Model calculations and measurements of shooting sound in practical situations.

Shooting sound in practical situations with propagation distances up to 300 m is investigated by means of model calculations and measurements. The results illustrate uncertainties in the model calculations for practical situations. The measurements were performed with various small-caliber weapons. Microphones were placed at positions screened by a noise barrier, and also at unscreened positions. The measured signals contain muzzle sound and bullet sound. The model calculations for muzzle sound and bullet sound take into account emission spectra and various propagation attenuation terms, including ground attenuation and barrier attenuation. The bullet sound model is based on a nonlinear theory of N waves generated by supersonic projectiles. For the unscreened situation, model and measurement results show that the sound levels are considerably reduced by ground attenuation. Ground-level variations and ground roughness in the measurement area play an important role. At a 300 m distance, the A-weighted bullet sound level is higher than the A-weighted muzzle sound level, which underlines the importance of bullet sound. For the screened situation, model and measurement results are used to analyze diffraction of bullet sound by the horizontal and vertical edges of the barrier. The diffraction is explained by considering Fresnel zones on the bullet trajectory.

Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection.

Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation.

Physiological Traits Determining Yield Tolerance of Wheat to Foliar Diseases.

Tolerance is defined as the ability of one cultivar to yield more than another cultivar under similar disease severity. If both cultivars suffer an equal loss in healthy (green) leaf area duration (HAD) over the grain filling period due to disease presence, then the yield loss per unit HAD loss is smaller for a more tolerant cultivar. Little is understood of what physiological and developmental traits of cultivars determine disease tolerance. In this study, we use a mathematical model of wheat to investigate the effect of a wide range of wheat phenotypes on tolerance. During the phase from stem extension to anthesis, the model calculates the assimilate source and sink potential, allowing for dynamic changes to the source-sink balance by partitioning assimilates between ear development and storage of water-soluble carbon (WSC) reserves, according to assimilate availability. To quantify tolerance, rates of epidemic progress were varied on each phenotype, leading to different levels of HAD loss during the postanthesis, grain-filling period. Model outputs show that the main determinant of tolerance is the total amount of assimilate produced per grain during the rapid grain-fill period, leading to a strong positive correlation between HAD per grain and tolerance. Reductions in traits that affect carbon assimilation rate and increases in traits that determine the amount of structural biomass in the plant increase disease tolerance through their associated reduction in number of grains per ear. Some of the most influential traits are the canopy green area index, carbon use efficiency, and leaf specific weight. Increased WSC accumulation can either increase or decrease tolerance. Furthermore, a cultivar is shown to be maximally tolerant when a crop is able to just fill its total sink size in the presence of disease. The model has identified influential functional traits and established that their associations with tolerance have a mechanistic basis.

Competitive displacement of sodium caseinate by low-molecular-weight emulsifiers and the effects on emulsion texture and rheology.

Low-molecular-weight (LMW) emulsifiers are used to promote controlled destabilization in many dairy-type emulsions in order to obtain stable foams in whippable products. The relation between fat globule aggregation induced by three LMW emulsifiers, lactic acid ester of monoglyceride (LACTEM), saturated monoglyceride (GMS), and unsaturated monoglyceride (GMU) and their effect on interfacial protein displacement was investigated. It was found that protein displacement by LMW emulsifiers was not necessary for fat globule aggregation in emulsions, and conversely fat globule aggregation was not necessarily accompanied by protein displacement. The three LMW emulsifiers had very different effects on emulsions. LACTEM induced shear instability of emulsions, which was accompanied by protein displacement. High stability was characteristic for emulsions with GMS where protein was displaced from the interface. Emulsions containing GMU were semisolid, but only low concentrations of protein were detected in the separated serum phase. The effects of LACTEM, GMS, and GMU may be explained by three different mechanisms involving formation of interfacial α-gel, pickering stabilization and increased exposure of bound casein to the water phase. The latter may facilitate partial coalescence. Stabilizing hydrocolloids did not have any effect on the LMW emulsifiers' ability to induce protein displacement.

Optimal fungicide application timings for disease control are also an effective anti-resistance strategy: a case study for Zymoseptoria tritici (Mycosphaerella graminicola) on wheat.

