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Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifiers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.Significance: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specific properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifies a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. Cancer Discov; 8(5); 648–61. ©2018 AACR.See related commentary by Maust et al., p. 534.This article is highlighted in the In This Issue feature, p. 517

Supplemental Table

Supplementary Figure 3. (A) Shown are western blots using antibodies directed against T202/Y204 phosphorylated ERK1/2 following incubation with a range of concentrations of LXH254 over a 4 - 72 hour period. Which individual RAF protein is not expressed in each HCT 116 variant is indicated above the relevant panels. (B) Shown are western blots using Abs directed against the indicated proteins in either whole cell lysates (WCL) or material immuno-precipitated from cell lysates using Abs directed against ARAF (ARAF IP) or BRAF (BRAF IP). Lysates were generated from either parental MIA PaCa-2 cells or a MIA PaCa-2 variant lacking expression of CRAF. (C) Recombinant MEK1 can be phosphorylated by immuno-precipitates from both LXH254 treated and untreated MIA PaCa-2 and MEL-JUSO cells using an anti-body directed against ARAF contains MEK1 kinase activity. Proteins detected in either whole cell lysates (WCL) or ARAF-Ab immuno-precipitates (IP:ARAF) are indicated on the right. (D) IP-kinase activity on recombinant MEK1 in immuno-precipitates from HEK293 cells expressing FLAG-tagged ARAF using Abs directed against FLAG requires ATP and occurs on both wild type (WT) and kinase-dead (K97M) MEK1. (E) Shown are western blots using antibodies directed against T202/Y204 phosphorylated ERK1/2 following incubation with a range of concentrations of LXH254 over a 4-72 hour period. The individual RAF protein expressed in each HCT 116 variant is indicated above the relevant panels. (F) Shown are western blots of phosphorylated MEK1/2 (S218/S221) and ERK1/2 (T202/Y204) following a 4 hr. incubation with a range of LXH254 concentrations in the RAS/RAF wild type cell line PC-9.

Purpose:Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254.Experimental Design:LXH254 was profiled in biochemical, in vitro, and in vivo assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of in vivo models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF.Results:We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive.Conclusions:LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.

Supplementary Legend

Proliferation IC50 values for various cell lines and cell line derivatives

KEYWORDS Louis Chu; patriarchy; urban fiction; vengeanceAlthough last year’s republication of Louis Chu’s Eat a Bowl of Tea as part of University of Washington Press’ Classics of Asian American Lit...

Satisficing consequentialism is often used as a way of solving the demandingness objection, but many forms of satisficing consequentialism fail to do so. Further, those that do are vulnerable to the objections Ben Bradley outlined in Against Satisficing Consequentialism. In this paper, I present a new type of satisficing consequentialism which resolves the demandingness objection, is in-line with common intuitions about moral responsibility, and avoids Bradley's criticisms.

These cases highlight the importance of monitoring choroidal nevi with benign imaging characteristics and the potential to quantify horizontal growth using optical coherence tomography (OCT), in the absence of color fundus photography.This study aimed to present reports of two patients with pigmented choroidal tumors with low malignant potential based on their multimodal imaging features at the time of referral, but access to prior OCT imaging confirmed horizontal growth consistent with melanoma.Two patients with pigmented, dome-shaped, subfoveal tumors were referred. Both tumors had basal diameters greater than 5 mm but no other risk factor for growth at the time of referral. Screening OCT scans had been taken of each patient's macula more than 5 years before referral, but color fundus photography was not available for either. Repeat OCT scanning at the time of referral showed horizontal growth of the tumors consistent with melanoma. As per the "To Find Small Ocular Melanoma-Do Imaging" risk factor assessment, the 5-year risk of growth of both tumors would be estimated at 11% at the time of referral, and in the absence of the documented horizontal growth on OCT scanning, the patients would have been monitored for growth. After discussion of the risks and benefits, both patients elected for their tumors to be managed as choroidal melanomas and underwent ruthenium plaque brachytherapy.Horizontal growth of choroidal tumors can be established using sequential OCT scans in the absence of color fundus photography. Access to prior imaging can expedite the diagnosis of choroidal melanoma, potentially allowing patients to be treated earlier.

