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Although reconsolidation-based interventions constitute a promising new avenue to treating fear and anxieties disorders, the success of the intervention is not guaranteed. The initiation of memory reconsolidation is dependent on whether a mismatch between the experienced and predicted outcome-a prediction error (PE)-occurs during fear memory reactivation. It remains, however, elusive whether any type of PE renders fear memories susceptible to reconsolidation disruption. Here, we investigated whether a value PE, elicited by an outcome that is better or worse than expected, is necessary to make fear memories susceptible to reconsolidation disruption or whether a model-based identity PE, i.e., a PE elicited by an outcome equally aversive but different than expected, would be sufficient. Blocking beta-adrenergic receptors with propranolol HCl after reactivation did, however, not reduce the expression of fear after either type of PE. Instead, we observed intact fear memory expression 24 h after reactivation in the value-, identity- and a no-PE control group. The present results do not corroborate our earlier findings of reconsolidation disruption and point towards challenges that the field is currently facing in observing evidence for memory reconsolidation at all. We provide potential explanations for the unexpected failure of replicating reconsolidation disruption and discuss future directions.

NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in integrating these treatments, with uncertainty in prevalence and optimal testing methods to identify eligible patients. We performed a systematic review of NTRK fusion prevalence to inform efficient diagnostic screening and scale of therapeutic uptake. We searched Medline, Embase and Cochrane databases on 31/03/2021. Inclusion criteria were studies reporting fusion rates in solid tumours, English language, post-2010 publication and minimum sample size. Critical appraisal was performed using a custom 11-item checklist. Rates were collated by cancer type and pooled if additional synthesis criteria were met. 160 studies were included, with estimates for 15 pan-cancer and 429 specific cancer types (63 paediatric). Adult pan-cancer estimates ranged 0.03–0.70%, with higher rates found in RNA-based assays. In common cancers, rates were consistently below 0.5%. Rare morphological subtypes, colorectal microsatellite instability, and driver mutation exclusion cancers had higher rates. Only 35.6% of extracted estimates used appropriate methods and sample size to identify NTRK fusions. NTRK fusion-positive cancers are rare and widely distributed across solid tumours. Small-scale, heterogeneous data confound prevalence prediction. Further large-scale, standardised genomic data are needed to characterise NTRK fusion epidemiology.

Philippi, D., Rothaus, K., & Castelli, M. (2023). A vision transformer architecture for the automated segmentation of retinal lesions in spectral domain optical coherence tomography images. Scientific Reports, 13(1), 1-14. [517]. https://doi.org/10.1038/s41598-023-27616-1 --- Funding Information: This work was supported by national funds through FCT (Fundação para a Ciência e a Tecnologia), under the project - UIDB/04152/2020 - Centro de Investigação em Gestão de Informação (MagIC)/NOVA IMS. Mauro Castelli acknowledges the financial support from the Slovenian Research Agency (research core funding no. P5-0410). Neovascular age-related macular degeneration (nAMD) is one of the major causes of irreversible blindness and is characterized by accumulations of different lesions inside the retina. AMD biomarkers enable experts to grade the AMD and could be used for therapy prognosis and individualized treatment decisions. In particular, intra-retinal fluid (IRF), sub-retinal fluid (SRF), and pigment epithelium detachment (PED) are prominent biomarkers for grading neovascular AMD. Spectral-domain optical coherence tomography (SD-OCT) revolutionized nAMD early diagnosis by providing cross-sectional images of the retina. Automatic segmentation and quantification of IRF, SRF, and PED in SD-OCT images can be extremely useful for clinical decision-making. Despite the excellent performance of convolutional neural network (CNN)-based methods, the task still presents some challenges due to relevant variations in the location, size, shape, and texture of the lesions. This work adopts a transformer-based method to automatically segment retinal lesion from SD-OCT images and qualitatively and quantitatively evaluate its performance against CNN-based methods. The method combines the efficient long-range feature extraction and aggregation capabilities of Vision Transformers with data-efficient training of CNNs. The proposed method was tested on a private dataset containing 3842 2-dimensional SD-OCT retina images, manually labeled by experts of the Franziskus Eye-Center, Muenster. While one of the competitors presents a better performance in terms of Dice score, the proposed method is significantly less computationally expensive. Thus, future research will focus on the proposed network’s architecture to increase its segmentation performance while maintaining its computational efficiency. publishersversion published

