northward migration of the inter-tropical convergence zone (ITCZ) during the Northern Hemisphere summer monsoon season, and major monsoon zones (African, South Asian, and East Asian) were seen to experience a suppression of rainfall of >1 mm d−1 during the monsoon (JJAS) season averaged for 2 years after each eruption. A substantial suppression of the Indian and North African summer monsoon (over the Nile River headwater region) was seen to strongly affect the modeled river flow in the catchment and discharge at river mouth. River mass flow over the basin was observed to decrease by 29 % and 38 % relative to an unperturbed (non-volcanic) annual mean flow in the first and second year, respectively, after the first (i.e., tropical) eruption. A moderate decrease ranging between 5 % and 18 % was observed after the third and fourth (extratropical) eruptions. These results indicate, in sum, that the first eruption likely produced a strong hydroclimate response, with the following extratropical eruptions prolonging this. These results also support the recently hypothesized association between ice-core-based signals of explosive volcanism and hydroclimatic variability during the Ptolemaic era, including the suppression of the agriculturally critical Nile summer flooding.

The 852/3 CE eruption of Mount Churchill, Alaska, was one of the largest first-millennium volcanic events, with a magnitude of 6.7 (VEI 6) and a tephra volume of 39.4–61.9 km3 (95 % confidence). The spatial extent of the ash fallout from this event is considerable and the cryptotephra (White River Ash east; WRAe) extends as far as Finland and Poland. Proximal ecosystem and societal disturbances have been linked with this eruption; however, wider eruption impacts on climate and society are unknown. Greenland ice core records show that the eruption occurred in winter 852/3 ± 1 CE and that the eruption is associated with a relatively moderate sulfate aerosol loading but large abundances of volcanic ash and chlorine. Here we assess the potential broader impact of this eruption using palaeoenvironmental reconstructions, historical records and climate model simulations. We also use the fortuitous timing of the 852/3 CE Churchill eruption and its extensively widespread tephra deposition of the White River Ash (east) (WRAe) to examine the climatic expression of the warm Medieval Climate Anomaly period (MCA; ca. 950–1250 CE) from precisely linked peatlands in the North Atlantic region. The reconstructed climate forcing potential of the 852/3 CE Churchill eruption is moderate compared with the eruption magnitude, but tree-ring-inferred temperatures report a significant atmospheric cooling of 0.8 ∘C in summer 853 CE. Modelled climate scenarios also show a cooling in 853 CE, although the average magnitude of cooling is smaller (0.3 ∘C). The simulated spatial patterns of cooling are generally similar to those generated using the tree-ring-inferred temperature reconstructions. Tree-ring-inferred cooling begins prior to the date of the eruption suggesting that natural internal climate variability may have increased the climate system's susceptibility to further cooling. The magnitude of the reconstructed cooling could also suggest that the climate forcing potential of this eruption may be underestimated, thereby highlighting the need for greater insight into, and consideration of, the role of halogens and volcanic ash when estimating eruption climate forcing potential. Precise comparisons of palaeoenvironmental records from peatlands across North America and Europe, facilitated by the presence of the WRAe isochron, reveal no consistent MCA signal. These findings contribute to the growing body of evidence that characterises the MCA hydroclimate as time-transgressive and heterogeneous rather than a well-defined climatic period. The presence of the WRAe isochron also demonstrates that no long-term (multidecadal) climatic or societal impacts from the 852/3 CE Churchill eruption were identified beyond areas proximal to the eruption. Historical evidence in Europe for subsistence crises demonstrate a degree of temporal correspondence on interannual timescales, but similar events were reported outside of the eruption period and were common in the 9th century. The 852/3 CE Churchill eruption exemplifies the difficulties of identifying and confirming volcanic impacts for a single eruption, even when the eruption has a small age uncertainty.

Polarisation analysis for neutron scattering experiments is a powerful tool suitable for a wide variety of studies, including soft-matter samples which have no bulk magnetic behaviour and/or a significant hydrogen content. Here, we describe a method to leverage the versatility and spin-polarisation capabilities of a cold triple-axis spectrometer to perform a measurement to separate coherent and incoherent neutron scattering for a non-magnetic sample in the quasielastic neutron scattering (QENS) regime. Such measurements are complementary to unpolarised QENS measurements, which may typically be performed on a backscattering or time-of-flight spectrometer instrument where polarisation analysis can be significantly more difficult to achieve, and utilise the strengths of each type of instrument.

Abstract Background Laparoscopic cholecystectomy (LC) is the gold standard for the treatment of cholelithiasis in most countries of the world. The objective of this study was to evaluate the outcomes of LC in the surgery department of Cure International Hospital, Kabul, Afghanistan. Methods A retrospective study was conducted on 1430 LC cases performed by the general surgery department of Cure International Hospital. Data was collected from patient files and the operation theatre registry for whom LC was performed during January 2008 through December, 2019. Results Mean age was 45.77 ± 13.45 years (14–90 years), with male/female ratio of 1:4.7. One third (33%) had comorbidities. Most of patients (~ 97%) were classified as ASA grade I and II. Of all patients, 26.8% of males and 13.2% of females had gallbladder inflammation (OR = 2.203, 95% CI 1.56–2.61, P = 0.000). Overall mean duration of anesthesia was 75 ± 25.6 min. The conversion rate to OC was 4.6% (N = 66), most commonly dense adhesions at Callot’s triangle (3.8%). The intraoperative complication rate was 17.5% (N = 249), where bile/stone spillage was the most common indication (N = 235, 16.4%). Immediate postoperative complication rate was 2.4% (N = 35). Average length of stay (ALOS) after LC was 2.23 ± 1.43 days (1–19 days). Conclusion This study shows that elective LC can be performed safely in Afghanistan with comparable outcomes in terms of complications, conversion rates, and ALOS to other countries of the region and the world. Proper case selection and careful preoperative evaluation and management can decrease further conversion, intra- and postoperative complications.