Phosphorus is an essential nutrient for crops. Precise spatiotemporal application of P fertilizer can improve plant P acquisition and reduce run‐off losses of P. Optimizing application would benefit from understanding the dynamics of P release from a fertilizer pellet into bulk soil, which requires space‐ and time‐resolved measurements of P concentration in soil solutions. In this study, we combined microdialysis and X‐ray computed tomography to investigate P transport in soil. Microdialysis probes enabled repeated solute sampling from one location with minimal physical disturbance, and their small dimensions permitted spatially resolved monitoring. We observed a rapid initial release of P from the source, producing high dissolved P concentrations within the first 24 h, followed by a decrease in dissolved P over time compatible with adsorption onto soil particles. Soils with greater bulk density (i.e., reduced soil porosity) impeded the P pulse movement, which resulted in a less homogeneous distribution of total P in the soil column at the end of the experiment. The model fit to the data showed that the observed phenomena can be explained by diffusion and adsorption. The results showed that compared with conventional measurement techniques (e.g., suction cups), microdialysis measurements present a less invasive alternative. The time‐resolved measurements ultimately highlighted rapid P dynamics that require more attention for improving P use efficiency., Core Ideas The initial release of P from fertilizer pellets is not well studiedMicrodialysis and X‐ray CT permit noninvasive time‐resolved monitoringA lab‐scale setup was used to study solution P concentrations in time and spaceA rapid initial release of P from the pellet was measured, with no replenishmentP concentration decreased over time, compatible with adsorption onto soil

Simple Summary Approximately 50% of patients with uveal melanoma will develop incurable metastatic disease. This can be predicted, but requires a biopsy of the eye, which outside of centres of excellence, are not routinely performed. Given that uveal melanoma spreads through the blood, utilising circulating tumour cells from the blood might provide an alternative minimally invasive method to avoid the biopsy. However, the clinical application hinges on the detection rate of circulating tumour cells. Herein we assessed markers to improve the capture and detection of uveal melanoma circulating tumour cells and found that they could be detected in 86% of patients. We further found that ≥3 circulating tumour cells was significantly associated with worse survival. Abstract (1) Background: The stratification of uveal melanoma (UM) patients into prognostic groups is critical for patient management and for directing patients towards clinical trials. Current classification is based on clinicopathological and molecular features of the tumour. Analysis of circulating tumour cells (CTCs) has been proposed as a tool to avoid invasive biopsy of the primary tumour. However, the clinical utility of such liquid biopsy depends on the detection rate of CTCs. (2) Methods: The expression of melanoma, melanocyte, and stem cell markers was tested in a primary tissue microarray (TMA) and UM cell lines. Markers found to be highly expressed in primary UM were used to either immunomagnetically isolate or immunostain UM CTCs prior to treatment of the primary lesion. (3) Results: TMA and cell lines had heterogeneous expression of common melanoma, melanocyte, and stem cell markers. A multi-marker panel of immunomagnetic beads enabled isolation of CTCs in 37/43 (86%) patients with UM. Detection of three or more CTCs using the multi-marker panel, but not MCSP alone, was a significant predictor of shorter progression free (p = 0.040) and overall (p = 0.022) survival. (4) Conclusions: The multi-marker immunomagnetic isolation protocol enabled the detection of CTCs in most primary UM patients. Overall, our results suggest that a multi-marker approach could be a powerful tool for CTC separation for non-invasive prognostication of UM.

Intellectual convergences between postcolonial studies, ethnicity studies and human–animal studies (HAS) hold the potential to go beyond “traditional” models of rehumanizing a formerly “inh...

Half of the nitrogen applied to arable-fields is lost through several processes linked to soil moisture. Low soil moisture limits nitrogen mobility reducing nitrogen-uptake while wetter conditions can increase nitrogen leaching. Rainfall ultimately governs soil moisture and the fate of nitrogen in soil. However, the interaction between rainfall and nitrogen use efficiency (NUE) remains poorly understood. We developed a field-scale modelling platform that describes coupled water and nitrogen transport, root growth and uptake, rainfall, the nitrogen-cycle and leaching to assess the NUE of split fertilisations with realistic rainfall patterns. The model was solved for every possible split fertilisation timing in 200+ growing seasons to determine optimal timings. Two previous field trials regarding rainfall and NUE had contrasting results: wetter years have enhanced fertiliser loss and drier years reduced plant nitrogen uptake. By choosing appropriate fertilisation timings in the model we could recreate the two contrasting trends and maintain variability in the data. However, we found by choosing other fertilisation timings we could mitigate the leaching in wetter years. Optimised timings could increase plant nitrogen uptake by up to 35% compared to the mean in dry years. Plant uptake was greatest under drier conditions due to mitigated leaching, but less likely to occur due to low nitrogen mobility. Optimal fertilisation timings varied dramatically depending on the rainfall patterns. Historic and projected rainfall patterns from 1950-2069 were used in the model. We found optimal NUE has a decrease from 2022-2040 due to increased heavy rainfall events and optimal fertilisation timings are later in the season but varied largely on a season-to-season basis. The results are a step towards achieving improved nitrogen efficiency in agriculture by using the ‘at the right time’ agronomic-strategy in the ‘4Rs’ of improved nitrogen fertilisation. Our results can help determine nitrogen fertilisation timings in changing climates.