Strategies to slow fungicide resistance evolution often advocate early "prophylactic" fungicide application and avoidance of "curative" treatments where possible. There is little evidence to support such guidance. Fungicide applications are usually timed to maximize the efficiency of disease control during the yield-forming period. This article reports mathematical modeling to explore whether earlier timings might be more beneficial for fungicide resistance management compared with the timings that are optimal for efficacy. There are two key timings for fungicide treatment of winter wheat in the United Kingdom: full emergence of leaf three (counting down the canopy) and full emergence of the flag leaf (leaf 1). These timings (referred to as T1 and T2, respectively) maximize disease control on the upper leaves of the crop canopy that are crucial to yield. A differential equation model was developed to track the dynamics of leaf emergence and senescence, epidemic growth, fungicide efficacy, and selection for a resistant strain. The model represented Zymoseptoria tritici on wheat treated twice at varying spray timings. At all fungicide doses tested, moving one or both of the two sprays earlier than the normal T1 and T2 timings reduced selection but also reduced efficacy. Despite these opposing effects, at a fungicide dose just sufficient to obtain effective control, the T1 and T2 timings optimized fungicide effective life (the number of years that effective control can be maintained). At a higher dose, earlier spray timings maximized effective life but caused some reduction in efficacy, whereas the T1 and T2 timings maximized efficacy but resulted in an effective life 1 year shorter than the maximum achievable.

Mitochondrial DNA as a marker for treatment-response in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a serious mental health condition thought to be mediated by a dysregulated stress response system. Stress, especially chronic stress, affects mitochondrial activity and their efficiency in duplicating their genomes. Human cells contain numerous mitochondria that harbor multiple copies of their own genome, which consist of a mixture of wild type and variant mtDNA - a condition known as mitochondrial heteroplasmy. Number of mitochondrial genomes in a cell and the degree of heteroplasmy may serve as an indicator of mitochondrial allostatic load. Changes in mtDNA copy number and the proportion of variant mtDNA may be related to mental disorders and symptom severity, suggesting an involvement of mitochondrial dysfunction also in PTSD. Therefore, we examined number and composition of mitochondrial DNA before and after six weeks of inpatient psychotherapy treatment in a cohort of 60 female PTSD patients. We extracted DNA from isolated monocytes before and after inpatient treatment and quantified cellular mtDNA using multiplex qPCR. We hypothesized that treatment would lead to changes in cellular mtDNA levels and that change in mtDNA level would be associated with PTSD symptom severity and treatment response. It could be shown that mtDNA copy number and the ratio of variant mtDNA decreased during therapy, however, this change did not correlate with treatment response. Our results suggest that inpatient treatment can reduce signs of mitochondrial allostatic load, which could have beneficial effects on mental health. The quantification of mtDNA and the determination of cellular heteroplasmy could represent valuable biomarkers for the molecular characterization of mental disorders in the future.

Propagation of uncertainties in soil and pesticide properties to pesticide leaching.

In the new Dutch decision tree for the evaluation of pesticide leaching to groundwater, spatially distributed soil data are used by the GeoPEARL model to calculate the 90th percentile of the spatial cumulative distribution function of the leaching concentration in the area of potential usage (SP90). Until now it was not known to what extent uncertainties in soil and pesticide properties propagate to spatially aggregated parameters like the SP90. A study was performed to quantify the uncertainties in soil and pesticide properties and to analyze their contribution to the uncertainty in SP90. First, uncertainties in the soil and pesticide properties were quantified. Next, a regular grid sample of points covering the whole of the agricultural area in the Netherlands was randomly selected. At the grid nodes, realizations from the probability distributions of the uncertain inputs were generated and used as input to a Monte Carlo uncertainty propagation analysis. The analysis showed that the uncertainty concerning the SP90 is 10 times smaller than the uncertainty about the leaching concentration at individual point locations. The parameters that contribute most to the uncertainty about the SP90 are, however, the same as the parameters that contribute most to uncertainty about the leaching concentration at individual point locations (e.g., the transformation half-life in soil and the coefficient of sorption on organic matter). Taking uncertainties in soil and pesticide properties into account further leads to a systematic increase of the predicted SP90. The important implication for pesticide regulation is that the leaching concentration is systematically underestimated when these uncertainties are ignored.