A substantial portion of seafood is mislabeled, causing significant impacts to human health, the environment, the economy, and society. Despite the large scientific literature documenting seafood mislabeling the public’s awareness of seafood mislabeling is unknown. We conducted an online survey to assess the public’s awareness and perceptions of seafood mislabeling. Of the 1,216 respondents, 38% had never heard of seafood mislabeling and 49% were only ‘vaguely familiar’ with it. After being provided the definition of seafood mislabeling 95% had some degree of concern. Respondents were the most concerned about environmental impacts caused by seafood mislabeling and the least concerned about the social justice implications. Respondents who were also more concerned and familiar with seafood mislabeling stated that they would be more likely to purchase seafood from a vendor where the labeling was independently verified.

Metastatic spread of testicular cancer has been well documented, with 95% of cases involving para-aortic retroperitoneal lymph nodes. Mesenteric lymphatic basins do not lie within the canonical drainage pathway of the testes and represent a rare site of metastasis. Various mechanisms of spread to the mesentery have been described, including direct extension and haematogenous dissemination. We present a case of a previously-well 43-year-old man who presented with right scrotal discomfort and intermittent lower back pain, who was found to have mesenteric metastases from a non-seminomatous germ cell tumour of the testis. Managing lymphadenopathy that lies outside of standard resection templates remains a complex surgical challenge. Here we present the first case in the English medical literature with co-existing supradiaphragmatic axillary and mediastinal nodal disease.

A 50-year-old male underwent small volume TURP for median lobe prostatic hypertrophy. Post-procedure, a 3-way urethral catheter was placed. He subsequently developed flank pain, anuria and creatinine rise. CT demonstrated bilateral obstructive uropathy.In the absence of obstructing lesions, it was suspected that the catheter balloon may have caused obstruction of bilateral ureteric orifices. Balloon deflation (from 30 to 10 mL) and catheter repositioning resulted in rapid resolution of pain and resumption of urine output.Urologists should consider the catheter balloon as a cause of obstructive uropathy, especially after procedures where normal trigonal anatomy is disrupted.

Acute Myeloid Leukemia (AML) develops following multiple mutations of differing impact. Here, the authors show that activating mutations of CSF3R co-operate with loss-of-function mutations of CEBPA to promote AML development through an enhancer-dependent mechanism.

In a recent work we demonstrated that Trypanosoma cruzi trypomastigotes change their motility patterns in the presence of mammalian cells, that the extent of the changes depends on the cell line, and that this extent is positively correlated with the efficiency with which parasites invade the different cell lines. These results open the question of what cellular characteristics are relevant for parasite identification and invasion. In the present work, we tackled such question. We performed infection-kinetics experiments on various cell lines, and developed a mathematical model to simulate the experimental outcomes. An analysis of the cell-parasite mechanisms included in the model, together with the parameter values that allowed it to replicate the experimental results, suggests that a process related to the cell replication rate may strongly influence the parasite invasion efficiency, and the infection dynamics in general.

Background: Occupational health laws must recognise the constitutional requirement of substantive equality, and its role in ‘the progressive realisation’ of the rights provided by Section 27. Objectives: Our main aim is to review current South African occupational health law (vis-à-vis workers’ constitutional rights) in relation to hearing loss. We focus on gaps in the law regarding occupational hearing loss in South Africa. Method: Our review of legal texts relies on experience as a methodological device augmented by the use of a critical science. Guided by literature or evidence synthesis methodologies, South African primary and secondary laws were reviewed along with unpublished (non-peer-reviewed) grey literature. An established six-step framework guided our thematic analysis. A semantic approach aided the critical interpretation of data using the Bill of Rights as a core analytical framework. Results: Four themes are discussed: (1) separate and unequal regulatory frameworks; (2) monologic foregrounding of noise; (3) minimisation of vestibular disorders; and (4) dilution of ototoxic agents. The highly divided legal framework of occupational health and safety in South Africa perpetuates a monologic ‘excessive noise-hearing loss’ paradigm that has implications for the rights of all workers to equal protections and benefits. There is a need to harmonise occupational health and safety law, and expand the scope of hearing-protection legislation to include the full range of established ototoxic hazards. Conclusion: Occupational audiology is dominated by efforts to address noise-induced hearing loss. A ‘noise’ despite the reality of workers’ exposures to a range of ototoxic stressors that act synergistically on the ear, resulting in audio-vestibular disorders.

Nanowire networks with memristive properties are promising for neuromorphic applications. Here, the authors observe the formation of a preferred conduction pathway which uses the lowest possible energy to get through the network and could be exploited for the design of optimal brain-inspired devices.

The degree to which human societies have responded to past climatic changes remains unclear. Here, using a novel combination of approaches, the authors show how volcanically-induced suppression of Nile summer flooding led to societal unrest in Ptolemaic Egypt (305–30 BCE).

Canavan disease is a leukodystrophy caused by mutations in the ASPA gene. This gene encodes the enzyme that converts N-acetylaspartate into acetate and aspartic acid. In Canavan disease, spongiform encephalopathy of the brain causes progressive mental retardation, motor deficit and death. We have isolated a mouse with a novel ethylnitrosourea-induced mutation in Aspa. This mutant, named deaf14, carries a c.516T>A mutation that is predicted to cause a p.Y172X protein truncation. No full-length ASPA protein is produced in deaf14 brain and there is extensive spongy degeneration. Interestingly, we found that deaf14 mice have an attenuated startle in response to loud noise. The first auditory brainstem response peak has normal latency and amplitude but peaks II, III, IV and V have increased latency and decreased amplitude in deaf14 mice. Our work reveals a hitherto unappreciated pathology in a mouse model of Canavan disease, implying that auditory brainstem response testing could be used in diagnosis and to monitor the progression of this disease.

