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Abstract Background Reverse triggering (RT) was described in 2013 as a form of patient-ventilator asynchrony, where patient’s respiratory effort follows mechanical insufflation. Diagnosis requires esophageal pressure (Pes) or diaphragmatic electrical activity (EAdi), but RT can also be diagnosed using standard ventilator waveforms. Hypothesis We wondered (1) how frequently RT would be present but undetected in the figures from literature, especially before 2013; (2) whether it would be more prevalent in the era of small tidal volumes after 2000. Methods We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, from 1950 to 2017, with key words related to asynchrony to identify papers with figures including ventilator waveforms expected to display RT if present. Experts labelled waveforms. ‘Definite’ RT was identified when Pes or EAdi were in the tracing, and ‘possible’ RT when only flow and pressure waveforms were present. Expert assessment was compared to the author’s descriptions of waveforms. Results We found 65 appropriate papers published from 1977 to now, containing 181 ventilator waveforms. 21 cases of ‘possible’ RT and 25 cases of ‘definite’ RT were identified by the experts. 18.8% of waveforms prior to 2013 had evidence of RT. Most cases were published after 2000 (1 before vs. 45 after, p = 0.03). 54% of RT cases were attributed to different phenomena. A few cases of identified RT were already described prior to 2013 using different terminology (earliest in 1997). While RT cases attributed to different phenomena decreased after 2013, 60% of ‘possible’ RT remained missed. Conclusion RT has been present in the literature as early as 1997, but most cases were found after the introduction of low tidal volume ventilation in 2000. Following 2013, the number of undetected cases decreased, but RT are still commonly missed. Prior Abstract Reverse Triggering, A Missed Phenomenon in the Literature. Critical Care Canada Forum 2019 Abstracts. Can J Anesth/J Can Anesth 67 (Suppl 1), 1–162 (2020). https://doi-org.myaccess.library.utoronto.ca/ https://doi.org/10.1007/s12630-019-01552-z .

Breeding for nitrogen use efficiency (NUE) is becoming more important as global uncertainty makes the production and application of nitrogen (N) fertilizers more expensive and environmentally unfriendly. Despite this, most cereal breeding programs still use yield-related components as proxies for NUE, likely due to the prohibitive cost and time of collecting and analyzing samples through traditional lab-based methods. Drone-based NUE phenotyping provides a viable and scalable alternative as it is quicker, non-destructive, and consistent. Here, we present a study that utilized financially accessible cost-effective drones mounted with red-green-blue (RGB) image sensors coupled with the open-source AirMeasurer platform and advanced statistical analysis to exclude low-NUE lines in multi-seasonal field experiments. The method helped us to identify high N agronomic use efficiency lines but was less effective with a high N recovery efficiency line. We found that the drone-powered approach was very effective at 180 kg N per hectare (N180, an optimized N-rate) as it completely removed low-NUE wheat lines in the trial, which would facilitate breeders to quickly reduce the number of lines taken through multi-year breeding programs. Hence, this encouraging and scalable approach demonstrates its ability to conduct NUE phenotyping in wheat. With continuous refinements in field experiments, this method would be employable as an openly accessible platform to identify NUE lines at different N-rates for breeding and resource use efficiency studies in wheat.

Wheat (Triticum aestivum) is one of the most important staple crops worldwide. To ensure its global supply, the timing and duration of its growth cycle needs to be closely monitored in the field so that necessary crop management activities can be arranged in a timely manner. Also, breeders and plant researchers need to evaluate growth stages (GSs) for tens of thousands of genotypes at the plot level, at different sites and across multiple seasons. These indicate the importance of providing a reliable and scalable toolkit to address the challenge so that the plot-level assessment of GS can be successfully conducted for different objectives in plant research. Here, we present a multimodal deep learning model called GSP-AI, capable of identifying key GSs and predicting the vegetative-to-reproductive transition (i.e., flowering days) in wheat based on drone-collected canopy images and multiseasonal climatic datasets. In the study, we first established an open Wheat Growth Stage Prediction (WGSP) dataset, consisting of 70,410 annotated images collected from 54 varieties cultivated in China, 109 in the United Kingdom, and 100 in the United States together with key climatic factors. Then, we built an effective learning architecture based on Res2Net and long short-term memory (LSTM) to learn canopy-level vision features and patterns of climatic changes between 2018 and 2021 growing seasons. Utilizing the model, we achieved an overall accuracy of 91.2% in identifying key GS and an average root mean square error (RMSE) of 5.6 d for forecasting the flowering days compared with manual scoring. We further tested and improved the GSP-AI model with high-resolution smartphone images collected in the 2021/2022 season in China, through which the accuracy of the model was enhanced to 93.4% for GS and RMSE reduced to 4.7 d for the flowering prediction. As a result, we believe that our work demonstrates a valuable advance to inform breeders and growers regarding the timing and duration of key plant growth and development phases at the plot level, facilitating them to conduct more effective crop selection and make agronomic decisions under complicated field conditions for wheat improvement.