Farias, E. C. D., Di Noia, C., Han, C., Sala, E., Castelli, M., & Rundo, L. (2021). Impact of GAN-based lesion-focused medical image super-resolution on the robustness of radiomic features. Scientific Reports, 11(21361), 1-12. [21361]. https://doi.org/10.1038/s41598-021-00898-z -----------------------------------------This work was partially supported by The Mark Foundation for Cancer Research and Cancer Research UK Cambridge Centre [C9685/A25177], the Wellcome Trust Innovator Award, UK [215733/Z/19/Z] and the CRUK National Cancer Imaging Translational Accelerator (NCITA) [C42780/A27066]. Additional support was also provided by the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. This work was partially supported by national funds through the FCT (Fundação para a Ciência e a Tecnologia) by the Projects GADgET (DSAIPA/DS/0022/2018) and the financial support from the Slovenian Research Agency (research core funding no. P5-0410). Robust machine learning models based on radiomic features might allow for accurate diagnosis, prognosis, and medical decision-making. Unfortunately, the lack of standardized radiomic feature extraction has hampered their clinical use. Since the radiomic features tend to be affected by low voxel statistics in regions of interest, increasing the sample size would improve their robustness in clinical studies. Therefore, we propose a Generative Adversarial Network (GAN)-based lesion-focused framework for Computed Tomography (CT) image Super-Resolution (SR); for the lesion (i.e., cancer) patch-focused training, we incorporate Spatial Pyramid Pooling (SPP) into GAN-Constrained by the Identical, Residual, and Cycle Learning Ensemble (GAN-CIRCLE). At 2× SR, the proposed model achieved better perceptual quality with less blurring than the other considered state-of-the-art SR methods, while producing comparable results at 4× SR. We also evaluated the robustness of our model’s radiomic feature in terms of quantization on a different lung cancer CT dataset using Principal Component Analysis (PCA). Intriguingly, the most important radiomic features in our PCA-based analysis were the most robust features extracted on the GAN-super-resolved images. These achievements pave the way for the application of GAN-based image Super-Resolution techniques for studies of radiomics for robust biomarker discovery. publishersversion published

Mendes, J. M., Baptista, H., Oliveira, A., Jardim, B., & De Castro Neto, M. (2022). Beyond comorbidities, sex and age have no effect on COVID-19 health care demand. Scientific Reports, 12(1), 1-12. [7356]. https://doi.org/10.1038/s41598-022-11376-5 -------------------------------- This research was supported by project Data4Covid19 (project ID: 62821), funded by the European Regional Development Fund, through the Operational Competitiveness Programme—COMPETE 2020, in the framework of 15/SI/2020—R&D Companies and Testing and Optimization Infrastructures (COVID-19). The authors acknowledge the editors and reviewers, whose comments and suggestions helped to improve the presentation of the paper. This paper explores the associations between sex, age and hospital health care pressure in the context of the COVID-19 pandemic in Portuguese mainland municipalities. To represent the impact of sex and age, we calculated COVID-19 standardised incidence ratios (SIR) in Portuguese mainland municipalities over fourteen months daily, especially focusing on the Porto metropolitan area. A daily novel indicator was devised for hospital health care pressure, consisting of an approximation to the ratio of hospitalisations per available hospital medical doctor (HPI). In addition, 14-day incidence rates were also calculated daily (DIR14), both as an approach and an alternative to the current national pandemic surveillance indicator (which is not calculated with such regularity). Daily maps were first visualised to evaluate spatial patterns. Pearson's correlation coefficients were then calculated between each proposed surveillance indicator (SIR and DIR14) and the HPI. Our results suggest that hospital pressure is not strongly associated with SIR (r = 0.34, p value = 0.08). However, DIR14 bears a stronger correlation with hospital pressure (r = 0.84, p value

Cognitive reserve (CR) is the capability of an individual to cope with a brain pathology through compensatory mechanisms developed through cognitive stimulation by mental and physical activity. Recently, it has been suggested that CR has a protective role against the initiation of substance use, substance consumption patterns and cognitive decline and can improve responses to treatment. However, CR has never been linked to cognitive function and neurotrophic factors in the context of alcohol consumption. The present cross-sectional study aims to evaluate the association between CR (evaluated by educational level), cognitive impairment (assessed using a frontal and memory loss assessment battery) and circulating levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in patients with alcohol use disorder (AUD). Our results indicated that lower educational levels were accompanied by earlier onset of alcohol consumption and earlier development of alcohol dependence, as well as impaired frontal cognitive function. They also suggest that CR, NT-3 and BDNF may act as compensatory mechanisms for cognitive decline in the early stages of AUD, but not in later phases. These parameters allow the identification of patients with AUD who are at risk of cognitive deterioration and the implementation of personalized interventions to preserve cognitive function.

Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) is a serious pest that is capable of bisexual and arrhenotokous reproduction. In arrhenotokous reproduction, virgin females initially produce male offspring; later, when their sons are sexually mature, the mothers begin bisexual reproduction by carrying out oedipal mating with their sons. Because a virgin female produces many male offspring before oedipal mating occurs, multiple oedipal mating is common. In this study, we investigated the effect of multiple oedipal mating on the population growth of F. occidentalis by using the age-stage, two-sex life table theory. In the arrhenotokous cohorts, all unfertilized eggs developed into males. In the bisexual cohorts, the offspring sex ratio was significantly female biased with the mean number of female offspring and male offspring being 72.68 and 29.00, respectively. These were the same as the net reproductive rate of female offspring and male offspring. In arrhenotokous cohorts, the number of males available for oedipal mating significantly affected the production of female offspring. The number of female offspring increased as the number of sons available for oedipal mating increased. Correctly characterizing this unique type of reproduction will provide important information for predicting the timing of future outbreaks of F. occidentalis, as well as aiding in formulating successful management strategies against the species. © 2018, The Author(s)., Qingdao Agricultural University National Basic Research Program of China (973 Program) National Natural Science Foundation of China, This study was funded by the National Natural Science Foundation of China (31501708), the National Key Research and Development Program of China (2016YFC1200600), the Shandong Modern Agricultural Technology & Industry System (SDAIT-05-13), and the Startup Fund for Distinguished Scholars (631316) supported by the Qingdao Agricultural University, China.