The present work is aimed at characterizing the motility of parasite T. cruzi in its epimastigote form. To that end, we recorded the trajectories of two strains of this parasite (a wild-type strain and a stable transfected strain, which contains an ectopic copy of LYT1 gene and whose motility is known to be affected). We further extracted parasite trajectories from the recorded videos, and statistically analysed the following trajectory-step features: step length, angular change of direction, longitudinal and transverse displacements with respect to the previous step, and mean square displacement. Based on the resulting observations, we developed a mathematical model to simulate parasite trajectories. The fact that the model predictions closely match most of the experimentally observed parasite-trajectory characteristics, allows us to conclude that the model is an accurate description of T. cruzi motility.

Over 120 loci are known to cause inherited hearing loss in humans. The deafness gene has been identified for only half of these loci. With the aim of identifying some of the remaining deafness genes, we performed an ethylnitrosourea mutagenesis screen for deaf mice. We isolated two mutants with semi-dominant hearing loss, Deaf11 and Deaf13. Both contained causative mutations in Atp2b2, which encodes the plasma membrane calcium ATPase 2. The Atp2b2 (Deaf11) mutation leads to a p. I1023S substitution in the tenth transmembrane domain. The Atp2b2 (Deaf13) mutation leads to a p. R561S substitution in the catalytic core. Mice homozygous for these mutations display profound hearing loss. Heterozygotes display mild to moderate, progressive hearing loss.

Implementation of the Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA) broke the automatic linkage between Medicaid eligibility/enrollment and welfare cash assistance for women eligible at welfare income levels. This study used data from the Pregnancy Risk Assessment Monitoring System (PRAMS) for the period 1996–1999 to examine insurance coverage of these and other pregnant women pre- and post-PRWORA. Controlling for individual characteristics and economic growth, the relative odds of having private insurance did not change while the odds of being Medicaid enrolled versus uninsured pre-pregnancy declined for welfare-eligible women post-PRWORA. The absolute effect was a decline of 7.9 percentage points in the probability of welfare-eligible women being insured. While these results apply to the early years of welfare reform, it is still likely that states can improve Medicaid outreach and enrollment of women eligible prior to pregnancy.

We present here the first measurement of the third-order spatial correlation function for atoms, made possible by cooling a metastable helium cloud to create an ultracold thermal ensemble just above the Bose–Einstein condensation point. The resulting large correlation length well exceeds the spatial resolution limit of the single-atom detection system, and enables extension of our earlier temporal measurements to evaluate the third-order correlation function in the spatial plane of the detector. The enhancement of the spatial third-order correlation function above a value of unity demonstrates the presence of spatial three-atom bunching, as expected for an incoherent source.

The 17-subunit RNA polymerase III (RNAP III) synthesizes essential untranslated RNAs such as tRNAs and 5S rRNA. In yeast and vertebrates, subunit C82 forms a stable subcomplex with C34 and C31 that is necessary for promoter-specific transcription initiation. Little is known about RNAP III transcription in trypanosomatid parasites. To narrow this knowledge gap, we characterized the C82 subunit in Trypanosoma brucei and Leishmania major. Bioinformatic analyses showed that the 4 distinctive extended winged-helix (eWH) domains and the coiled-coil motif are present in C82 in these microorganisms. Nevertheless, C82 in trypanosomatids presents certain unique traits, including an exclusive loop within the eWH1 domain. We found that C82 localizes to the nucleus and binds to RNAP III-dependent genes in the insect stages of both parasites. Knock-down of C82 by RNA interference significantly reduced the levels of tRNAs and 5S rRNA and led to the death of procyclic forms of T. brucei. Tandem affinity purifications with both parasites allowed the identification of several C82-interacting partners, including C34 and some genus-specific putative regulators of transcription. However, the orthologue of C31 was not found in trypanosomatids. Interestingly, our data suggest a strong association of C82 with TFIIIC subunits in T. brucei, but not in L. major.

This tutorial presents topic models for organizing and comparing documents. The technique and corresponding discussion focuses on analysis of short text documents, particularly micro-blogs. However, the base topic model and R implementation are generally applicable to text analytics of document databases. [ABSTRACT FROM AUTHOR]