The role of keratinocyte subpopulations in the different phases of the viral cycle during HPV16 infection remains to be characterised. Here, single cell RNA sequencing of HPV16 infected and uninfected organoids identifies 12 distinct keratinocyte populations including an HPV-reprogrammed keratinocyte subpopulation that is linked to cancer.

The Society of Jesus was an international Catholic order involved in educational and missionary activities around the globe. What was the origin of the men who joined the Society of Jesus? This article analyzes the profile of the Jesuits stationed on the five colegios in the Mexican city Puebla de los Ángeles in 1767 at the moment of the expulsion from Spanish territories. It finds, as have other studies, that the majority of the Jesuits were men born in the Americas, and mostly in Mexico. King Carlos III ordered them sent into exile in the Papal States in Italy, although a small number were held as prisoners in Spain. While the majority in Puebla were American-born, it also finds that Jesuits leaders showed a preference for European-born members of the Society on the frontier missions. This was the case of missions on the northern frontier of Mexico, and on the missions among the Guaraní in South America. Finally, the article discusses the process of the expulsion of the Jesuits from Puebla

As one of the most consumed stable foods around the world, wheat plays a crucial role in ensuring global food security. The ability to quantify key yield components under complex field conditions can help breeders and researchers assess wheat’s yield performance effectively. Nevertheless, it is still challenging to conduct large-scale phenotyping to analyse canopy-level wheat spikes and relevant performance traits, in the field and in an automated manner. Here, we present CropQuant-Air, an AI-powered software system that combines state-of-the-art deep learning (DL) models and image processing algorithms to enable the detection of wheat spikes and phenotypic analysis using wheat canopy images acquired by low-cost drones. The system includes the YOLACT-Plot model for plot segmentation, an optimised YOLOv7 model for quantifying the spike number per m2 (SNpM2) trait, and performance-related trait analysis using spectral and texture features at the canopy level. Besides using our labelled dataset for model training, we also employed the Global Wheat Head Detection dataset to incorporate varietal features into the DL models, facilitating us to perform reliable yield-based analysis from hundreds of varieties selected from main wheat production regions in China. Finally, we employed the SNpM2 and performance traits to develop a yield classification model using the Extreme Gradient Boosting (XGBoost) ensemble and obtained significant positive correlations between the computational analysis results and manual scoring, indicating the reliability of CropQuant-Air. To ensure that our work could reach wider researchers, we created a graphical user interface for CropQuant-Air, so that non-expert users could readily use our work. We believe that our work represents valuable advances in yield-based field phenotyping and phenotypic analysis, providing useful and reliable toolkits to enable breeders, researchers, growers, and farmers to assess crop-yield performance in a cost-effective approach.

Global wetlands are the largest and most uncertain natural source of atmospheric methane (CH _4 ). The FLUXNET-CH _4 synthesis initiative has established a global network of flux tower infrastructure, offering valuable data products and fostering a dedicated community for the measurement and analysis of methane flux data. Existing studies using the FLUXNET-CH _4 Community Product v1.0 have provided invaluable insights into the drivers of ecosystem-to-regional spatial patterns and daily-to-decadal temporal dynamics in temperate, boreal, and Arctic climate regions. However, as the wetland CH _4 monitoring network grows, there is a critical knowledge gap about where new monitoring infrastructure ought to be located to improve understanding of the global wetland CH _4 budget. Here we address this gap with a spatial representativeness analysis at existing and hypothetical observation sites, using 16 process-based wetland biogeochemistry models and machine learning. We find that, in addition to eddy covariance monitoring sites, existing chamber sites are important complements, especially over high latitudes and the tropics. Furthermore, expanding the current monitoring network for wetland CH _4 emissions should prioritize, first, tropical and second, sub-tropical semi-arid wetland regions. Considering those new hypothetical wetland sites from tropical and semi-arid climate zones could significantly improve global estimates of wetland CH _4 emissions and reduce bias by 79% (from 76 to 16 TgCH _4 y ^−1 ), compared with using solely existing monitoring networks. Our study thus demonstrates an approach for long-term strategic expansion of flux observations.