Our previous data show that hepatitis C virus (HCV) genotype 1 patients expressing the HLA-DQB1 * 0301 allele have a combined response probability of 69%, while the remaining 31% do not respond, probably because the HCV immunodominant epitope (IE) against the DQB1 * 0301 allele is mutated. HCV IE (region sequenced in NS3 is a region encoding aa 1253–1272) from 37 patients (21 Sustained Virological Response, SVR; 16 non-SVR) HLA-DQB1 * 0301+, were analysed by pyrosequencing. In vitro cultures were also determined by CD4+ proliferation, using non-mutated IE (wild-type synthetic peptide) and synthetic mutated peptide. The pyrosequencing study revealed 34 different haplotypes. The SVR patients had fewer haplotypes (P = 0.07), mutations/haplotypes (P = 0.01) and polymorphic sites (P = 0.02) than non-SVR. Three polymorphic sites were associated with the non-SVR patients: haplotype 7 (L5P); haplotype 11 (L7P); and haplotype 15, (L15S) (P = 0.02). The in vitro study (n = 7) showed that in 4/7 patients (Group 1) the CD4+ proliferation obtained with wild-type synthetic peptide was higher than that obtained with the negative control and with the synthetic mutated peptide (P = 0.039). However, in the remaining 3/7 patients (Group 2) this pattern was not observed (P = 0.7). Our findings suggest that HLA-DQB1 * 0301+ patients with high antigenic variability in HCV IE (NS31253-1272) have a lower SVR rate, due to reduced CD4+ proliferation as a result of incorrect viral HLA-Ag binding.

Norway spruce is one of the most important commercial forestry species in Europe, and is commonly infected by the bark beetle-vectored necrotrophic fungus, Endoconidiophora polonica. Spruce trees display a restricted capacity to respond to environmental perturbations, and we hypothesized that water limitation will increase disease severity in this pathosystem. To test this prediction, 737 seedlings were randomized to high (W+) or low (W−) water availability treatment groups, and experimentally inoculated with one of three E. polonica strains or mock-inoculated. Seedling mortality was monitored throughout an annual growing season, and total seedling growth and lesion length indices were measured at the experiment conclusion. Seedling growth was greater in the W+ than W− treatment group, demonstrating limitation due to water availability. For seedlings infected with two of the fungal strains, no differences in disease severity occurred in response to water availability. For the third fungal strain, however, greater disease severity (mortality and lesion lengths) occurred in W− than W+ seedlings. While the co-circulation in nature of multiple E. polonica strains of varying virulence is known, this is the first experimental evidence that water availability can alter strain-specific disease severity.

In daily life we regularly must decide whether to act dishonestly for personal gain or to be honest and maintain a positive image of ourselves. While evidence suggests that acute stress influences moral decisions, it is unclear whether stress increases or decreases immoral behavior. Here, we hypothesize that stress, through its effects on cognitive control, has different effects on moral decision making for different individuals, depending on their moral default. We test this hypothesis by combining a task which allows for inconspicuously measuring spontaneous cheating with a well-established stress induction task. Our findings confirm our hypothesis, revealing that effects of stress on dishonesty are not uniform, but instead depend on the individual: for those who are relatively dishonest, stress increases dishonesty, whereas for participants who are relatively honest stress makes them more honest. These findings go a long way in resolving the conflicting findings in the literature on the effects of stress on moral decisions, suggesting that stress affects dishonesty differently for different individuals, depending on their moral default.

Several countries have implemented lockdowns to control their COVID-19 epidemic. However, questions like “where” and “when” still require answers. We assessed the impact of national and regional lockdowns considering the French first epidemic wave of COVID-19 as a case study. In a regional lockdown scenario aimed at preventing intensive care units (ICU) saturation, almost all French regions would have had to implement a lockdown within 10 days and 96% of ICU capacities would have been used. For slowly growing epidemics, with a lower reproduction number, the expected delays between regional lockdowns increase. However, the public health costs associated with these delays tend to grow with time. In a quickly growing pandemic wave, defining the timing of lockdowns at a regional rather than national level delays by a few days the implementation of a nationwide lockdown but leads to substantially higher morbidity, mortality, and stress on the healthcare system.

Evidence showing a strengthening of intense cold surge event (CSE) in East Asia, e.g. CSE of Jan 2016 and Jan–Feb 2008, is focusing attention towards the science of CSE onset prediction. Predicting the onset of such strong CSEs remains elusive as the extent of these surges varies over spatial and temporal scales. Changes in radiative cooling over Siberia in winter as potentially affected by changes in the Arctic are further expected to influence CSE occurrences in East Asia. Moreover, unprecedented and long lasting CSEs in East Asia have a very distinct Jet Stream pattern via their shifts from the climatological mean, influencing the lower troposphere. Here, using modelling framework we propose a new relationship between Jet Stream and Aleutian Low for identifying and characterizing atmospheric process that leads to CSEs in East Asia. Our results reveal new insight into the mechanisms of CSEs occurrences, the absence of which may lead to major constraints on reducing CSE onset prediction error.