Background: Whether stereotactic body radiotherapy (SBRT) is noninferior to conventionally or moderately hypofractionated regimens with respect to biochemical or clinical failure in patients with localized prostate cancer is unclear., Methods: We conducted a phase 3, international, open-label, randomized, controlled trial. Men with stage T1 or T2 prostate cancer, a Gleason score of 3+4 or less, and a prostate-specific antigen (PSA) level of no more than 20 ng per milliliter were randomly assigned (in a 1:1 ratio) to receive SBRT (36.25 Gy in 5 fractions over a period of 1 or 2 weeks) or control radiotherapy (78 Gy in 39 fractions over a period of 7.5 weeks or 62 Gy in 20 fractions over a period of 4 weeks). Androgen-deprivation therapy was not permitted. The primary end point was freedom from biochemical or clinical failure, with a critical hazard ratio for noninferiority of 1.45. The analysis was performed in the intention-to-treat population., Results: A total of 874 patients underwent randomization at 38 centers (433 patients in the SBRT group and 441 in the control radiotherapy group) between August 2012 and January 2018. The median age of the patients was 69.8 years, and the median PSA level was 8.0 ng per milliliter; the National Comprehensive Cancer Network risk category was low for 8.4% of the patients and intermediate for 91.6%. At a median follow-up of 74.0 months, the 5-year incidence of freedom from biochemical or clinical failure was 95.8% (95% confidence interval [CI], 93.3 to 97.4) in the SBRT group and 94.6% (95% CI, 91.9 to 96.4) in the control radiotherapy group (unadjusted hazard ratio for biochemical or clinical failure, 0.73; 90% CI, 0.48 to 1.12; P = 0.004 for noninferiority), which indicated the noninferiority of SBRT. At 5 years, the cumulative incidence of late Radiation Therapy Oncology Group (RTOG) grade 2 or higher genitourinary toxic effects was 26.9% (95% CI, 22.8 to 31.5) with SBRT and 18.3% (95% CI, 14.8 to 22.5) with control radiotherapy (P<0.001), and the cumulative incidence of late RTOG grade 2 or higher gastrointestinal toxic effects was 10.7% (95% CI, 8.1 to 14.2) and 10.2% (95% CI, 7.7 to 13.5), respectively (P = 0.94)., Conclusions: Five-fraction SBRT was noninferior to control radiotherapy with respect to biochemical or clinical failure and may be an efficacious treatment option for patients with low-to-intermediate-risk localized prostate cancer as defined in this trial. (Funded by Accuray and others; PACE-B ClinicalTrials.gov number, NCT01584258.)., (Copyright © 2024 Massachusetts Medical Society.)

Background and Objective: Randomised data on patient-reported outcomes (PROs) for stereotactic body radiotherapy (SBRT) and prostatectomy in localised prostate cancer are lacking. PACE-A compared patient-reported health-related quality of life after SBRT with that after prostatectomy., Methods: PACE is a phase 3 open-label, randomised controlled trial. PACE-A randomised men with low- to intermediate-risk localised prostate cancer to SBRT or prostatectomy (1:1). Androgen deprivation therapy (ADT) was not permitted. The coprimary outcomes were the Expanded Prostate Index Composite (EPIC-26) number of absorbent urinary pads required daily and bowel domain score at 2 yr. The secondary endpoints were clinician-reported toxicity, sexual functioning, and other PROs., Key Findings and Limitations: In total, 123 men were randomised (60 undergoing prostatectomy and 63 SBRT) from August 2012 to February 2022. The median follow-up time was 60.7 mo. The median age was 65.5 yr and the median prostate-specific antigen (PSA) value 7.9 ng/ml; 92% had National Comprehensive Cancer Network (NCCN) intermediate-risk disease. Fifty participants received prostatectomy and 60 received SBRT. At 2 yr, 16/32 (50%) prostatectomy and three of 46 (6.5%) SBRT participants used one or more urinary pads daily (p < 0.001; 15 and two, respectively, used one pad daily); the estimated difference was 43% (95% confidence interval [CI]: 25%, 62%). At 2 yr, bowel scores were better for prostatectomy (median [interquartile range] 100 [100-100]) than for SBRT (87.5 [79.2-100]; p < 0.001), with an estimated mean difference of 8.9 between these (95% CI: 4.2, 13.7); sexual scores were worse for prostatectomy (18 [13.8-40.3]) than for SBRT (62.5 [32.0-87.5]). The limitations were slow recruitment and incomplete 2-yr PRO response rates., Conclusions and Clinical Implications: SBRT was associated with less patient-reported urinary incontinence and sexual dysfunction, and slightly more bowel bother than prostatectomy. These randomised data should inform treatment decision-making for patients with localised, intermediate-risk prostate cancer., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Patient-reported outcomes (PRO) are currently collected from trial participants using paper questionnaires by the Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU). Streamlining PRO collection using electronic questionnaires (ePRO) may improve data collection and patient experience. Here, we outline our protocol for a Study within a trial of electronic versus paper-based Patient-Reported oUtcomes CollEction (SPRUCE), which investigates the acceptability of ePRO in oncology clinical trials., Methods and Analysis: SPRUCE was developed alongside patient and public contributors. SPRUCE runs in multiple host trials with a partially randomised patient preference design, allowing participants to be randomised or choose their preference of electronic or paper questionnaires. Questionnaires are scheduled in accordance with host trial follow-up. The primary objective will assess differences in return rates (compliance) between ePRO and paper PROs at the first timepoint post-host trial intervention in the randomised group. Paper PRO compliance is expected to be 90%. 244 randomised participants are required to exclude ≤80% compliance rates with ePRO (10% non-inferiority margin, with 80% power and one-sided alpha=0.05). SPRUCE aims to assess acceptability of ePRO in oncology clinical trials, establish whether ePRO is acceptable to ICR-CTSU trial participants and can capture complete PRO data, consistent with paper PROs., Ethics and Dissemination: The SPRUCE protocol (ICR-CTSU/2021/10074) was approved by the Coventry and Warwick Central Research Ethics Committee (21/WM/0223) on 21 October 2021. Results will be disseminated via presentations, publications and lay summaries. No participant identifiable data will be included., Trial Registration: SWAT169., Competing Interests: Competing interests: EH receives support from a Cancer Research UK (CRUK) core grant (C1491/A25351) and LP receives support from her PhD by a CRUK clinical trials fellowship (A30384); no other authors have any potential conflicts of interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Conventional protein kinase C (cPKC) isozymes tune the signaling output of cells, with loss-of-function somatic mutations associated with cancer and gain-of-function germline mutations identified in neurodegeneration. PKC with impaired autoinhibition is removed from the cell by quality-control mechanisms to prevent the accumulation of aberrantly active enzyme. Here, we examine how a highly conserved residue in the C1A domain of cPKC isozymes permits quality-control degradation when mutated to histidine in cancer (PKCβ-R42H) and blocks down-regulation when mutated to proline in the neurodegenerative disease spinocerebellar ataxia (PKCγ-R41P). Using FRET-based biosensors, we determined that mutation of R42 to any residue, including lysine, resulted in reduced autoinhibition as indicated by higher basal activity and faster agonist-induced plasma membrane translocation. R42 is predicted to form a stabilizing salt bridge with E655 in the C-tail and mutation of E655, but not neighboring E657, also reduced autoinhibition. Western blot analysis revealed that whereas R42H had reduced stability, the R42P mutant was stable and insensitive to activator-induced ubiquitination and down-regulation, an effect previously observed by deletion of the entire C1A domain. Molecular dynamics (MD) simulations and analysis of stable regions of the domain using local spatial pattern (LSP) alignment suggested that P42 interacts with Q66 to impair mobility and conformation of one of the ligand-binding loops. Additional mutation of Q66 to the smaller asparagine (R42P/Q66N), to remove conformational constraints, restored degradation sensitivity. Our results unveil how disease-associated mutations of the same residue in the C1A domain can toggle between gain- or loss-of-function of PKC., (© 2023 The Author(s).)