Genomic selection has recently become an established part of breeding strategies in cereals. However, a limitation of linear genomic prediction models for complex traits such as yield is that these are unable to accommodate Genotype by Environment effects, which are commonly observed over trials on multiple locations. In this study, we investigated how this environmental variation can be captured by the collection of a large number of phenomic markers using high-throughput field phenotyping and whether it can increase GS prediction accuracy. For this purpose, 44 winter wheat (Triticum aestivum L.) elite populations, comprising 2,994 lines, were grown on two sites over 2 years, to approximate the size of trials in a practical breeding programme. At various growth stages, remote sensing data from multi- and hyperspectral cameras, as well as traditional ground-based visual crop assessment scores, were collected with approximately 100 different data variables collected per plot. The predictive power for grain yield was tested for the various data types, with or without genome-wide marker data sets. Models using phenomic traits alone had a greater predictive value (R2 = 0.39–0.47) than genomic data (approximately R2 = 0.1). The average improvement in predictive power by combining trait and marker data was 6%–12% over the best phenomic-only model, and performed best when data from one full location was used to predict the yield on an entire second location. The results suggest that genetic gain in breeding programmes can be increased by utilisation of large numbers of phenotypic variables using remote sensing in field trials, although at what stage of the breeding cycle phenomic selection could be most profitably applied remains to be answered.

Inefficient nitrogen (N) utilization in agricultural production has led to many negative impacts such as excessive use of N fertilizers, redundant plant growth, greenhouse gases, long-lasting toxicity in ecosystem, and even effect on human health, indicating the importance to optimize N applications in cropping systems. Here, we present a multiseasonal study that focused on measuring phenotypic changes in wheat plants when they were responding to different N treatments under field conditions. Powered by drone-based aerial phenotyping and the AirMeasurer platform, we first quantified 6 N response-related traits as targets using plot-based morphological, spectral, and textural signals collected from 54 winter wheat varieties. Then, we developed dynamic phenotypic analysis using curve fitting to establish profile curves of the traits during the season, which enabled us to compute static phenotypes at key growth stages and dynamic phenotypes (i.e., phenotypic changes) during N response. After that, we combine 12 yield production and N-utilization indices manually measured to produce N efficiency comprehensive scores (NECS), based on which we classified the varieties into 4 N responsiveness (i.e., N-dependent yield increase) groups. The NECS ranking facilitated us to establish a tailored machine learning model for N responsiveness-related varietal classification just using N-response phenotypes with high accuracies. Finally, we employed the Wheat55K SNP Array to map single-nucleotide polymorphisms using N response-related static and dynamic phenotypes, helping us explore genetic components underlying N responsiveness in wheat. In summary, we believe that our work demonstrates valuable advances in N response-related plant research, which could have major implications for improving N sustainability in wheat breeding and production.

Rice (Oryza sativa) is an essential stable food for many rice consumption nations in the world and, thus, the importance to improve its yield production under global climate changes. To evaluate different rice varieties’ yield performance, key yield-related traits such as panicle number per unit area (PNpM2) are key indicators, which have attracted much attention by many plant research groups. Nevertheless, it is still challenging to conduct large-scale screening of rice panicles to quantify the PNpM2 trait due to complex field conditions, a large variation of rice cultivars, and their panicle morphological features. Here, we present Panicle-Cloud, an open and artificial intelligence (AI)-powered cloud computing platform that is capable of quantifying rice panicles from drone-collected imagery. To facilitate the development of AI-powered detection models, we first established an open diverse rice panicle detection dataset that was annotated by a group of rice specialists; then, we integrated several state-of-the-art deep learning models (including a preferred model called Panicle-AI) into the Panicle-Cloud platform, so that nonexpert users could select a pretrained model to detect rice panicles from their own aerial images. We trialed the AI models with images collected at different attitudes and growth stages, through which the right timing and preferred image resolutions for phenotyping rice panicles in the field were identified. Then, we applied the platform in a 2-season rice breeding trial to valid its biological relevance and classified yield production using the platform-derived PNpM2 trait from hundreds of rice varieties. Through correlation analysis between computational analysis and manual scoring, we found that the platform could quantify the PNpM2 trait reliably, based on which yield production was classified with high accuracy. Hence, we trust that our work demonstrates a valuable advance in phenotyping the PNpM2 trait in rice, which provides a useful toolkit to enable rice breeders to screen and select desired rice varieties under field conditions.