Sepsis is a major public and global health concern. Every hour of delay in detecting sepsis significantly increases the risk of death, highlighting the importance of accurately predicting sepsis in a timely manner. A growing body of literature has examined developing new or improving the existing machine learning (ML) approaches for timely and accurate predictions of sepsis. This study contributes to this literature by providing clear insights regarding the role of the recency and adequacy of historical information in predicting sepsis using ML. To this end, we implemented a deep learning model using a bidirectional long short-term memory (BiLSTM) algorithm and compared it with six other ML algorithms based on numerous combinations of the prediction horizons (to capture information recency) and observation windows (to capture information adequacy) using different measures of predictive performance. Our results indicated that the BiLSTM algorithm outperforms all other ML algorithms and provides a great separability of the predicted risk of sepsis among septic versus non-septic patients. Moreover, decreasing the prediction horizon (in favor of information recency) always boosts the predictive performance; however, the impact of expanding the observation window (in favor of information adequacy) depends on the prediction horizon and the purpose of prediction. More specifically, when the prediction is responsive to the positive label (i.e., Sepsis), increasing historical data improves the predictive performance when the prediction horizon is short-moderate.

The leadership role can be demanding and depleting. Using self-regulation and social exchange theory as a framework, we developed a three-step sequential mediation model that explains how feelings of depletion can degrade leaders’ own performance level, via the reciprocating behavior of their employees. Specifically, we hypothesized that leader depletion is negatively related to their trust beliefs. This lack of trust is expected to be reciprocated by employees in such a way that they display less citizenship behaviors towards their leader. These lowered citizenship behaviors are, in turn, predicted to negatively impact leader performance. Additionally, we hypothesized that these negative effects of feeling depleted are more pronounced for leaders who believe that their willpower is limited. Studies 1 and 2 illustrated that leader depletion indirectly influences their own performance level through leaders’ trust beliefs and employees’ leader-directed citizenship behaviors. Study 3 extended these findings from the inter-individual to the intra-individual level, and demonstrated the predicted moderating role of belief in limited willpower. Together, our studies provide new and useful insights in the broader, more distal implications of leader depletion, which have not yet been considered in existing self-regulation models.

Calcium sparks are involved in major physiological and pathological processes in vertebrate muscles but have never been characterized in invertebrates. Here, dynamic confocal imaging on intact skeletal muscle cells isolated enzymatically from the adult honey bee legs allowed the first spatio-temporal characterization of subcellular calcium release events (CREs) in an insect species. The frequency of CREs, measured in x–y time lapse series, was higher than frequencies usually described in vertebrates. Honey bee CREs had a larger spatial spread at half maximum than their vertebrate counterparts and a slightly ellipsoidal shape, two characteristics that may be related to ultrastructural features specific to invertebrate cells. In line-scan experiments, the histogram of CREs’ duration followed a bimodal distribution, supporting the existence of both sparks and embers. Unlike in vertebrates, embers and sparks had similar amplitudes, a difference that could be related to genomic differences and/or excitation–contraction coupling specificities in honey bee skeletal muscle fibres. The first characterization of CREs from an arthropod which shows strong genomic, ultrastructural and physiological differences with vertebrates may help in improving the research field of sparkology and more generally the knowledge in invertebrates cell Ca2+ homeostasis, eventually leading to a better understanding of their roles and regulations in muscles but also the myotoxicity of new insecticides targeting ryanodine receptors.

Animal models, human neuroimaging and lesion studies revealed that the gut microbiota can influence the interaction between the central and the enteric nervous systems via the gut–brain axis (GBA) and can affect brain regions linked to basic emotional and cognitive processes. The role of the gut microbiota in decision-making in healthy humans thus far remains largely unknown. Our study establishes a functional relationship between the gut microbiota and healthy humans’ decisions that involve risk and time. We conducted a between subjects’ placebo-controlled double-blinded design, with two groups and two sessions separated by 28 days, during which participants received daily doses of probiotics or a placebo. We investigated whether the prolonged and controlled intake of probiotics affects risk-taking behavior and intertemporal choices using incentivized economic tasks. We found a significant decrease in risk-taking behavior and an increase in future-oriented choices in the probiotics group as compared to the placebo group. These findings provide the first direct experimental evidence suggesting a potential functional role on the part of the microbiota-gut-brain axis in decision-making, creating a path for potential clinical applications and allowing for a better understanding of the underlying neural mechanisms of risk-taking behavior and intertemporal choices.

Funding: PhD Studentship at the University of St Andrews, jointly funded by NatureScot via the Marine Alliance for Science and Technology for Scotland (MASTS), and the Centre for Research into Ecological and Environmental Modelling. Data were collected as part of research funded by NatureScot (project 015960) and Marine Scotland (projects SP004 and SP02B0) via the Movement Ecology of Flapper Skate project. MASTS and Shark Guardian also provided some funding to this project. These data were made available from previous studies for this work and we have acknowledged this in the manuscript. The manuscript uses a model (WeStCOMS) whose development and expansion was supported by the EU's INTERREG VA and AA Programmes, managed by the Special EU Programmes Body via ‘Collaborative Oceanography and Monitoring for Protected Areas and Species’ (COMPASS) and ‘Predicting Risk and Impact of Harmful Events on the Aquaculture Sector’ (PRIMROSE) projects, as well as two UKRI grants: ‘Evaluating the Environmental Conditions Required for the Development of Offshore Aquaculture’ (OFF-AQUA, BB/S004246/1)’ and ‘Combining Autonomous observations and Models for Predicting and Understanding Shelf seas‘ (CAMPUS, NE/R00675X/1). Developments in animal electronic tagging and tracking have transformed the field of movement ecology, but interest is also growing in the contributions of tagged animals to oceanography. Animal-borne sensors can address data gaps, improve ocean model skill and support model validation, but previous studies in this area have focused almost exclusively on satellite-telemetered seabirds and seals. Here, for the first time, we develop the use of benthic species as animal oceanographers by combining archival (depth and temperature) data from animal-borne tags, passive acoustic telemetry and citizen-science mark-recapture records from 2016–17 for the Critically Endangered flapper skate (Dipturus intermedius) in Scotland. By comparing temperature observations to predictions from the West Scotland Coastal Ocean Modelling System, we quantify model skill and empirically validate an independent model update. The results from bottom-temperature and temperature-depth profile validation (5,324 observations) fill a key data gap in Scotland. For predictions in 2016, we identified a consistent warm bias (mean = 0.53 °C) but a subsequent model update reduced bias by an estimated 109% and improved model skill. This study uniquely demonstrates the use of benthic animal-borne sensors and citizen-science data for ocean model validation, broadening the range of animal oceanographers in aquatic environments. Publisher PDF