Plant community assembly outcomes can be contingent upon establishment year (year effects) due to variations in the environment. Stochastic events such as interannual variability in climate, particularly in the first year of community assembly, contribute to unpredictable community outcomes over the short term, but less is known about whether year effects produce transient or persistent states on a decadal timescale. To test for short-term (5-year) and persistent (decadal) effects of establishment year climate on community assembly outcomes, we restored prairie in an agricultural field using the same methods in four different years (2010, 2012, 2014, and 2016) that captured a wide range of initial (planting) year climate conditions. Species composition was measured for 5 years in all four restored prairies and for 9 and 11 years in the two oldest restored prairies established under average precipitation and extreme drought conditions. The composition of the four assembled communities showed large and significant differences in the first year of restoration, followed by dynamic change over time along a similar trajectory due to a temporary flush of annual volunteer species. Sown perennial species eventually came to dominate all communities, but communities remained distinct from each other in year five. Precipitation in June and July of the establishment year explained short-term coarse community metrics (i.e., species richness and grass/forb cover), with wet establishment years resulting in a higher cover of grasses and dry establishment years resulting in a higher cover of forbs in restored communities. Short-term differences in community composition, species richness, and grass/forb cover in restorations established under average precipitation and drought conditions persisted for 9-11 years, with low interannual variability in the composition of each prairie over the long term, indicating persistently different states on a decadal timescale. Thus, year effects resulting from stochastic variation in climate can have decadal effects on community assembly outcomes., (© 2023 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

The application of mulch films for preserving soil moisture and preventing weed growth has been a part of agricultural practice for decades. Different materials have been used as mulch films, but polyethylene plastic has been considered most effective due to its excellent mechanical strength, low cost and ability to act as a barrier for sunlight and water. However, its use carries a risk of plastic pollution and health hazards, hence new laws have been passed to replace it completely with other materials over the next few years. Research to find out about new biodegradable polymers for this purpose has gained impetus in the past few years, driven by regulations and the United Nations Organization's Sustainable Development Goals. The primary requisite for these polymers is biodegradability under natural climatic conditions without the production of any toxic residual compounds. Therefore, biodegradable polymers developed from fossil fuels, microorganisms, animals and plants are viable options for using as mulching material. However, the solution is not as simple since each polymer has different mechanical properties and a compromise has to be made in terms of strength, cost and biodegradability of the polymer for its use as mulch film. This review discusses the history of mulching materials, the gradual evolution in the choice of materials, the process of biodegradation of mulch films, the regulations passed regarding material to be used, types of polymers that can be explored as potential mulch films and the future prospects in the area.

Only half of atrial fibrillation (AF) patients with elevated stroke risk receive anticoagulation (AC). Electronic health record (EHR) alerts have the potential to close the gap. We designed an outpatient EHR alert (linked to an order set for ordering AC, labs, and specialty referrals) that fired when cardiology and primary care providers (PCPs) saw AF patients not on AC. We assigned all untreated patients seen by cardiology providers and PCPs in the 8 months before and after the alert launch to pre- and post-launch intervention cohorts, respectively. Untreated AF patients seeing other types of providers became controls. We then compared the difference in AC starts between intervention and control patients post-launch to the same difference prelaunch (adjusting for covariates). We measured alert responsiveness as how often patients had at least one encounter with a provider, who interacted with the alert. The adjusted percentage of AC starts for the prelaunch cohort was 20% for intervention patients and 17% for controls (difference = 3%); post-launch, the percentage was 13% for both post-launch intervention and controls (difference = 0%). The difference in difference was - 3% (p value 0.63). For half of patients, at least one provider was responsive to our alert. Reasons for no AC commonly included relative contraindications (e.g. fall, gastrointestinal bleed). Our alert did not increase AC starts but responsiveness to it was high. Increasing AC starts will likely require education surrounding relative contraindications., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Six million Americans suffer from atrial fibrillation (AF), a heart rhythm abnormality that significantly increases the risk of stroke. AF is responsible for 15% of ischemic strokes, which lead to permanent disability in 60% of cases and death in up to 20%. Anticoagulation (AC) is the mainstay for stroke prevention in patients with AF. Despite guidelines recommending AC for patients, up to half of eligible patients are not on AC. Clinical decision support tools in the electronic health record (EHR) can help bridge the disparity in AC prescription for patients with AF., Objective: To enhance and assess the effectiveness of our previous rule-based alert on AC initiation and persistence in a diverse patient population from UMass-Memorial Medical Center and University of Florida at Jacksonville., Methods/results: Using the EHR, we will track AC initiation and persistence. We will interview both patients and providers to determine a measure of satisfaction with AC management. We will track digital crumbs to better understand the alert's mechanism of effect and further add enhancements. These enhancements will be used to refine the alert and aid in developing an implementation toolkit to facilitate use of the alert at other health systems., Conclusion: If the number of AC starts, the likelihood of persisting on AC, and the frequency alert use are found to be higher among intervention vs control providers, we believe such findings will confirm our hypothesis on the effectiveness of our alert., (© 2021 Heart Rhythm Society.)