Canonical finger-numeral configurations facilitate the processing of Arabic numerals in adults: An Event-Related Potential study.

Various studies claim that early-learned, culture-typical (canonical) finger configurations used to communicate or represent numerosity, have stronger connections to numerical concepts stored in long-term memory than cultural-unfamiliar finger configurations, thereby allowing for faster access to their numerical meaning. The current study investigated whether presentation of canonical finger configurations gesturing numerosities 1-4 or 6-9 would facilitate young adults' behavioral and neural processing of Arabic numerals. Thirty-one adults performed a number comparison task in which they had to decide whether simultaneously presented Arabic numerals and canonical or non-canonical finger configurations showed the same or a different numerosity, while measuring their performance and Event-Related Potentials (ERPs). The results showed faster responses when comparisons involved canonical (versus non-canonical) finger configurations, but only on numerosity-congruent trials where finger configuration and Arabic numeral matched in number identity. Canonical, and small-number finger configurations 1-4 in general (irrespective of their canonicity), also elicited enhanced amplitude of the early right-parietal P2p, and the later centro-parietal P3 on numerosity-congruent trials. We suggest these P2p and P3 findings respectively reflect facilitated numerical access and easier categorization of canonical finger-numeral configurations. The current results provide behavioral and neurophysiological evidence for the embodiment of culture-specific, canonical, finger-numeral configurations, and their link with other number representations in the adult brain, likely emerging from their more frequent use in daily life communication and/or in early childhood during number symbol acquisition.

Spatioregional assessment of the gut microbiota in experimental necrotizing pancreatitis.

BACKGROUND: Infectious complications following experimental pancreatitis involve major disruptions in the gut microbiota. The aim of this study was to characterize this disruption by examining the spatioregional distribution in microbial community structure and function following experimental pancreatitis associated with pancreatic infection. METHODS: Mice were subjected to infusion of the pancreatic duct with either taurocholate to induce necrotizing pancreatitis or normal saline (control group). The spatial (lumen versus mucosa) and regional composition and function of the microbiota from the duodenum, ileum, caecum, colon, pancreas and blood were evaluated using 16S rRNA gene amplicon sequencing. RESULTS: Mice that developed necrotizing pancreatitis demonstrated a decrease in microbial richness and significantly altered microbiota in distal parts of the gastrointestinal tract, compared with controls. Among the most differentially increased taxa were the mucus-degrading Akkermansia muciniphila, and there was a decrease of butyrate-producing bacteria following pancreatitis. Application of the SourceTracker tool to the generated metadata indicated that the duodenum was the most probable source of bacteria that subsequently infected pancreatic tissue in this model. The functional prediction annotation using pathway analyses indicated a diminished capacity of the caecal microbiota to metabolize carbohydrate, and fatty and amino acids. DISCUSSION: The distal gut microbiota was significantly impacted in this model of experimental necrotizing pancreatitis. Data suggest that the duodenal microbiota might also play a role in bacterial translation and secondary infections.

Major histocompatibility complex class II-expressing endothelial cells induce allospecific nonresponsiveness in naive T cells.

The role of endothelial cells (EC) in initiating a primary T cell response is of importance in clinical transplantation and autoimmunity since EC are the first allogeneic target encountered by the recipient's immune system and may display tissue-specific autoantigens in the context of an inflammatory response. In this study, we have investigated the antigen-presenting cell function of human umbilical vein-derived EC (HUVEC), depleted of constitutively major histocompatibility complex class II+ cells and induced to express class II molecules by interferon-gamma. The results show that HUVEC do not express B7 but can support proliferation by antigen-specific T cell clones. In contrast, they were unable to initiate a primary alloresponse using three independent HUVEC cultures and MHC class II-mismatched CD4+ T cells from eight donors. The response to HUVEC was reconstituted by trans-costimulation provided by DAP.3 transfectants expressing human B7.1. Coculture of peripheral blood T cells with EC expressing allogeneic DR molecules had markedly different effects on CD45RO+ and RA+ subsets. Subsequent reactivity of the RO+ T cells was unaffected by exposure to EC, indicating a neutral encounter. In contrast, culture with DR+ EC induced allospecific nonresponsiveness in RA+ T cells.