bioRxiv: doi: https://doi.org/10.1101/2020.01.09.893701 Synaptic adhesion molecules play an important role in the formation, maintenance and refinement of neuronal connectivity. Recently, several leucine rich repeat (LRR) domain containing neuronal adhesion molecules have been characterized including netrin G-ligands, SLITRKs and the synaptic adhesion-like molecules (SALMs). Dysregulation of these adhesion molecules have been genetically and functionally linked to various neurological disorders. Here we investigated the molecular structure and mechanism of ligand interactions for the postsynaptic SALM3 adhesion protein with its presynaptic ligand, receptor protein tyrosine phosphatase sigma (PTP sigma). We solved the crystal structure of the dimerized LRR domain of SALM3, revealing the conserved structural features and mechanism of dimerization. Furthermore, we determined the complex structure of SALM3 with PTP sigma using small angle X-ray scattering, revealing a 2:2 complex similar to that observed for SALM5. Solution studies unraveled additional flexibility for the complex structure, but validated the uniform mode of action for SALM3 and SALM5 to promote synapse formation. The relevance of the key interface residues was further confirmed by mutational analysis with cellular binding assays and artificial synapse formation assays. Collectively, our results suggest that SALM3 dimerization is a pre-requisite for the SALM3-PTP sigma complex to exert synaptogenic activity.

The domestic dog represents an ideal model for identifying susceptibility genes, many of which are shared with humans. In this study, we investigated the genetic contribution to individual differences in 40 clinically important measurements by a genome-wide association study (GWAS) in a multinational cohort of 472 healthy dogs from eight breeds. Meta-analysis using the binary effects model after breed-specific GWAS, identified 13 genome-wide significant associations, three of them showed experimental-wide significant associations. We detected a signal at chromosome 13 for the serum concentration of alanine aminotransferase (ALT) in which we detected four breed-specific signals. A large proportion of the variance of ALT (18.1–47.7%) was explained by this locus. Similarly, a single SNP was also responsible for a large proportion of the variance (6.8–78.4%) for other measurements such as fructosamine, stress during physical exam, glucose, and morphometric measurements. The genetic contribution of single variant was much larger than in humans. These findings illustrate the importance of performing meta-analysis after breed-specific GWAS to reveal the genetic contribution to individual differences in clinically important measurements, which would lead to improvement of veterinary medicine.

The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). The aim of this study was to investigate infiltration of B lymphocytes into CRC tumours, and their clinical relevance, prognostic value and relation to other immune cell subsets. We used multiplexed immunohistochemistry and multispectral imaging to assay the amount of infiltrating CD20+ B lymphocytes along with infiltration of CD8+ cytotoxic T cells, FOXP3+ T regulatory cells, CD68+ macrophages and CD66b+ neutrophils, in 316 archival CRC tissue specimens. A higher density of infiltrating CD20+ B lymphocytes was associated with tumours of the right colon (P = 0.025) and of lower stages (P = 0.009). Furthermore, patients whose tumours were highly infiltrated by CD20+ B lymphocytes had a significantly improved disease-specific survival (HR = 0.45, 95% CI 0.28–0.73, P = 0.001), which remained significant in multivariable analysis. CD20+ B lymphocytes were highly and positively associated with CD8+ T lymphocytes (P + B lymphocytes in CRC. Furthermore, a cooperative prognostic effect between CD20+ B lymphocytes and CD8+ T lymphocytes is suggested.

Purpose Molecular and cellular studies reported a role of cadmium in risk of advanced breast cancer (BC). However epidemiological evidence is limited. Our previous study suggests that cadmium might be related to a decreased risk of ER- and ER-PR- breast tumors. In this study, we further explored the association between long-term exposure to airborne cadmium and risk of BC by stage, grade of differentiation, and histological types at diagnosis. Methods A nested case-control study of 4,401 cases and 4,401 matched controls was conducted within the French E3N cohort. A Geographic Information System (GIS) based metric was employed to evaluate outdoor airborne exposure to cadmium. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Results There was no statistically significant association between cadmium exposure and stage of BC in the multivariable analyses. The adjusted ORs for the fifth versus first quintile were 1.02 (95% CI: 0.83–1.25), 1.11 (95% CI: 0.84–1.49), and 0.67 (95% CI: 0.37–1.24) for stages I, II, and III-IV BC, respectively. The subgroup analyses showed no statistically significant association between cadmium exposure and grade of differentiation of BC at diagnosis. However, further analyses by histological type suggested a positive dose-response association between cadmium and risk of invasive tubular carcinoma (ITC) BC (OR for the fifth versus first quintile = 3.44 (95% CI: 1.10–10.7)). Conclusions Our results do not support the hypothesis that airborne cadmium exposure may have a role in advanced BC risk, but suggest that cadmium may be associated with an increased risk of ITC. However, these results should be considered with caution, and more epidemiological studies are needed to confirm our findings and to improve our understanding of the effects of cadmium exposure according to several clinic-pathological characteristics of BC.