Rationale: African-American mothers in the U.S. experience high rates of stress, placing them at risk for depression, anxiety, and preterm births, and their children at risk for poor social-emotional development later in childhood. Yet, few studies have developed and tested family-based interventions that target optimal management of stress in this population., Objective: The current mixed methods study examined whether a six-week family-based intervention (e.g., cognitive behavioral stress management intervention component for mothers and mindfulness-based kindness curriculum for their children) was effective in improving psychosocial outcomes among low-income African-American mothers and increasing prosocial behaviors in their children., Method: Seventy-two mothers (28% pregnant, 72% postpartum) completed pre- and post-intervention assessments of stress, depression, anxiety, and self-efficacy for stress management. Prosocial behaviors for 38 of their children (3-10 years of age) were also assessed via mother's self-report and two observational child assessments of sharing and helping behaviors. Qualitative interviews at post-intervention and reunion focus groups (up to two years later) were also conducted., Results: Mothers showed significant reductions in perceived stress, depressive symptoms, and anxiety, as well as improved self-efficacy for stress management at post-intervention. Although observational assessments of children's sharing and helping behaviors did not change, mothers' qualitative responses indicated improvements in their child's prosocial behaviors at home. Qualitative responses also revealed unique stressors that mothers experienced, the short- and long-term impact of these interventions on mothers and their children, and program recommendations., Conclusions: These results support the efficacy of family-based stress management interventions in this at-risk population., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mental ill health affects individual well-being and national economic prosperity and makes up a substantial portion of the burden of disease globally, especially in the Asia-Pacific region. Integrating mental health into primary care is widely considered a key strategy to improve access to mental health care. Integration, however, is a complex process that needs to be addressed at multiple levels. A collaboration between the Asia-Pacific Economic Cooperation (APEC) Digital Hub for Mental Health and the World Organization of Family Doctors (WONCA) is described in this paper, which outlines a framework and next steps to improve the mental health of communities in APEC economies. This paper notes gaps related to the integration of mental health into primary care across the region and identifies enablers and current best practices from several APEC economies. The potential of digital technology to benefit primary mental health care for populations in the APEC region, including delivery of training programs for healthcare staff and access to resources for patients, is described. Finally, key next steps are proposed to promote enhanced integration into primary care and improve mental health care throughout the APEC region., Competing Interests: Dowrick C. has nothing to disclose. Kassai R. has nothing to disclose. Lam CLK. has nothing to disclose. Lam RW. reports personal fees from Allergan, Lundbeck Institute, Hansoh, Otsuka, Canadian Network for Mood & Anxiety Treatments, and Myriad Neuroscience; grants from Asia-Pacific Economic Cooperation, grants from VGH-UBCH Foundation, BC Leading Edge Endowment Fund, and St. Jude Medical; and grants and personal fees from Janssen, Lundbeck, and Pfizer, outside the submitted work. Manning G. has nothing to disclose. Murphy J. reports grants from MITACS outside the submitted work. Ng CH. reports travel support and honorarium for delivery of talks from Pfizer, Lundbeck and Janssen outside the submitted work. Thuraisingham C. has nothing to disclose. Lam RW. and Murphy J. report no other potential conflicts of interest for this work., (© 2020 Dowrick et al.)

Background: Metastatic breast cancer is the leading cause of cancer death in women, but the genomics of metastasis in breast cancer are poorly studied., Methods: We explored a set of 11,616 breast tumors, including 5,034 metastases, which had undergone targeted sequencing during standard clinical care., Results: Besides the known hotspot mutations in ESR1, we observed a metastatic enrichment of previously unreported, lower-prevalence mutations in the ligand-binding domain, implying that these mutations may also be functional. Furthermore, individual ESR1 hotspots are significantly enriched in specific metastatic tissues and histologies, suggesting functional differences between these mutations. Other alterations enriched across all metastases include loss of function of the CDK4 regulator CDKN1B, and mutations in the transcription factor CTCF. Mutations enriched at specific metastatic sites generally reflect biology of the target tissue and may be adaptations to growth in the local environment. These include PTEN and ASXL1 alterations in brain metastases and NOTCH1 alterations in skin. We observed an enrichment of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases. However, the patterns of other mutations in these tumors indicate that these are misdiagnosed lung primaries rather than breast metastases., Conclusions: An order-of-magnitude increase in samples relative to previous studies allowed us to detect novel genomic characteristics of metastatic cancer and to expand and clarify previous findings., Competing Interests: All authors were employees and may have held shares of Genentech/Roche or Foundation Medicine at the time this work was completed. Both companies are involved in the development of cancer drugs and clinical assays for metastatic breast cancer, and have multiple patents in related areas. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinase-domain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit necroptosis by sequestering RIPK3 via its kinase domain to thwart MLKL engagement and phosphorylation. These data support an ancestral role for necroptosis in defense against pathogens. Furthermore, mimicry of a cellular pseudokinase by a pathogen adds to the growing repertoire of functions performed by pseudokinases in signal transduction., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Campylobacter is the leading cause of bacterial enteritis in the developed world, and infections with the organism are largely sporadic in nature. Links between sporadic cases have not been established, with the majority of infections thought to be caused by genetically distinct isolates. Using a read-mapping approach, 158 clinical isolates collected during 2014 from the greater Nottinghamshire area were analysed to assess the local population structure and investigate potential case linkages between sporadic cases of campylobacteriosis. Four instances (2.5 %) of case linkage were observed across the dataset. This study demonstrates that case linkage does occur between sporadic Campylobacter infections, and provides evidence that a dual multi-locus sequence typing/within-lineage single nucleotide polymorphism typing approach to Campylobacter genomic epidemiology provides a benefit to public-health investigations.