Activated human lymphocytes and aggressive non-Hodgkin's lymphomas express a homologue of the rat metastasis-associated variant of CD44.

A recently described splice variant of CD44 expressed in metastasizing cell lines of rat tumors, has been shown to confer metastatic potential to nonmetastasizing rat pancreatic carcinoma and sarcoma cell lines. Using antibodies raised against a bacterial fusion protein encoded by variant CD44 sequences, we have explored the expression of variant CD44 glycoproteins on human lymphoid cells and tissues and on non-Hodgkin's lymphomas. Normal lymphohematopoietic cells express barely detectable low levels of variant CD44 glycoproteins, whereas T lymphocytes, upon activation by mitogen or antigen, transiently upregulate expression of specific CD44 variant glycoproteins. The reaction pattern of various antibodies indicates that these CD44 variants contain the domain encoded by exon v6, which is part of the variant that in the rat confers metastatic capability. It is interesting that overexpression of v6 was also found in several aggressive, but not low-grade, non-Hodgkin's lymphomas.

Evolutionary bi-stability in pathogen transmission mode.

Many pathogens transmit to new hosts by both infection (horizontal transmission) and transfer to the infected host's offspring (vertical transmission). These two transmission modes require specific adaptations of the pathogen that can be mutually exclusive, resulting in a trade-off between horizontal and vertical transmission. We show that in mathematical models such trade-offs can lead to the simultaneous existence of two evolutionary stable states (evolutionary bi-stability) of allocation of resources to the two modes of transmission. We also show that jumping between evolutionary stable states can be induced by gradual environmental changes. Using quantitative PCR-based estimates of abundance in seed and vegetative parts, we show that the pathogen of wheat, Phaeosphaeria nodorum, has jumped between two distinct states of transmission mode twice in the past 160 years, which, based on published evidence, we interpret as adaptation to environmental change. The finding of evolutionary bi-stability has implications for human, animal and other plant diseases. An ill-judged change in a disease control programme could cause the pathogen to evolve a new, and possibly more damaging, combination of transmission modes. Similarly, environmental changes can shift the balance between transmission modes, with adverse effects on human, animal and plant health.

Periodicity in host availability does not account for evolutionary branching as observed in many plant pathogens: an application to Gaeumannomyces graminis var. tritici.

Periodicity in host availability is common in agricultural systems. Although it is known to have profound effects on plant pathogen abundance, the evolutionary consequences of periodicity for the pathogen population have not previously been analyzed. An epidemiological model incorporating periodic absence of the host crop is combined with the theory of adaptive dynamics to determine whether or not seasonality in host presence plays a role in the occurrence of evolutionary branching, leading to coexisting yet genetically distinct pathogen phenotypes. The study is motivated and illustrated by the specific example of take-all disease of wheat, caused by the pathogen Gaeumannomyces graminis var. tritici, for which two coexisting but genetically distinct types and a trade-off related to seasonality in host presence have been identified. Numerical simulations are used to show that a trade-off between the pathogen transmission rate and the survival of the pathogen between cropping seasons cannot account for the evolutionary branching observed in many pathogens. Model elaborations show that this conclusion holds for a broad range of putative mechanisms. Although the analysis is motivated and illustrated by the specific example of take-all of wheat, the results apply to a broad range of pathogens.

Ratios between Alpha-, Beta- and Gamma-proteobacteria in tap water determined by the ProteoQuant assay.

AIMS: Proteobacteria are widespread on earth. Recently, it has been discovered that a diverse repertoire of proteobacteria are also dominant in tap water. It is therefore important to use high-throughput monitoring tools for tap water. Here, the high-throughput assay ProteoQuant was developed to quantify the main proteobacterial phyla in tap water. METHODS AND RESULTS: The principle of ProteoQuant is proteobacterial-selective 23S rRNA gene PCR amplification, with multiple competitive TaqMan probes for quantifying the phyla Alpha-, Beta- and Gamma-proteobacteria. The ProteoQuant assay was evaluated, analysing both designed proteobacterial mixes and rRNA gene clone libraries from tap water. These evaluations showed a good coverage and accuracy of the ProteoQuant assay. CONCLUSIONS: Large-scale tap water screening using ProteoQuant revealed a dominance of Beta-proteobacteria and a potential interaction between Alpha- and Beta-proteobacteria. Gamma-proteobacteria, on the other hand, seemed independent of the two other phyla. SIGNIFICANCE AND IMPACT OF THE STUDY: The ProteoQuant assay will potentially be important for future understanding of the ecological forces shaping the tap water microbiota.