Proliferative diabetic retinopathy (PDR) is a sight-threatening diabetic complication in urgent need of new therapies. In this study we identify potential molecular mechanisms and target candidates in the pathogenesis of PDR fibrovascular tissue formation. We performed mRNA sequencing of RNA isolated from eleven excised fibrovascular membranes of type 1 diabetic PDR patients and two non-diabetic patients with rhegmatogenous retinal detachment with proliferative vitreoretinopathy. We determined differentially expressed genes between these groups and performed pathway and gene ontology term enrichment analyses to identify potential underlying mechanisms, pathways, and regulators. Multiple pro-angiogenic processes, including VEGFA-dependent and -independent pathways, as well as processes related to lymphatic development, epithelial to mesenchymal transition (EMT), wound healing, inflammation, fibrosis, and extracellular matrix (ECM) composition, were overrepresented in PDR. Overrepresentation of different angiogenic processes may help to explain the transient nature of the benefits that many patients receive from current intravitreal anti-angiogenic therapies, highlighting the importance of combinatorial treatments. Enrichment of genes and pathways related to lymphatic development indicates that targeting lymphatic involvement in PDR progression could have therapeutic relevance. Together with overrepresentation of EMT and fibrosis as well as differential ECM composition, these findings demonstrate the complexity of PDR fibrovascular tissue formation and provide avenues for the development of novel treatments.

An increasing number of studies have found that the implementation of feeding sites for wildlife-related tourism can affect animal health, behaviour and reproduction. Feeding sites can favour high densities, home range overlap, greater sedentary behaviour and increased interspecific contacts, all of which might promote parasite transmission. In the Yunnan snub-nosed monkey (Rhinopithecus bieti), human interventions via provisioning monkeys at specific feeding sites have led to the sub-structuring of a group into genetically differentiated sub-groups. The fed subgroup is located near human hamlets and interacts with domesticated animals. Using high-throughput sequencing, we investigated Entamoeba species diversity in a local host assemblage strongly influenced by provisioning for wildlife-related tourism. We identified 13 Entamoeba species or lineages in faeces of Yunnan snub-nosed monkeys, humans and domesticated animals (including pigs, cattle, and domestic chicken). In Yunnan snub-nosed monkeys, Entamoeba prevalence and OTU richness were higher in the fed than in the wild subgroup. Entamoeba polecki was found in monkeys, pigs and humans, suggesting that this parasite might circulates between the wild and domestic components of this local social–ecological system. The highest proportion of faeces positive for Entamoeba in monkeys geographically coincided with the presence of livestock and humans. These elements suggest that feeding sites might indirectly play a role on parasite transmission in the Yunnan snub-nosed monkey. The implementation of such sites should carefully consider the risk of creating hotspots of disease transmission, which should be prevented by maintaining a buffer zone between monkeys and livestock/humans. Regular screenings for pathogens in fed subgroup are necessary to monitor transmission risk in order to balance the economic development of human communities dependent on wildlife-related tourism, and the conservation of the endangered Yunnan snub-nosed monkey.

Zika virus (ZIKV) infections in humans are considered to be mild or subclinical. However, during the recent epidemics in the Pacific Islands and the Americas, the infection was associated with Quillain-Barré syndrome and congenital infections with fetal brain abnormalities, including microcephaly. Thus, more detailed understanding of ZIKV-host cell interactions and regulation of innate immune responses by strains of differential evolutionary origin is required. Here, we characterized the infection and immune responses triggered by two epidemic Asian/American lineage viruses, including an isolate from fetal brains, and a historical, low passage 1947 African lineage virus in human monocyte-derived dendritic cells (DCs) and macrophages. The epidemic Asian/American ZIKV replicated well and induced relatively good antiviral responses in human DCs whereas the African strain replicated less efficiently and induced weaker immune responses. In macrophages both the African and Asian strains showed limited replication and relatively weak cytokine gene expression. Interestingly, in macrophages we observed host protein degradation, especially IRF3 and STAT2, at early phases of infection with both lineage viruses, suggesting an early proteasomal activation in phagocytic cells. Our data indicates that ZIKV evolution has led to significant phenotypic differences in the replication characteristics leading to differential regulation of host innate immune responses.