Background: Approximately one in five breast cancers are driven by amplification and overexpression of the human epidermal growth factor receptor 2 (HER2) receptor kinase, and HER2-enriched (HER2E) is one of four major transcriptional subtypes of breast cancer. We set out to understand the genomics of HER2 amplification independent of subtype, and the underlying drivers and biology of HER2E tumors., Methods: We investigated published genomic data from 3155 breast tumors and 5391 non-breast tumors., Results: HER2 amplification is a distinct driver event seen in all breast cancer subtypes, rather than a subtype marker, with major characteristics restricted to amplification and overexpression of HER2 and neighboring genes. The HER2E subtype has a distinctive transcriptional landscape independent of HER2A that reflects androgen receptor signaling as replacement for estrogen receptor (ER)-driven tumorigenesis. HER2 amplification is also an event in 1.8% of non-breast tumors., Conclusions: These discoveries reveal therapeutic opportunities for combining anti-HER2 therapy with anti-androgen agents in breast cancer, and highlight the potential for broader therapeutic use of HER2 inhibitors.

Atrazine is a selective triazine herbicide widely used in the United States primarily for control of broadleaf weeds in corn and sorghum. In 2003, the US Environmental Protection Agency (USEPA) concluded that atrazine poses potential risks to sensitive aquatic species. Consequently, a surface water monitoring program was developed to assess whether measured levels of atrazine could impact aquatic plants in vulnerable watersheds. To facilitate evaluation of the monitoring data, the Agency needed to establish a level of concern (LOC) below which atrazine would not cause unacceptable adverse effects to aquatic plant communities. Several attempts at developing a community-level LOC have followed from USEPA but none have been formally accepted or endorsed by independent Scientific Advisory Panels. As part of registration review, the USEPA needs to revisit development of a community-level LOC for atrazine that will be protective of aquatic plant communities. This article reviews 4 methods that can or have been used for this purpose. Collectively, the methods take advantage of the large number of single species and mesocosm studies that have been conducted for aquatic plants exposed to atrazine. The Plant Assemblage Toxicity Index (PATI) and the Comprehensive Aquatic Systems Model for atrazine (CASM ATZ2 ) incorporate single-species toxicity data but are calibrated with micro- and mesocosm study results to calculate community-level LOCs. The Brock et al. scoring system relies exclusively on mesocosm studies. Single-species toxicity data were used in a modified version of the USEPA's Water Quality Criteria (WQC) method. The 60-day LOCs calculated using the 4 methods ranged from 19.6 to 26 µg/L. A weight-of-evidence assessment indicated that the CASM ATZ2 method was the most environmentally relevant and statistically reliable method. Using all 4 methods with weights based on method reliability, the weighted 60-day LOC was 23.6 µg/L. Integr Environ Assess Manag 2017;13:686-701. © 2016 SETAC., (© 2016 SETAC.)

Protein phosphatases are the essential opposite to protein kinases; together, these enzymes regulate all protein phosphorylation and most cellular processes. To better understand the global roles of protein phosphorylation, we cataloged the human protein phosphatome, composed of 189 known and predicted human protein phosphatase genes. We also identified 79 protein phosphatase pseudogenes or retrogenes, some of which may have residual function. We traced the origin and diversity of phosphatases by building protein phosphatomes for eight other eukaryotes, from the protist Dictyostelium to the sea urchin. We classified protein phosphatases from all nine species into a hierarchy of 10 protein folds, 21 families, and 178 subfamilies. We found that >80% of the 101 human subfamilies were conserved across the animal kingdom, but show substantial differences in evolution, including losses and expansions of individual subfamilies and changes in accessory domains. Protein phosphatases show similar evolutionary dynamics to those of kinases, with substantial losses in major model organisms. Sequence analysis predicts that 26 human protein phosphatase domains are catalytically disabled and that this disability is mostly conserved across orthologs. This genomic and evolutionary perspective on protein phosphatases provides a framework for global analysis of protein phosphorylation throughout the animal kingdom., (Copyright © 2017, American Association for the Advancement of Science.)

Ionizing radiation (IR) exposure of cells in vitro and in vivo triggers a complex cellular response among which modifications of gene expression have been consistently reported. Nevertheless, little is currently known about the transcriptionally responsive genes which play a role in the inflammation response. In order to improve our understanding of such transcriptional response to radiation in vivo , we simultaneously monitored the expression of 249 genes associated with the inflammation response over the course of the radiotherapy treatment in blood of patients treated for endometrial or head and neck cancer. We have identified genes whose transcriptional expression is either upregulated ( ARG1, BCL2L1 ) or downregulated ( MYC ) several fold in vivo . These modifications were consistently detected across patients and further confirmed by quantitative real-time polymerase chain reaction (QRT-PCR); they were specifically significant toward the end of the radiotherapy treatment, 5 weeks following the first radiation fraction and more pronounced in endometrial patients (respectively, 2.9, 4.1, and 1.8 times). Importantly, in an attempt to correlate expression levels with normal tissue reaction to IR, we also identified three other genes CD40, OAS2 , and CXCR1 whose expression level fluctuations during radiotherapy were more pronounced in patients developing late normal tissue responses to curative radiotherapy after the end of the radiotherapy treatment. Overall, we identified inflammation-associated genes which are promising biomarkers of IR exposure and susceptibility to radiation-induced toxicity.