Meta-analysis and field synopsis of genetic variants associated with the risk and severity of acute pancreatitis.

BACKGROUND: Genetic risk factors can provide insight into susceptibility for acute pancreatitis (AP) and disease progression towards (infected) necrotizing pancreatitis and persistent organ failure. The aim of the study was to undertake a systematic review of the genetic evidence for AP. METHODS: Online databases (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) were searched to 8 February 2018. Studies that reported on genetic associations with AP susceptibility, severity and/or complications were eligible for inclusion. Meta-analyses were performed of variants that were reported by at least two data sources. Venice criteria and Bayesian false-discovery probability were applied to assess credibility. RESULTS: Ninety-six studies reporting on 181 variants in 79 genes were identified. In agreement with previous meta-analyses, credible associations were established for SPINK1 (odds ratio (OR) 2·87, 95 per cent c.i. 1·89 to 4·34), IL1B (OR 1·23, 1·06 to 1·42) and IL6 (OR 1·64, 1·15 to 2·32) and disease risk. In addition, two novel credible single-nucleotide polymorphisms were identified in Asian populations: ALDH2 (OR 0·48, 0·36 to 0·64) and IL18 (OR 1·47, 1·18 to 1·82). Associations of variants in TNF, GSTP1 and CXCL8 genes with disease severity were identified, but were of low credibility. CONCLUSION: Genetic risk factors in genes related to trypsin activation and innate immunity appear to be associated with susceptibility to and severity of AP.

ANTECEDENTES: Los factores de riesgo genético pueden contribuir a determinar la susceptibilidad para desarrollar una pancreatitis aguda (acute pancreatitis, AP) y de su progresión a pancreatitis necrotizante (infectada) e insuficiencia orgánica crónica. Nuestro objetivo fue revisar de forma sistemática la evidencia genética de la pancreatitis aguda. MÉTODOS: Se revisaron las bases de datos electrónicas (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) hasta febrero de 2018. Se incluyeron estudios que presentaban información de las asociaciones genéticas y la susceptibilidad de AP, gravedad y/o complicaciones. Se realizó un metaanálisis de las variantes genéticas descritas en al menos dos fuentes. Se aplicaron los criterios de Venecia y la probabilidad bayesiana de falsa alarma para la valoración de la credibilidad. RESULTADOS: Se identificaron 96 estudios que analizaron 181 variantes en 79 genes. De acuerdo con un metaanálisis previo, se establecieron asociaciones creibles con el riesgo de enfermedad para SPINK1 (razón de oportunidades, odds ratio, OR 2,87, i.c. del 95% 1,89-4,34), IL1B (OR 1,23, i.c. del 95% 1,06-1,42) e IL6 (OR 1,64, i.c. del 95% 1,15-2,32). Además, en poblaciones asiáticas, se identificaron dos nuevos polimorfismos de nucleótico único (SNP) creibles en ALDH2 (OR 0,48, i.c. del 95% 0,36-0,64) e IL18 (OR 1,47, i.c. del 95% 1,18-1,82). En cuanto a la gravedad de la enfermedad se identificaron variantes en los genes TNF, GSTP1 y CXCL8, pero de baja credibilidad en función de nuestra evaluación. CONCLUSIÓN: Los factores de riesgo genéticos en genes relacionados con la activación de la tripsina y la inmunidad innata parecen ser estar asociados con la susceptibilidad y gravedad de la pancreatitis aguda.

A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps.