In the research field of extracellular vesicles (EVs), the use of fetal bovine serum (FBS) depleted of EVs for in vitro studies is advocated to eliminate the confounding effects of media derived EVs. EV-depleted FBS may either be prepared by ultracentrifugation or purchased commercially. Nevertheless, these preparations do not guarantee an RNA-free FBS for in vitro use. In this study we address the RNA contamination issue, of small non-coding (nc)RNA in vesicular or non-vesicular fractions of FBS, ultracentrifugation EV-depleted FBS, commercial EV-depleted FBS, and in our recently developed filtration based EV-depleted FBS. Commercially available serum- and xeno-free defined media were also screened for small ncRNA contamination. Our small ncRNA sequencing data showed that all EV-depleted media and commercially available defined media contained small ncRNA contaminants. Out of the different FBS preparations studied, our ultrafiltration-based method for EV depletion performed the best in depleting miRNAs. Certain miRNAs such miR-122 and miR-203a proved difficult to remove completely and were found in all media. Compared to miRNAs, other small ncRNA (snRNA, Y RNA, snoRNA, and piRNA) were difficult to eliminate from all the studied media. Additionally, our tested defined media contained miRNAs and other small ncRNAs, albeit at a much lower level than in serum preparations. Our study showed that no media is free of small ncRNA contaminants. Therefore, in order to screen for baseline RNA contamination in culturing media, RNA sequencing data should be carefully controlled by adding a media sample as a control. This should be a mandatory step before performing cell culture experiments in order to eliminate the confounding effects of media.

Baffin Bay hosts the largest and most productive of the Arctic polynyas: the North Water (NOW). Despite its significance and active role in water mass formation, the history of the NOW beyond the observational era remains poorly known. We reconcile the previously unassessed relationship between long-term NOW dynamics and ocean conditions by applying a multiproxy approach to two marine sediment cores from the region that, together, span the Holocene. Declining influence of Atlantic Water in the NOW is coeval with regional records that indicate the inception of a strong and recurrent polynya from ~ 4400 yrs BP, in line with Neoglacial cooling. During warmer Holocene intervals such as the Roman Warm Period, a weaker NOW is evident, and its reduced capacity to influence bottom ocean conditions facilitated northward penetration of Atlantic Water. Future warming in the Arctic may have negative consequences for this vital biological oasis, with the potential knock-on effect of warm water penetration further north and intensified melt of the marine-terminating glaciers that flank the coast of northwest Greenland.

Wildfires are a major disturbance to forest carbon (C) balance through both immediate combustion emissions and post-fire ecosystem dynamics. Here we use a process-based biogeochemistry model, the Terrestrial Ecosystem Model (TEM), to simulate C budget in Alaska and Canada during 1986-2016, as impacted by fire disturbances. We extracted the data of difference Normalized Burn Ratio (dNBR) for fires from Landsat TM/ETM imagery and estimated the proportion of vegetation and soil C combustion. We observed that the region is a C source of 2.74 Pg C during the 31-year period. The observed C loss, 57.1 Tg C yr-1, was attributed to fire emissions, overwhelming the net ecosystem production (1.9 Tg C yr-1) in the region. Our simulated during-fire emissions for Alaska and Canada are within the range of field measurements and other model estimates. As burn severity increases, combustion emission tended to switch from vegetation origin towards soil origin. Burn severity regulates post-fire C dynamics. Low severity fires increase soil temperature and decrease soil moisture and thus, enhance soil respiration. However, the opposite trend was found under moderate or high burn severity. The proportion of post-fire soil emission in total emissions increased with burn severity. Net nitrogen mineralization gradually recovered after fire, enhancing net primary production. Net ecosystem production recovered fast under higher burn severities. The impact of fire disturbance on the C balance of northern ecosystems and the associated uncertainties can be better characterized with long-term, prior, during- and post-disturbance data across the geospatial spectrum. Our findings suggest that the regional source of carbon to the atmosphere will persist if the observed forest wildfire occurrence and severity continues into the future.

Situations where independent agents need to align their activities to achieve individually and socially beneficial outcomes are abundant, reaching from everyday situations like fixing a time for a meeting to global problems like climate change agreements. Often such situations can be described as stag-hunt games, where coordinating on the socially efficient outcome is individually optimal but also entails a risk of losing out. Previous work has shown that in fixed interaction neighborhoods agents’ behavior mostly converges to the collectively inefficient outcome. However, in the field, interaction neighborhoods often can be self-determined. Theoretical work investigating such circumstances is ambiguous in whether the efficient or inefficient outcome will prevail. We performed an experiment with human subjects exploring how free neighborhood choice affects coordination. In a fixed interaction treatment, a vast majority of subjects quickly coordinates on the inefficient outcome. In a treatment with neighborhood choice, the outcome is dramatically different: behavior quickly converges to the socially desirable outcome leading to welfare gains 2.5 times higher than in the environment without neighborhood choice. Participants playing efficiently exclude those playing inefficiently who in response change their behavior and are subsequently included again. Importantly, this mechanism is effective despite that only few exclusions actually occur.