Photosynthesis relies on the transport of water and sugars from roots to leaves facilitated by two key tissues: xylem and phloem. Blockages in the xylem/phloem, either by structures formed by the pathogen itself or those formed by the plant as a defence mechanism, disrupt the soil-plant-atmosphere continuum and cause many vascular plant disease symptoms. Xylella fastidiosa (X. fastidiosa) is a bacterium that colonises internal plant vascular networks causing pathogenic effects on several commercially important crops, including those associated with the olive quick decline syndrome causing devastating olive decline in Apulia, Southern Italy. Despite a growing research effort since the recent detection of X. fastidiosa in Europe, the exact processes leading to X. fastidiosa disease symptoms are not fully understood due to difficulties in observing internal plant structures. Our goal is to utilise models to elucidate fundamental processes that lead to olive quick decline syndrome. We are developing a mathematical model describing within-host biofilm development that predicts water-stresses that ultimately inhibit plant functionality. Our approach is centred on the assumption that the biofilm structure is determined by the arrangement of extracellular polysaccharide (EPS) molecules, and as such, our model contains a polymer-physical description of X. fastidiosa biofilm formation dynamics. We used our model, requiring minimal empirical assumptions, to replicate biofilm aggregation observed by microfluidics. We have also produced X-ray Computed Tomography (XCT) images of vascular networks in both resistant and susceptible olive cultivars. We are using these images to test whether susceptibility is correlated with morphological differences that might influence fluid flow through the plant. This work improves the understanding of possible cultivar resistance mechanisms to aid informed breeding and orchard management, and model simulations will provide insights for understanding xylem blockages and their relation to observed symptom severity.

Phosphorus (P) is critical for plant growth and can limit crop yields, but rock phosphate (the primary source of agricultural P) is a finite resource which is predicted to run out within 50-250 years. However, since P is important for short-term yield gains, it is often over-applied, causing run-off and water pollution. It is crucial to apply the right fertilisers at the most efficient rate, time, and place to protect our food security and environment for the future. Optimal application requires an understanding of the processes affecting P availability to plants. Fertilisers range from soluble in water (e.g TSP) to only slightly soluble (e.g. struvite). However, experiments testing the efficacy of fertilisers with different solubilities have reached variable results. Standard soil testing methods sample at fixed time points, while the dissolution, diffusion, sorption and uptake of P are dynamic processes, so to make predictions we must understand those dynamics. We used image-based modelling to investigate the predicted effects of dissolution rate and soil buffer power on P uptake by spring wheat root systems taken from X-ray CT images. We added a P source to represent a fertiliser granule and modelled the predicted P uptake based on 1 day, 1 week, and 14 week dissolution of the same amount of P for two realistic soil buffer powers. We demonstrated that rapid dissolution increased short-term root uptake, but dissolution over 1 week did not differ from dissolution over 1 day. We also found that root system architecture has a large effect on the efficiency of a P fertiliser pellet, highlighting the importance of application location. These results provide a starting point for predictive modelling of the efficacy of different P fertilisers in different soils, and our image-based approach gives the ability to add different root architectures for different species or varieties.

Phosphorus (P) is a limiting nutrient for crops and it is therefore highly managed in human activities such as agriculture. Not only the global phosphate rock reserves are going to be exhausted in a century, but P can also be lost from fields with the runoff ending up contaminating water bodies and causing eutrophication. This study is aimed at investigating P release from a fertiliser granule at high spatial and temporal resolution to optimise fertilisation timing, match crop requirements and reduce runoff. Experimental data consist of time-resolved P concentration in the soil solution at three different depths and total P concentration profile determined via total soil digestion. We observed a rapid, single-pulse release of P from the fertiliser granule shortly after soil wetting ( As the experimental data did not match the model-predicted P diffusion behaviour, a new modelling approach was used to reproduce the data. The model accounts for P diffusion and adsorption onto soil particles, resulting in the temporal evolution of P concentrations both in the soil solution and adsorbed onto soil particles. As the final total P concentration in soil reflects the initial P concentration profile in the soil solution, the model shows that adsorption onto soil particles happens faster than diffusion. Additionally, the model gives an estimate of diffusion, adsorption and desorption rates, as well as the maximum distance that P can travel from the source. Combining high-resolution experiments with modelling provided a new insight into P release and diffusion from a fertiliser granule. The results can inform optimal fertilisation timings to improve crop yields while reducing P application rates and undesirable side effects such as eutrophication.