Three-dimensional (3D) culturing techniques can recapitulate the stratified nature of multicellular epithelial tissues. Organotypic 3D epithelial tissue culture methods have several applications, including the study of tissue development and function, drug discovery and toxicity testing, host-pathogen interactions, and the development of tissue-engineered constructs for use in regenerative medicine. We grew 3D organotypic epithelial tissues from foreskin, cervix, and tonsil-derived primary cells and characterized the transcriptome of these in vitro tissue equivalents. Using the same 3D culturing method, all three tissues yielded stratified squamous epithelium, validated histologically using basal and superficial epithelial cell markers. The goal of this study was to use RNA-seq to compare gene expression patterns in these three types of epithelial tissues to gain a better understanding of the molecular mechanisms underlying their function and identify potential therapeutic targets for various diseases. Functional profiling by over-representation and gene set enrichment analysis revealed tissue-specific differences: i.e., cutaneous homeostasis and lipid metabolism in foreskin, extracellular matrix remodeling in cervix, and baseline innate immune differences in tonsil. Specifically, tonsillar epithelia may play an active role in shaping the immune microenvironment of the tonsil balancing inflammation and immune responses in the face of constant exposure to microbial insults. Overall, these data serve as a resource, with gene sets made available for the research community to explore, and as a foundation for understanding the epithelial heterogeneity and how it may impact their in vitro use. An online resource is available to investigate these data (https://viz.datascience.arizona.edu/3DEpiEx/).

Abstract Phenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.

This article provides an introduction to this special section of James Baldwin Review 7 devoted to Baldwin and film. Jackson considers Baldwin’s distinct approach to film criticism by pairing him with James Agee, another writer who wrote fiction as well as nonfiction in several genres, and who produced a large body of film criticism, especially during the 1940s. While Agee, a white southerner born almost a generation before Baldwin, might seem an unlikely figure to place alongside Baldwin, the two shared a great deal in terms of temperament and vision, and their film writings reveal a great deal of consensus in their diagnoses of American pathologies. Another important context for Baldwin’s complex relationship to film is television, which became a dominant media form during the 1950s and exerted a great influence upon both the mainstream reception of the civil rights movement and Baldwin’s reception as a public intellectual from the early 1960s to the end of his life. Finally, the introduction briefly discusses the articles that constitute this special section.

Abstract Phenylketonuria (PKU) is an autosomal recessive inborn error of l-phenylalanine (Phe) metabolism. It is caused by a partial or complete deficiency of the enzyme phenylalanine hydroxylase (PAH), which is necessary for conversion of Phe to tyrosine (Tyr). This metabolic error results in buildup of Phe and reduction of Tyr concentration in blood and in the brain, leading to neurological disease and intellectual deficits. Patients exhibit retarded body growth, hypopigmentation, hypocholesterolemia and low levels of neurotransmitters. Here we report first attempt at creating a homozygous Pah knock-out (KO) (Hom) mouse model, which was developed in the C57BL/6 J strain using CRISPR/Cas9 where codon 7 (GAG) in Pah gene was changed to a stop codon TAG. We investigated 2 to 6-month-old, male, Hom mice using comprehensive behavioral and biochemical assays, MRI and histopathology. Age and sex-matched heterozygous Pah-KO (Het) mice were used as control mice, as they exhibit enough PAH enzyme activity to provide Phe and Tyr levels comparable to the wild-type mice. Overall, our findings demonstrate that 6-month-old, male Hom mice completely lack PAH enzyme, exhibit significantly higher blood and brain Phe levels, lower levels of brain Tyr and neurotransmitters along with lower myelin content and have significant behavioral deficit. These mice exhibit phenotypes that closely resemble PKU patients such as retarded body growth, cutaneous hypopigmentation, and hypocholesterolemia when compared to the age- and sex-matched Het mice. Altogether, biochemical, behavioral, and pathologic features of this novel mouse model suggest that it can be used as a reliable translational tool for PKU preclinical research and drug development.

ABSTRACT Upon infection, DNA viruses can be sensed by pattern recognition receptors (PRRs), leading to the activation of type I and III interferons to block infection. Therefore, viruses must inhibit these signaling pathways, avoid being detected, or both. Papillomavirus virions are trafficked from early endosomes to the Golgi apparatus and wait for the onset of mitosis to complete nuclear entry. This unique subcellular trafficking strategy avoids detection by cytoplasmic PRRs, a property that may contribute to the establishment of infection. However, as the capsid uncoats within acidic endosomal compartments, the viral DNA may be exposed to detection by Toll-like receptor 9 (TLR9). In this study, we characterized two new papillomaviruses from bats and used molecular archeology to demonstrate that their genomes altered their nucleotide compositions to avoid detection by TLR9, providing evidence that TLR9 acts as a PRR during papillomavirus infection. Furthermore, we showed that TLR9, like other components of the innate immune system, is under evolutionary selection in bats, providing the first direct evidence for coevolution between papillomaviruses and their hosts. Finally, we demonstrated that the cancer-associated human papillomaviruses show a reduction in CpG dinucleotides within a TLR9 recognition complex. IMPORTANCE Viruses must avoid detection by the innate immune system. In this study, we characterized two new papillomaviruses from bats and used molecular archeology to demonstrate that their genomes altered their nucleotide compositions to avoid detection by TLR9, providing evidence that TLR9 acts as a PRR during papillomavirus infection. Furthermore, we demonstrated that TLR9, like other components of the innate immune system, is under evolutionary selection in bats, providing the first direct evidence for coevolution between papillomaviruses and their hosts.