A recently described splice variant of CD44 expressed in metastasizing cell lines of rat tumors has been shown to confer metastatic potential to a non-metastasizing rat pancreatic carcinoma cell line and to non-metastasizing sarcoma cells. Homologues of this variant as well as several other CD44 splice variants are also expressed at the RNA level in human carcinoma cell lines from lung, breast, and colon, and in immortalized keratinocytes. Using antibodies raised against a bacterial fusion protein encoded by variant CD44 sequences, we studied the expression of variant CD44 glycoproteins in normal human tissues and in colorectal neoplasia. Expression of CD44 variant proteins in normal human tissues was readily found on several epithelial tissues including the squamous epithelia of the epidermis, tonsils, and pharynx, and the glandular epithelium of the pancreatic ducts, but was largely absent from other epithelia and from most non-epithelial cells and tissues. In human colorectal neoplasia CD44 variant proteins, including homologues of those which confer metastatic ability to rat tumors, were found on all invasive carcinomas and carcinoma metastases. Interestingly, focal expression was also observed in adenomatous polyps, expression being related to areas of dysplasia. The distribution of the CD44 variants in human tissues suggests that they play a role in a few restricted differentiation pathways and that in colorectal tumors one of these pathways has been reactivated. The finding that metastasis-related variants are already expressed at a relatively early stage in colorectal carcinogenesis and tumor progression, i.e., in adenomatous polyps, suggests the existence of a yet unknown selective advantage linked to CD44 variant expression. The continued expression in metastases would be compatible with a role in the metastatic process.

The basic reproduction number of plant pathogens: matrix approaches to complex dynamics.

The basic reproduction number, R0, is defined as the total number of infections arising from one newly infected individual introduced into a healthy (disease-free) host population. R0 is widely used in ecology and animal and human epidemiology, but has received far less attention in the plant pathology literature. Although the calculation of R0 in simple systems is straightforward, the calculation in complex situations is challenging. A very generic framework exists in the mathematical and biomathematical literature, which is difficult to interpret and apply in specific cases. In this paper we describe a special case of this general framework involving the use of matrix population models. Leading by example, we explain the existing mathematical literature on this subject in such a way that plant pathologists can apply the method for a wide range of pathosystems.

The Smallest Intestine (TSI)-a low volume in vitro model of the small intestine with increased throughput.

There is a growing interest in understanding the fate and behaviour of probiotic microorganisms and bioactive compounds during passage of the human gastrointestinal tract (GIT). Here, we report the development of a small volume in vitro model called The smallest Intestine (TSI) with increased throughput focusing on simulating passage through the stomach and small intestine (SI). The basic TSI module consists of five reactors, with a working volume of 12 ml each. During the simulated passage through the SI, bile is absorbed and pH is adjusted to physiologically relevant values for duodenum, jejunum and ileum. A consortium of seven representative bacterial members of the ileum microbiota is included in the ileal stage of the model. The behaviour of three putative probiotic Lactobacillus strains during in vitro simulated upper GIT passage was tested in the model and results were compared to previous studies describing probiotic survival. It was found, that probiotic persistence is strongly related to whether food was ingested, but also to presence of the ileal microbiota, which significantly impacted probiotic survival. In conclusion, TSI allows testing a substantial number of samples, at low cost and short time, and is thus suitable as an in vitro screening platform.

The elasticity of the epidemic growth rate to observed weather patterns with an application to yellow rust.

ABSTRACT We extend a previously developed method that quantifies the sensitivity of the exponential epidemic growth rate, r, to weather changes, through a pathogen's life cycle components (basic reproduction number, latent period, and mean and standard deviation of the spore production curve). Here a method is developed to study the elasticities of the system and subsequently the model is linked to observed weather patterns. This enables a direct comparison between the effects of different weather variables (temperature, surface wetness duration, and light quantity) under realistic weather scenarios. The three sites studied represent areas within the United Kingdom with contrasting climates. Yellow rust, caused by Puccinia striiformis, on winter wheat is studied as a key application. Our results show that temperature and more importantly changes in temperature through their effect on pathogen reproduction have the largest effect on r. The long latent period at low winter temperatures is not a key component in the epidemic development, which is contrary to general beliefs. The results combined with long term average yellow rust severity patterns show that it is winter survival and not summer survival that controls the eventual disease severity. The results also show that within the current United Kingdom spraying regime on wheat crops against yellow rust, the first spray should mainly affect the basic reproduction number, i.e., should be a protectant spray, whereas the second spray should also affect the latent period, i.e., should also have curative action.