Plant roots secrete polymeric gels during root growth known as mucilage, which aid in root growth, nutrient acquisition, and water retention. Mucilage plays an important role in augmenting many soil physical and biogeochemical processes local to the root zone. However, most studies infer the effects of mucilage by reporting changes in the bulk soil. This investigation quantifies the isolated physical behaviour of plant mucilage in a highly simplified soil-analogous environment. We placed drops of hydrated mucilage between two flat surfaces to form liquid bridges and monitored their evolution under drying conditions considering different mucilage mass fractions. We used this information to develop a multi-phase model that characterises the mucilage-water interactions based on a polymeric description of the mucilage volume fraction. Unlike pure water liquid bridges that rupture, the hydrated mucilage liquid bridges collapsed under drying, but maintain connection between the surfaces. NMR imaging shows loss of water from the liquid bridge, particularly from the regions furthest from the surface contacts. Model of drying liquid bridges quantifies mucilage accumulation near the corners of the boundary where the adherence to surfaces is likely to occur. The modelled accumulation times overlapped with monitored bridge collapse for the different mass fractions. Consistency with the model and measurement results highlight the model’s ability to predict a transition when the hydrated mucilage mixture no longer behaves like a liquid. Results suggest that diffusion type models are not adequate for describing pore scale mucilage transport processes, indicating that mucilage’s zone of influence is local to the root, and the transition out of this zone is spatially sharp.

Xylella fastidiosa (X. fastidiosa) is a bacterium that colonises internal plant vascular networks causing pathogenic effects on several commercially important crops (e.g. olives, grapes, coffee, etc.). Despite a growing research effort since the recent detection of X. fastidiosa in Europe, the exact processes leading to X. fastidiosa disease symptoms are not fully understood due to difficulties in observing internal plant structures. Our goal is to utilise models to elucidate fundamental processes that lead to olive quick decline syndrome, the disease responsible for the devastating olive decline in Apulia, Southern Italy. We endeavour to do this by developing a fundamental mathematical modelling framework describing within-host biofilm development, and the resulting water-stresses that ultimately inhibit plant functionality and development. We have begun work on developing a fluid mechanics model that invokes a polymer-physical description of X.fastidiosa biofilm formation dynamics. Our approach is centred on the assumption that the biofilm structure is determined by the arrangement of extracellular polysaccharide (EPS) molecules. We have also produced X-ray Computed Tomography (XCT) images of both resistant and susceptible olive cultivars to determine possible morphological differences between the vascular networks of the cultivars. Preliminary modelling results of EPS dominant biofilm formation characterise biofilm coalescence in a consistent manner with early microfluidic controlled experiments and require fewer empirical assumptions. We intend to generate model domains with the XCT images and apply our theoretical frame work to simulate infection in actual vascular networks via image based modelling. We hope our work will improve the understanding of possible cultivar resistance mechanisms to enable informed breeding and effective replanting in Apulia, and that model simulations will provide insights for improving the efficiency of current sampling techniques., GB; PDF; ncw1e19@soton.ac.uk

Soil microbial communities contribute many ecosystem services including soil structure maintenance, crop synergy, and carbon sequestration. However, it is not fully understood how the health of microbial communities is effected by fertilization at the pore scale. This study investigates the nature of nitrogen (N) transport and reactions at the soil pore scale in order to better understand the influence of soil structure and moisture content on microbial community health. Using X-ray Computed Tomography (XRCT) scans, we reconstructed a microscale description of a dry soil-pore geometry as a computational mesh. Solving two-phase water/air models produced pore-scale water distributions at 15, 30 and 70% water-filled pore volume. The model considers ammonium (NH4+), nitrate (NO3-) and dissolved organic N (DON), and includes N immobilization, ammonification and nitrification processes, as well as diffusion in soil-solution. We simulated the dissolution of a fertilizer pellet and a pore scale N cycle at the three different water saturation conditions. To aid interpretation of the model results, microbial activity at a range of N concentrations was quantified experimentally using labelled C to infer microbial activity based on CO2 respiration measurements in bulk soil. The pore-scale model showed that the diffusion and concentration of N in water films is critically dependent upon soil moisture and N species. We predicted that the maximum NH4+ and NO3- concentrations in soil solution around the pellet under low water saturation conditions (15%) are in the order of 1x103 and 1x104 mol m-3 respectively (1-10 M), and under higher water saturation conditions (70%) where on the order of 2x102 and 1x103 mol m-3, respectively (0.1-1 M). Supporting experimental evidence regarding microbial respiration suggests that these concentrations at the pore-scale would be sufficient to reduce microbial activity in the zone immediately around the fertilizer pellet (ranging from 0.9 to 3.8 mm depending on soil moisture status), causing a major loss of soil biological activity by up to 90%. This model demonstrates the importance of pore-scale processes in regulating N movement in soil with special capability to predict the effects of fertilizers on rhizosphere-scale processes and the root microbiome.