“Interventions” was the organizing term for the presentations of three Baldwin scholars at the Modern Language Association Convention in Chicago in January of 2019. Baldwin’s travels and activities in spaces not traditionally associated with him, including the U.S. South and West, represent interventions of a quite literal type, while his aesthetic and critical encounters with these and other cultures, including twenty-first-century contexts of racial, and racist, affect—as in the case of Raoul Peck’s 2016 film I Am Not Your Negro—provide opportunities to reconsider his work as it contributes to new thinking about race, space, property, citizenship, and aesthetics.

Abstract Objectives Growth hormone‐releasing hormone (GHRH) is a potent stimulator of growth hormone (GH) secretion from the pituitary gland. Although GHRH is essential for the growth of immune cells, the regulatory effects of its antagonist in granulomatous disease remain unknown. Methods Here, we report expression of GHRH receptor (R) in human tissue with sarcoidosis granuloma and demonstrate the anti‐inflammatory effects of MIA602 (a GHRH antagonist) in two in vitro human granuloma models and an in vivo granuloma model using different methods including ELISA, immunohistochemistry, RNA‐seq analysis and flow cytometry. Results MIA602 decreases the levels of IL‐2, IL‐2R, IL‐7, IL‐12, IL‐17A and TNF‐α in an in vitro granuloma model. Further, we show that the anti‐inflammatory effect of MIA602 appears to be mediated by a reduction in CD45+CD68+ cells in granulomatous tissue and upregulation in PD‐1 expression in macrophages. Analysis of the expression of proteins involved in the mitochondrial stage of apoptosis showed that MIA602 increases the levels of caspase‐3, BCL‐xL/BAK dimer and MCl‐1/Bak dimer in the granuloma. These findings indicate that MIA602 may not induce apoptosis. Conclusions Our findings further suggest that GHRH‐R is potentially a clinical target for the treatment of granulomatous disease and that MIA602 may be used as a novel therapeutic agent for sarcoidosis.

Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.

This software assimilates data from an arbitrary number of weather radars together with other spatial wind fields (eg numerical weather forecasting model data) in order to retrieve high resolution three dimensional wind fields. PyDDA uses NumPy and SciPy’s optimization techniques combined with the Python Atmospheric Radiation Measurement (ARM) Radar Toolkit (Py-ART) in order to create wind fields using the 3D variational technique (3DVAR). PyDDA is hosted and distributed on GitHub at https://github.com/openradar/PyDDA. PyDDA has the potential to be used by the atmospheric science community to develop high resolution wind retrievals from radar networks. These retrievals can be used for the evaluation of numerical weather forecasting models and plume modelling. This paper shows how wind fields from 2 NEXt generation RADar (NEXRAD) WSR-88D radars and the High Resolution Rapid Refresh can be assimilated together using PyDDA to create a high resolution wind field inside Hurricane Florence. Funding statement: The development of this software is supported by the Climate Model Development and Validation (CMDV) activity which is funded by the Office of Biological and Environmental Research in the US Department of Energy Office of Science.

Information on crop pedigrees can be used to help maximise genetic gain in crop breeding and allow efficient management of genetic resources. We present a pedigree resource of 2,657 wheat (Triticum aestivum L.) genotypes originating from 38 countries, representing more than a century of breeding and variety development. Visualisation of the pedigree enables illustration of the key developments in United Kingdom wheat breeding, highlights the wide genetic background of the UK wheat gene pool, and facilitates tracing the origin of beneficial alleles. A relatively high correlation between pedigree- and marker-based kinship coefficients was found, which validated the pedigree and enabled identification of errors in the pedigree or marker data. Using simulations with a combination of pedigree and genotype data, we found evidence for significant effects of selection by breeders. Within crosses, genotypes are often more closely related than expected by simulations to one of the parents, which indicates selection for favourable alleles during the breeding process. Selection across the pedigree was demonstrated on a subset of the pedigree in which 110 genotyped varieties released before the year 2000 were used to simulate the distribution of marker alleles of 45 genotyped varieties released after the year 2000, in the absence of selection. Allelic diversity in the 45 varieties was found to deviate significantly from the simulated distributions at a number of loci, indicating regions under selection over this period. The identification of one of these regions as coinciding with a strong yield component quantitative trait locus (QTL) highlights both the potential of the remaining loci as wheat breeding targets for further investigation, as well as the utility of this pedigree-based methodology to identify important breeding targets in other crops. Further evidence for selection was found as greater linkage disequilibrium (LD) for observed versus simulated genotypes within all chromosomes. This difference was greater at shorter genetic distances, indicating that breeder selections have conserved beneficial linkage blocks. Collectively, this work highlights the benefits of generating detailed pedigree resources for crop species. The wheat pedigree database developed here represents a valuable community resource and will be updated as new varieties are released at https://www.niab.com/pages/id/501/UK_Wheat_varieties_Pedigree.