Purpose: This collaboration of five established European gene expression labs investigated the potential impact of culture conditions on the transcriptional response of peripheral blood to radiation exposure., Materials and Methods: Blood from one healthy donor was exposed ex vivo to a Cobalt 60 source to produce a calibration curve in addition to four unknown doses. After exposure, the blood samples were either diluted with RPMI medium or left untouched. After 24-h incubation at 37 °C the diluted blood samples were lysed, while the undiluted samples were mixed with the preservative RNALater and all samples were shipped frozen to the participating labs. Samples were processed by each lab using microarray (one lab) and QRT-PCR (four labs)., Results: We show that although culture conditions affect the total amount of RNA recovered (p < .0001) and its integrity (p < .0001), it does not significantly affect dose estimates (except for the true dose at 1.1 Gy). Most importantly, the different analysis approaches provide comparable mean absolute difference of estimated doses relative to the true doses (p = .9) and number of out of range (>0.5 Gy) measurements (p = .6)., Conclusion: This study confirms the robustness of gene expression as a method for biological dosimetry.

Purpose: RENEB, 'Realising the European Network of Biodosimetry and Physical Retrospective Dosimetry,' is a network for research and emergency response mutual assistance in biodosimetry within the EU. Within this extremely active network, a number of new dosimetry methods have recently been proposed or developed. There is a requirement to test and/or validate these candidate techniques and inter-comparison exercises are a well-established method for such validation., Materials and Methods: The authors present details of inter-comparisons of four such new methods: dicentric chromosome analysis including telomere and centromere staining; the gene expression assay carried out in whole blood; Raman spectroscopy on blood lymphocytes, and detection of radiation-induced thermoluminescent signals in glass screens taken from mobile phones., Results: In general the results show good agreement between the laboratories and methods within the expected levels of uncertainty, and thus demonstrate that there is a lot of potential for each of the candidate techniques., Conclusions: Further work is required before the new methods can be included within the suite of reliable dosimetry methods for use by RENEB partners and others in routine and emergency response scenarios.

Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased leukaemia and solid tumour risks following cumulative doses of <100mSv and dose rates of <10mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30-60mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Exposure to ionizing radiation increases the incidence of acute myeloid leukemia (AML), which has been diagnosed in Japanese atomic bombing survivors, as well as patients treated with radiotherapy. The genetic basis for susceptibility to radiation-induced AML is not well characterized. We previously identified a candidate murine gene for susceptibility to radiation-induced AML (rAML): C-terminal binding protein (CTBP)-interacting protein (CTIP)/retinoblastoma binding protein 8 (RBBP8). This gene is essential for embryonic development, double-strand break (DSB) resection in homologous recombination (HR) and tumor suppression. In the 129S2/SvHsd mouse strain, a nonsynonymous single nucleotide polymorphism (nsSNP) in Ctip, Q418P, has been identified. We investigated the role of Q418P in radiation-induced carcinogenesis and its effect on CTIP function in HR. After whole-body exposure to 3 Gy of X rays, 11 out of 113 (9.7%) 129S2/SvHsd mice developed rAML. Furthermore, 129S2/SvHsd mouse embryonic fibroblasts (MEFs) showed lower levels of recruitment of HR factors, Rad51 and replication protein A (RPA) to radiation-induced foci, compared to CBA/H and C57BL/6 MEFs, isolated from rAML-sensitive and resistant strains, respectively. Mitomycin C and alpha particles induced lower levels of sister chromatid exchanges in 129S2/SvHsd cells compared to CBA/H and C57BL/6. Our data demonstrate that Q418P nsSNP influences the efficiency of CTIP function in HR repair of DNA DSBs in vitro and in vivo, and appears to affect susceptibility to rAML.

A combined transcriptome and proteome analysis of mouse radiation-induced AMLs using two primary AMLs, cell lines from these primaries, another cell line and its in vivo passage is reported. Compared to haematopoietic progenitor and stem cells (HPSC), over 5000 transcriptome alterations were identified, 2600 present in all materials. 55 and 3 alterations were detected in the proteomes of the cell lines and primary/in vivo passage material respectively, with one common to all materials. In cell lines, approximately 50% of the transcriptome changes are related to adaptation to cell culture, and in the proteome this proportion was higher. An AML 'signature' of 17 genes/proteins commonly deregulated in primary AMLs and cell lines compared to HPSCs was identified and validated using human AML transcriptome data. This also distinguishes primary AMLs from cell lines and includes proteins such as Coronin 1, pontin/RUVBL1 and Myeloperoxidase commonly implicated in human AML. C-Myc was identified as having a key role in radiation leukaemogenesis. These data identify novel candidates relevant to mouse radiation AML pathogenesis, and confirm that pathways of leukaemogenesis in the mouse and human share substantial commonality., Competing Interests: The authors declare no conflicts of interest.

Necroptosis is a regulated form of necrosis, with the dying cell rupturing and releasing intracellular components that can trigger an innate immune response. Toll-like receptor 3 and 4 agonists, tumor necrosis factor, certain viral infections, or the T cell receptor can trigger necroptosis if the activity of the protease caspase-8 is compromised. Necroptosis signaling is modulated by the kinase RIPK1 and requires the kinase RIPK3 and the pseudokinase MLKL. Either RIPK3 deficiency or RIPK1 inhibition confers resistance in various animal disease models, suggesting that inflammation caused by necroptosis contributes to tissue damage and that inhibitors of these kinases could have therapeutic potential. Recent studies have revealed unexpected complexity in the regulation of cell death programs by RIPK1 and RIPK3 with the possibility that necroptosis is but one mechanism by which these kinases promote inflammation.

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy., (Copyright © 2016 Elsevier Inc. All rights reserved.)