Phosphorus (P) is a development-limiting nutrient for crops, hence global food production relies on P fertilizer application. However, P mobility in soil depends on many abiotic and biological processes, most notably its chemical interactions with the soil particles. Optimizing the timing and amount of fertilization could lead to higher production efficiencies and also reduce P runoff and subsequent contamination of water bodies. Plants have developed strategies to improve P uptake by optimizing the root system architecture and exuding organic acids for enhancing P mining locally to the root tips. However, these adaptations are mainly a response to low P availability or to already immobilized P patches in soil, and little is known about the fate of P in the early stages of fertilization.In this framework, we developed an experimental assay for investigating P release from the fertilizer pellets, and its movement through soil using non-invasive microdialysis sampling techniques and inductively coupled plasma - mass spectrometry (ICP-MS) analytical techniques. Microdialysis allowed for time resolved in-situ samplings and the small size of the probes also allows for a fine spatial resolution.Results showed a very rapid release of the P from the fertilizer pellet (triple super phosphate, TSP), producing a high concentration pulse that lasts a few hours. P concentrations then decrease over time until reaching steady low concentrations after 6-8 days and P replenishment from the pellet was not observed after the first pulse. The experiments showed that the speed of P movement in soil is greatly influenced by soil particle size distribution, and that gravity plays an important role in promoting quick P movement in the downward direction, while diffusion can account for P observed in the upward direction. Modelling was also applied to data fitting for quantifying trends and deriving an effective P diffusion coefficient in saturated soil.

Sufficient nitrogen fertilisation is essential for obtaining the crop yields required to feed the growing population. Moreover, nitrogen applied to fields is often lost to a number of processes including denitrification, surface run-off and leaching. These processes can damage the local ecology and contaminate water supplies. Additionally, nitrogen lost as ammonia gas and the large energy input required to synthesize ammonia are both large contributors to global greenhouse gas emissions. Choosing fertilisation strategies to optimise the proportion of nitrogen taken up by crops (nitrogen use efficiency) can reduce the production of ammonia and the pollution of water supplies.We developed a mathematical model that describes the movement of water and multiple nitrogen species in soil at the field scale over a growing season. The model was then used to assess the nitrogen use efficiency of varying fertilisation strategies. We consider the effects of a number of biological, chemical, and physical processes including: root growth, root uptake, the transformation of nitrogen between different nitrogen species, and the effect of soil water movement on nitrogen transport. The resulting model is comprised of a coupled system of partial and ordinary differential equations that describe the mathematical interplay between nitrogen transport, water movement, and root uptake, which were solved numerically using a finite element approach. Numerical experiments were conducted to determine how nitrogen uptake efficiency was affected by different fertilisation strategies. We examine numerous cases by varying the quantity of fertiliser applied to the soil and the fertiliser application times.The numerical experiments suggest that, under uniform rainfall rates, the optimal fertilisation times (within the bounds of typical times found in agriculture) can result in 25% more nitrogen uptake than the worst strategies. However, there were large time periods, 28 days for the first application and 10 days for the second, which resulted in close-to-optimal nitrogen use efficiency. The results of this study, in addition to crop health and past and predicted rainfall, could be taken into consideration by farmers while choosing fertilisation times to optimise nitrogen uptake efficiency.

From Frederic Henry and Catherine Barkley in Ernest Hemingway's A Farewell to Arms (1929) to Lloyd Gruver and Hana-ogi in James A. Michener's Sayonara (1953), the trope of romantic relationships between American servicemen and the foreign women whom they encounter overseas has recurred throughout twentieth-century American literature. In this article, I examine the ideological assumptions rooted in these depictions, paying particular attention to the challenges that the Iraq War, an apparently “sexless” conflict, has posed to contemporary fiction writers. Using a close reading of Phil Klay's short story “In Vietnam they had Whores” (2014) and Atticus Lish's novel Preparation for the Next Life (2015), I argue that these two authors have “pivoted” away from Iraq towards Asia in ways that reveal an increased willingness on the part of war writers to critique or dispense with old narrative stereotypes.

In 1926 a new shipping route was established between Durban and Osaka, on which Laurens van der Post and William Plomer, fresh from their collaboration as writers for the literary magazine Voorslag, embarked as privileged passengers. The opportunity to reside in Japan would exercise a profound influence over the literary output of both figures, though in considerably different ways. This article revisits the 1926 sojourn in Japan as a formative moment in the lives of two South African writers that would subsequently be reformed, and to some extent deformed in their writings following the atomic bombing of Hiroshima in August 1945. Though the sojourn itself deserves restitution to the annals of South African literary history, its true value, the author argues, does not lie in enlarging our understanding of literary trends associated with the interwar years so much as isolating the specific challenges and transmutations those self-same trends underwent in the aftermath of the atomic holocaust. As each writer struggled to reformulate his subjectivity, a prophetic mode of writing became increasingly central as a framing device by which Hiroshima could be “contained” and “approached” from afar. The events of 1926, along with van der Post's experience of imprisonment under the Japanese during the war years, were mobilized in the authorial imagination to serve that purpose.