Infections of stratified epithelia contribute to a large group of common diseases, such as dermatological conditions and sexually transmitted diseases. To investigate how epithelial structure affects infection dynamics, we develop a general ecology-inspired model for stratified epithelia. Our model allows us to simulate infections, explore new hypotheses and estimate parameters that are difficult to measure with tissue cell cultures. We focus on two contrasting pathogens: Chlamydia trachomatis and Human papillomaviruses (HPV). Using cervicovaginal parameter estimates, we find that key infection symptoms can be explained by differential interactions with the layers, while clearance and pathogen burden appear to be bottom-up processes. Cell protective responses to infections (e.g. mucus trapping) generally lowered pathogen load but there were specific effects based on infection strategies. Our modeling approach opens new perspectives for 3D tissue culture experimental systems of infections and, more generally, for developing and testing hypotheses related to infections of stratified epithelia.

Three-dimensional cell culturing to capture a life-like experimental environment has become a versatile tool for basic and clinical research. Mucosal and skin tissues can be grown as “organoids” in a petri dish and serve a wide variety of research questions. Here, we report our experience with human cervical organoids which could also include an immune component, e.g., Langerhans cells. We employ commercially available human cervical keratinocytes and fibroblasts as well as a myeloid cell line matured and purified into langerin-positive Langerhans cells. These are then seeded on a layer of keratinocytes with underlying dermal equivalent. Using about 10-fold more than the reported number in healthy cervical tissue (1–3%), we obtain differentiated cervical epithelium after 14 days with ~1% being Langerhans cells. We provide a detailed protocol for interested researchers to apply the described “aseptic” organoid model for all sorts of investigations—with or without Langerhans cells.

This article outlines some issues in incorporating the study of religions, together with non-religious world views, into the curricula of publicly funded schools in Western democratic states. Attention is given to examples from work on this topic conducted within the Council of Europe since 2002, with a particular focus on Signposts: Policy and Practice for Teaching about Religions and Nonreligious World Views in Intercultural Education, a text published by the Council of Europe in 2014. Signposts is designed to assist policy makers and practitioners in interpreting and applying ideas from the 2008 Recommendation from the Committee of Ministers (the Foreign Ministers of the 47 member states) dealing with education about religions and non-religious convictions. Various issues raised by the Signposts document are considered. Towards the end of the article, recent UK and Council of Europe policies which emphasise the study of religions and beliefs as a means to counter extremism, and which have appeared since the publication of Signposts, are summarised and discussed critically. Attention is drawn to the dangers of certain policies, and also to the plurality of aims which studies of religions and non-religious world views need to have in providing a balanced educational programme.

Infective endocarditis has different presentations depending on the involvement of valvular and perivalvular structures, and it is associated with high morbidity and mortality. Aortocavitary fistula is a rare complication. We introduce the case of a 48-year-old female with native valve endocarditis, complicated by aortocavitary fistula to the right atrium, and consequently presented with syncope.

This paper argues for a reconsideration of social cohesion as an analytical concept and a policy goal in response to increasing levels of religious diversity in contemporary Australia. In recent decades, Australian has seen a revitalization of religion, increasing numbers of those who do not identify with a religion (the “nones”), and the growth of religious minorities, including Islam, Buddhism, Hinduism, and Sikhism. These changes are often understood as problematic for social cohesion. In this paper, we review some conceptualizations of social cohesion and religious diversity in Australia, arguing that the concept of social cohesion, despite its initial promise, is ultimately problematic, particularly when it is used to defend privilege. We survey Australian policy responses to religious diversity, noting that these are varied, often piecemeal, and that the hyperdiverse state of Victoria generally has the most sophisticated set of public policies. We conclude with a call for more nuanced and contextualized analyses of religious diversity and social cohesion in Australia. Religious diversity presents both opportunities as well as challenges to social cohesion. Both these aspects need to be considered in the formation of policy responses.