During the years of Japan's “bubble” economy, writers and artists in the United States became increasingly susceptible to “Japan-bashing,” a discourse that objectified Japanese for their trade practices, overseas purchases, and tourist presence. In the following article, I draw upon a range of cultural texts, from Truman Capote's novellaBreakfast at Tiffany'sto Michael Crichton's novelRising Sun, in order to investigate how the trope of the camera-toting Japanese expatriate encapsulated the fears of the era. I then move to explore the ways in which Japanese Americans negotiated these tropes in their writings, paying particular attention to Ruth Ozeki's novelMy Year of Meats. I hypothesize that Japanese Americans remained aware of the phenomenon of “Japan-bashing” throughout the era, yet did not confront it in a sustained fashion. Instead, tropes were either dismissed out of hand or, as in Ozeki's case, incorporated into a narrative before undergoing a process of gradual dismantlement.

Root citrate exudation is thought to be important for phosphate solubilization. Previous research has concluded that cluster-like roots benefit most from this exudation in terms of increased phosphate uptake, suggesting that root structure plays an important role in citrate-enhanced uptake (additional phosphate uptake due to citrate exudation). Time-resolved computed tomography images of wheat root systems were used as the geometry for 3D citrate-phosphate solubilization models. Citrate-enhanced uptake was correlated with morphological measures of the root systems to determine which had the most benefit. A large variation of citrate-enhanced uptake over 11 root structures was observed. Root surface area dominated absolute phosphate uptake, but did not explain citrate-enhanced uptake. Number of exuding root tips correlated well with citrate-enhanced uptake. Root tips in close proximity could collectively exude high amounts of citrate, resulting in a delayed spike in citrate-enhanced uptake. Root system architecture plays an important role in citrate-enhanced uptake. Singular morphological measurements of the root systems cannot entirely explain variations in citrate-enhanced uptake. Root systems with many tips would benefit greatly from citrate exudation. Quantifying citrate-enhanced uptake experimentally is difficult as variations in root surface area would overwhelm citrate benefits.

Rhizosphere soil has distinct physical and chemical properties from bulk soil. However, besides root induced physical changes, chemical changes have not been extensively measured in situ on the pore scale. In this study we couple structural information, previously obtained using synchrotron X-ray computed tomography (XCT), with synchrotron X-ray Fluorescence (SR-XRF) microscopy and X-ray Absorption Near-Edge Structure (XANES) to unravel chemical changes induced by plant roots. Our results suggest that iron (Fe) and sulfur (S) increase notably in the direct vicinity of the root via solubilization and microbial activity. XANES further shows that Fe is slightly reduced, S is increasingly transformed into sulfate (SO42-) and that P is increasable adsorbed to humic substances in this enrichment zone. In addition, the ferrihydrite fraction decreases drastically suggesting the preferential dissolution and the formation of more stable Fe-oxides. Additionally, the increased transformation of organic S to sulfate indicates that the microbial activity in this zone is increased. These changes in soil chemistry correspond to the soil compaction zone as previously measured via X-ray CT.The fact that these changes are co-located near the root and the compaction zone suggests that decreased permeability due to soil structural changes acts as a barrier creating a zone with increased rhizosphere chemical interactions via surface mediated processes, microbial activity and acidification.

A robust finding from the eyewitness literature is that children are as accurate as adults on target-present lineups from the age of five years, whereas they continue to make an erroneous false positive identification from a target-absent lineup up until around fourteen years of age (Pozzulo & Lindsay, 1998). The current study explores whether the same pattern occurs when voices are used instead of faces. A total of 334 participants from six age groups (6-7-year-olds, 8-9-year-olds, 10-11-year-olds, 12-13-year-olds, 14-15-year-olds and adults) listened to a 30 second audio clip of an unfamiliar voice and were then presented with either a six person target-present or target-absent voice lineup. Overall, participants were more accurate with target-present than target-absent lineups. Moreover, performance on target-present lineups showed adult-like levels of attainment by 8-9 years of age. In contrast, performance on target-absent lineups was extremely poor, with all age groups tending to make a false identification. Confidence was higher when participants made correct rather than incorrect decisions for both types of lineup and this did not change with increasing age. Given these results, both child and adult earwitness evidence needs to be treated with considerable caution.

In this paper, we use multiple scale homogenisation to derive a set of averaged macroscale equations that describe the movement of nutrients in partially saturated soil that contains growing potato tubers. The soil is modelled as a poroelastic material, which is deformed by the growth of the tubers, where the growth of each tuber is dependent on the uptake of nutrients via a sink term within the soil representing root nutrient uptake. Special attention is paid to the reduction in void space, resulting change in local water content and the impact on nutrient diffusion within the soil as the tubers increase in size. To validate the multiple scale homogenisation procedure, we compare the system of homogenised equations to the original set of equations and find that the solutions between the two models differ by \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\lesssim 2 \%$$\end{document}≲2%. However, we find that the computation time between the two sets of equations differs by several orders of magnitude. This is due to the combined effects of the complex three-dimensional geometry and the implementation of a moving boundary condition to capture tuber growth.

Phosphorus fertilisation is crucial for crop yields. However, traditional phosphate resources are dwindling, thus a more efficient use of phosphorus fertilisers is required for sustainable farming. This study demonstrates the scope of image-based models parameterised by elemental maps by assessing how a dynamic root system architecture may improve phosphorus root uptake from a fertiliser pellet. A multi-image based modelling method was developed by utilising structural imaging coupled with elemental maps. Structural imaging was used to capture barley (Hordeum vulgare L. cv. Optic) root, soil and fertiliser pellet configurations as a domain for numerical simulations. Elemental mapping was used to image phosphorus in soil thin-sections of the same samples. These two imaging modes were aligned using an automated method and image-based models describing the diffusion and root-uptake of phosphorus in soil were parametrised using the elemental maps. Structural imaging showed root length density was increased inside and near the fertiliser pellet. Averaging elemental data revealed phosphorus gradients from the pellet. Modelling results suggested: the pellet only enhances phosphorus uptake of roots within 2 mm over 30 days, densely packed roots decrease phosphorus uptake efficiency, and a root system that responded to nutrients from a fertiliser have comparatively increased phosphorus uptake efficiency near the pellet. The combination of structural and elemental imaging provides the means to accurately parameterise both the geometric and chemical aspects of models describing phosphorus movement in root-soil-fertiliser systems. This approach may be applicable to other plant-soil systems where structure and elemental quantities are important to the problem.

Among the items of military equipment associated with the ground or naval engagements of World War II, few resonate as strongly as the airplane does for the air war (Leahy and Dechow 315). Its iconic status pervades the boyish adventurism of British author Jack Higgins, the biting satire of Joseph Heller’s Catch-22 (1961), the numbed silences of German critic W. G. Sebald, and the nostalgic turn taken in Japanese film director Hayao Miyazaki’s The Wind Rises (2013). Across any number of different forms and media, the airplane retains its distinctive allure, sometimes tinged with menacing or polemical undertones (Grayling 76; Beevor, Bishop, Grayling, and Overy) but more often erring toward a hagiographic turn. When the latter holds true, standard fare involves accentuating the war record of aviators on one’s own side while leaving the identities and motivations of enemy pilots and flight crews largely unaddressed, a trend that reprises the one-sidedness of wartime propaganda (Hase 2-3). Needless to say, this neglect of enemy subjectivity is present in depictions of personnel across every service branch, and yet the post-war years have seen noteworthy attempts to depict enemy ground troops sympathetically. As early as 1948, for example, American author Irwin Shaw paid close attention to the life experiences of Nazi soldiers in his novel The Young Lions, the South African author Laurens van der Post was uncommonly sympathetic to Japanese prison guards in his 1963 novella The Seed and the Sower, and British author Louis de Bernieres’s novel Captain Corelli’s Mandolin (1994) has made life in the Italian army appear almost bucolic.

In this introduction to part 4 of the Common Knowledge symposium “Peace by Other Means,” the journal's editor assesses the argument made by Peace, the spokesperson of Erasmus in his Querela Pacis (1521), that the desire to impute and avenge wrongs against oneself is insatiable and at the root of both individual and social enmities. He notes that, in a symposium about how to resolve and prevent enmity, most contributions have to date expressed caveats about how justice and truth must take precedence over peace, how recovery from ill treatment may be impossible, how quietism is not a moral option, and how realism demands a national policy and a personal strategy of, at best, contingent forgiveness. He concedes that the attitudes of those opposed to quietism are healthy but suggests that there may be goods worthier than health of human devotion. This essay concludes that the main differences between what it terms “judgmental” and “irenic” regimes are disagreements over anthropology and metaphysics. The presumptions that truths are objectively knowable and that human beings are moral and rational agents characterize judgmental regimes; irenic regimes are characterized by disillusionment with those assumptions.