Recombinant adeno-associated viral (rAAV) vectors containing oversized genomes provide transgene expression despite low efficiency packaging of complete genomes. Here, we characterized the properties of oversized rAAV2/8 vectors (up to 5.4 kb) encoding human factor VIII (FVIII) under the transcriptional control of three liver promoters. All vectors provided sustained production of active FVIII in mice for 7 months and contained comparable levels of vector genomes and complete expression cassettes in liver. Therefore, for the 5.4 kb genome size range, a strong expression cassette was more important for FVIII production than the vector genome size. To evaluate the potency of slightly oversized vectors, a 5.1 kb AAVrh8R/FVIII vector was compared to a 4.6 kb (wild-type size) vector with an identical expression cassette (but containing a smaller C1-domain deleted FVIII) for 3 months in mice. The 5.1 kb vector had twofold to threefold lower levels of plasma FVIII protein and liver vector genomes than that obtained with the 4.6 kb vector. Vector genomes for both vectors persisted equally and existed primarily as high molecular weight concatemeric circular forms in liver. Taken together, these results indicate that the slightly oversized vectors containing heterogeneously packaged vector genomes generated a functional transgene product but exhibited a twofold to threefold lower in vivo potency.

Abstract We have created a didactic tool for early radiology and nonradiology trainees that facilitates the approach to image interpretation for given clinical questions from the ground up. This team-based learning (TBL) module is designed to provide residents with a brief and straightforward guide to the interpretation of imaging studies for patients with head trauma. It is intended for use by first-year radiology residents but can also be used to train neurosurgery and emergency medicine residents as well. The module was developed in 2013 and improved in 2014 with the addition of new cases. It is part of an ongoing project consisting of multiple modules developed to introduce a systematic approach for different complaints/scenarios. Learning involves preclass reading, in-class readiness assurance exercises, and group application exercises. All the students are evaluated using the Readiness Assurance Test before the class starts. The score of the test is not intended to evaluate the student but to help the evaluator designate equally balanced groups of three to five students who can teach and help each other during the group application exercises. We presented this TBL module to first-year residents from an academic university program, and 100% of them were satisfied with the session. Although we do not have specific quantitative data about the outcomes of this specific module, other publications support that course content learned through TBL correlates with higher scores on examinations.

Bu makale, yazarın ?Religious Education: An Interpretive Approach' adlı eserinde de olduğu gibi öncelikle temsil, yorumlama ve düşünümsellik anahtar kavramlarını tartışarak yorumlayıcı din eğitimi yaklaşımını tanıtma amacını gütmektedir. Makale, bu fikirlerin deneysel bir program geliştirme projesi olan Warwich Din Eğitimi Projesine (The Warwich RE Project) nasıl uygulandığını göstererek devam etmektedir. Nihayet Warwich Din Eğitimi Projesinin tamamlayıcısı olarak görülen yorumlayıcı yaklaşımın dört değişkeninin üzerinde durulmaktadır. İkisi İngiltere'deki Warwich Din ve Eğitim Araştırmaları Biriminde yapılan çalışmayla (Krisman ve O'Grady'nin çalışmaları) bağlantılıdır. Diğerleri ise Güney Afrika (Stonier, Kwenda ve Mndende) ve İsveç'teki (Eriksson) din eğitimcilerinden alınmıştır.

What is it about propaganda that Alan Turing deemed sufficient in describing a statement about puzzles, problems and solutions? Despite not being an overtly political writer, Turing’s relevancy is undoubtedly important for the politics of digital culture today: particularly concerning relationships between culture, computation, mathematics, digital transmission and even the purported recognition of the “post-digital”. What on earth provoked him to describe a mathematical idea as propaganda? Might it not be understood as a retroactive sign of a post-digital affect, or, perhaps an expected symptom of embedded life within a politics of mathematical propagation? The purpose of this article is to outline what such a description might provoke.

Infection with a transforming human papillomavirus (HPV) such as type 16 (of species Alphapapillomavirus 9) causes ano-genital and oral tumours via viral persistence in human squamous cell epithelia. Epidemiological studies showed that the naturally occurring HPV16 Asian-American (AA) variant (sublineage D2/D3) is found more often than the European Prototype (EP) (sublineage A1) in high-grade cervical neoplasia and tumours compared to non-cancer controls. Just three amino acid changes within the early gene, E6, of HPV16 AA have been linked to this augmented tumourigenicity. The AAE6 variant's greater immortalizing and transforming potential over EPE6 has recently been confirmed in retrovirally-transduced keratinocytes expressing the E6 gene only. However, the tumourigenic role of the full-length viral genome of HPV16 has not yet been addressed with regard to these E6 variants. To investigate this process in the context of these two HPV16 E6 genotypes, an organotypic tissue culture model was used to simulate the HPV infectious life cycle. The AAE6 variant demonstrated an enhanced ability over EPE6 to drive the viral life cycle toward tumourigenesis, as evidenced phenotypically-by a more severe grade of epithelial dysplasia with higher proliferation and deregulated differentiation, and molecularly-by high viral oncogene E6 and E7 expression, but lack of productive viral life cycle markers. In contrast, EPE6 had low E6 and E7 but high E1∧E4 expression, indicative of a productive life cycle. We suggest increased viral integration into the host genome for AAE6 as one possible mechanism for these observed differences from EPE6. Additionally, we found downstream effects on immortalization and host innate immune evasion. This study highlights how minor genomic variations in transforming viruses can have a significant affect on their tumourigenic ability.

The human papillomavirus (HPV) directly infects cervical keratinocytes and interferes with TLR signalling. To shed light on the effect of HPV on upstream receptors, we evaluated TLRs 1–9 gene expression in HPV-negative normal and HPV-positive pre-malignant and malignant ex vivo cervical tissue. Quantitative real-time polymerase chain reaction was performed separately for epithelial and stromal tissue compartments. Differences in gene expression were analyzed by the Jonckheere-Terpstra trend test or the Student's t-test for pairwise comparison. Laser capture microdissection revealed an increase in TLR3 and a decrease in TLR1 mRNA levels in dysplastic and carcinoma epithelium, respectively. In the stroma, a trend of increasing TLR 1, 2, 5, 6, and 9 mRNA levels with disease severity was found. These findings implicate the involvement of TLR3 and TLR1 in early and late cervical carcinogenesis, respectively, suggesting that stromal upregulation of TLRs may play a role in cervical disease progression.

High-risk types of human papillomavirus (HPV), such as HPV16, have been found in nearly all cases of cervical cancer. Therapies targeted at blocking the HPV16 E6 protein and its deleterious effects on the tumour suppressor pathways of the cell can reverse the malignant phenotype of affected keratinocytes while sparing uninfected cells. Through a strong interdisciplinary collaboration between engineering and biology, a novel, non-invasive intracellular delivery method for the HPV16 E6 antibody, F127-6G6, was developed. The method employs high intensity focused ultrasound (HIFU) in combination with microbubbles, in a process known as sonoporation. In this proof of principle study, it was first demonstrated that sonoporation antibody delivery into the HPV16 positive cervical carcinoma derived cell lines CaSki and SiHa was possible, using chemical transfection as a baseline for comparison. Delivery of the E6 antibody using sonoporation significantly restored p53 expression in these cells, indicating the antibody is able to enter the cells and remains active. This delivery method is targeted, non-cytotoxic, and non-invasive, making it more easily translatable for in vivo experiments than other transfection methods.

On September 19 and 20, 2003, the Seventeenth Southern Writers Symposium, organized around the theme of "Region," was hosted by Methodist College in Fayetteville, North Carolina. The occasion provided the scholars who now make up the Editorial Board of Southern Spaces with an excellent opportunity to advance their "cornerstone" missions: providing a location for discussions about Southern place and space and offering a variety of means through which to map diverse, often oppositional, always shifting delineations of the South's boundaries—ideological and mythological as well as geographical. The idea of an inaugural web forum made up of contributions from the scholarly gathering in Fayetteville came to fruition as Symposium participants were invited to submit their papers to be considered for posting with Southern Spaces. Scholars John Shelton Reed and Jon Smith, who were keynote speakers at the Symposium, made the final selection of the four papers that are presented below. We acknowledge with gratitude the energy and care with which they made their decisions. We also wish to thank Professor Emily Wright of Methodist College, the Conference Director, for giving us this opportunity and providing indispensable editorial oversight and review. The papers that were selected prove that the southerner's faith in potluck church suppers might also apply to undertakings such as this one: the contributions to the repast combined serendipitously to produce a wonderful blend, as though the whole menu had been carefully pre-ordained. The four papers that we present here are integral to Southern Spaces' effort to make available an array of new tools that will allow scholars to expand their ideas—concerning how and where they can meet as well as how and what they can discuss—in their pursuit of the contours that constitute the range, but not the limits, of the South.

In this article, I draw on my own experience as a researcher, writer on theory and pedagogy of religion education¹ and contributor to European policy documents. This provides a basis to discuss some issues pertinent to Cornelia Roux's personal and professional journey as a researcher in religion education and related fields, including intercultural education, human rights education and citizenship education. I refer to our meetings over the years, both in and beyond South Africa, especially in the context of the International Network for Interreligious and Intercultural Education, and to the development of Professor Roux's ideas on Religion in Education (RiE), Religion and Education (RaE). An attempt is then made to articulate a view on the question of liberalism in relation to human rights, which connects to a stance on intercultural education and to religion education and values education more widely. The position developed is consistent with the approach to empirical research developed by Professor Roux and her team. The article concludes by relating Cornelia Roux's personal journey to some of the themes considered above.