This article surveys the Far East prisoner of war novel from its inception in English public school narratives and racially inflected character profiles to the more critically engaged publications of the last two decades. During the latter period, linear reconstructions of imprisonment, analogous institutional paradigms, and authors' own memories of captivity have gradually declined in influence. Although not wholly absent, their place has been taken by an emphasis on intergenerational trauma, international relations (especially those involving the 1995 commemoration of the end of the war), and real or imagined meetings between surviving prisoners and their former torturers or interrogators. Through a close reading of journalist Jim Lehrer's novel The Special Prisoner (2000), this essay examines the ways in which international relations inflect an imagined encounter between a surviving prisoner and his former torturer. The novelist's sensitivity to contending notions of collective guilt and collective victimhood serve to illustrate the complications that arise at the individual level when forgiveness is freely offered by a trauma survivor and roundly rejected by the agent of that trauma.

South African patrols on ‘search and destroy’ missions operate with impunity far across the border into Angola. The ‘troopies,’ young border soldiers that patrol the bush land in armored vehicles r...

Tumor-associated macrophages are a major constituent of malignant tumors and are known to stimulate key steps in tumor progression. In our review in this journal in 2006, we postulated that functionally distinct subsets of these cells exist in different areas within solid tumors. Here, we review the many experimental and clinical studies conducted since then to investigate the function(s), regulation, and clinical significance of macrophages in these sites. The latter include three sites of cancer cell invasion, tumor nests, the tumor stroma, and areas close to, or distant from, the tumor vasculature. A more complete understanding of macrophage diversity in tumors could lead to the development of more selective therapies to restore the formidable, anticancer functions of these cells. Cancer Res; 78(19); 5492–503. ©2018 AACR.

This article examines the fiction writing of two American authors, James A. Michener and John Oliver Killens, and asks how the American ‘occupation’ of Australia during the Second World War featured, or failed to feature, in their writings. The Second World War arguably remains the watershed moment in which American servicemen and Australians from all walks of life entered into a prolonged awareness of one another, courtesy of the presence of around a million enlisted Americans who passed through Australia on their way to the war against Imperial Japan. In his short story ‘The Jungle’, Michener structured international gender relations in ways that anticipated his novel Sayonara (1954), allowing the reader to draw parallels between the American–Australian and American–Japanese social dynamic but also subordinating the wartime social history of Australia to American current affairs. For his part, Killens was likewise preoccupied with American social history, specifically the rights of enlisted African-American servicemen. His novel And Then We Heard the Thunder (1963) deployed Australian characters in a race war fantasy that had hitherto imagined an alliance between African Americans and Japanese. In summary, Michener and Killens both subordinated Australian wartime history to American current affairs, albeit with different literary objectives in mind.

Novelizations of the story of the Manhattan Project at Los Alamos have been in publication almost from the moment when news of the Project first broke. In this article I survey these productions, from their earliest beginnings in the writings of Upton Sinclair to their latest manifestation in Nora Gallagher’s novel Changing Light (2007). The best way in which to read these works is to locate them within a larger cultural trend, prevalent in the US, which takes stories of scientific achievement as a means to deflect attention from the atomic bombings of Hiroshima and Nagasaki. However, one might also see these narratives as inadvertently revealing a gulf in the writer’s capacity to represent nuclear apocalypse within the genre of the historical novel.

During the 1980s Japanese corporations acquired a strong foothold in the American market, prompting media commentators to speculate that American society was being undermined by an encroaching Japanese “takeover”. Employing a comparative approach, I place New Zealand source material in conversation with an American cultural context in order to expose the mobility and malleability of Japanophobic discourses. New Zealand culture provides a basis for comparison in that the nation contained no hi-tech or car manufacturing industries, and yet writers there took issue with the presence of Japanese tourists and their increasing purchasing power. Writers Keri Hulme and Vivienne Plumb portrayed the Japanese as vampires and body-snatchers, while Ian Middleton suggested that the Japanese were seeking an escape from modern culture into an “untouched”, pre-modern environment. These features set New Zealand writing apart from the thriller genre adopted by Michael Crichton, Steven Schlossstein, and Tom Clancy. But in spite of these differences, a crosscurrent runs through both the New Zealand and American sources, making them more alike than not — that is, they all hark back to the wartime tropes of the Pacific War, which were reinstated within the context of the 1980s.

This article reviews and compares the literary fictions of the United States and New Zealand, as they have sought to respond to the ‘occupation,’ 1942–1944. During the period in question, approximately 100,000 United States Army and Marine Corps servicemen landed and resided in New Zealand, where they undertook final preparations for the island campaigns of the Pacific War. In the aftermath of the war, American fiction writers wrote of the social and cultural difficulties endured by New Zealand civilians, but New Zealand writers took longer to come to terms with the events.