Estimates of population structure and gene flow allow exploring the historical and contemporary processes that determine a species’ biogeographic pattern. In mangroves, large-scale genetic studies to estimate gene flow have been conducted predominantly in the Indo-Pacific and Atlantic region. Here we examine the genetic diversity and connectivity of Rhizophora mucronata across a > 3,000 km coastal stretch in the Western Indian Ocean (WIO) including WIO islands. Based on 359 trees from 13 populations and using 17 polymorphic microsatellite loci we detected genetic breaks between populations of the (1) East African coastline, (2) Mozambique Channel Area (3) granitic Seychelles, and (4) Aldabra and northern Madagascar. Genetic structure, diversity levels, and patterns of inferred connectivity, aligned with the directionality of major ocean currents, driven by bifurcation of the South Equatorial Current, northward into the East African Coastal Current and southward into the Mozambique Channel Area. A secondary genetic break between nearby populations in the Delagoa Bight coincided with high inbreeding levels and fixed loci. Results illustrate how oceanographic processes can connect and separate mangrove populations regardless of geographic distance., SCOPUS: ar.j, info:eu-repo/semantics/published

Chlamydia trachomatis (CT) increases its plasmid numbers when stressed, as occurs in clinical trachoma samples. Most CT tests target the plasmid to increase the test sensitivity, but some only target the chromosome. We investigated clinical urogenital samples for total plasmid copy numbers to assess its diagnostic value and intra-bacterial plasmid copy numbers to assess its natural variation. Both plasmid and chromosome copies were quantified using qPCR, and the plasmid:chromosome ratio (PCr) calculated in two cohorts: (1) 383 urogenital samples for the total PCR (tPCr), and (2) 42 vaginal swabs, with one half treated with propium-monoazide (PMA) to prevent the quantification of extracellular DNA and the other half untreated to allow for both tPCr and intra-bacterial PCr (iPCr) quantification. Mann–Whitney U tests compared PCr between samples, in relation to age and gender. Cohort 1: tPCr varied greatly (1–677, median 16). Median tPCr was significantly higher in urines than vaginal swabs (32 vs. 11, p

Clostridium botulinum poses a serious threat to food safety and public health by producing potent neurotoxin during its vegetative growth and causing life-threatening neuroparalysis, botulism. While high temperature can be utilized to eliminate C. botulinum spores and the neurotoxin, non-thermal elimination of newly germinated C. botulinum cells before onset of toxin production could provide an alternative or additional factor controlling the risk of botulism in some applications. Here we introduce a putative phage lysin that specifically lyses vegetative C. botulinum Group I cells. This lysin, called CBO1751, efficiently kills cells of C. botulinum Group I strains at the concentration of 5 µM, but shows little or no lytic activity against C. botulinum Group II or III or other Firmicutes strains. CBO1751 is active at pH from 6.5 to 10.5. The lytic activity of CBO1751 is tolerant to NaCl (200 mM), but highly susceptible to divalent cations Ca2+ and Mg2+ (50 mM). CBO1751 readily and effectively eliminates C. botulinum during spore germination, an early stage preceding vegetative growth and neurotoxin production. This is the first report of an antimicrobial lysin against C. botulinum, presenting high potential for developing a novel antibotulinal agent for non-thermal applications in food and agricultural industries.

International audience; The spatial distributions of populations are both influenced by local variables and by characteristics of surrounding landscapes. Understanding how landscape features spatially structure the frequency of a trait in a population, the abundance of a species or the species’ richness remains difficult specially because the spatial scale effects of the landscape variables are unknown. Various methods have been proposed but their results are not easily comparable. Here, we introduce “siland”, a general method for analyzing the effect of landscape features. Based on a sequential procedure of maximum likelihood estimation, it simultaneously estimates the spatial scales and intensities of landscape variable effects. It does not require any information about the scale of effect. It integrates two landscape effects models: one is based on focal sample site ( Bsiland, b for buffer) and one is distance weighted using Spatial Influence Function ( Fsiland , f for function). We implemented “siland” in the adaptable and user-friendly R eponym package. It performs landscape analysis on georeferenced point observations (described in a Geographic Information System shapefile format) and allows for effects tests, effects maps and models comparison. We illustrated its use on a real dataset by the study of a crop pest (codling moth densities).

The distinctiveness of human cumulative culture raises the question of whether humans respond differently to information originating from social sources, compared with information from other sources. Further, does any such differential responding set humans apart from other species? We studied how capuchin monkeys and 2- to 5-year-old children used information originating from their own actions, those of a human demonstrator, or an animated cue. This information, presented via a touchscreen, always revealed in the first trial (T1) the reward value (rewarded or unrewarded) of one stimulus from a 2- or 3-item array, and could be used in a follow-up trial (T2) involving the same stimulus array. Two monkeys achieved a level of proficiency indicating their appreciation of the T1–T2 relationship, i.e., reliably repeating rewarded (“win”) selections and actively avoiding repetition of unrewarded (“lose”) selections well above chance levels. Neither the two task-proficient monkeys nor the children showed overall performance differences between the three source conditions. Non-task-proficient monkeys, by contrast, did show effects of source, performing best with individually-acquired information. The overall pattern of results hints at an alternative perspective on evidence typically interpreted as showing a human advantage for social information use.

The aim was to examine cross-sectional association between moderate alcohol consumption and total brain volume in a cohort of participants in early middle-age, unconfounded by age-related neuronal change. 353 participants aged 39 to 45 years reported on their alcohol consumption using the AUDIT-C measure. Participants with alcohol abuse were excluded. Brain MRI was analyzed using a fully automated method. Brain volumes were adjusted by intracranial volume expressed as adjusted total brain volume (aTBV). AUDIT-C mean of 3.92 (SD 2.04) indicated moderate consumption. In a linear regression model, alcohol consumption was associated with smaller aTBV (B = − 0.258, p B = − 0.258, p = 0.003) and females (B = − 0.214, p = 0.011). Adjusted for current smoking, the association remained in males (B = − 0.268, p = 0.003), but not in females. When alcohol consumption increased, total brain volume decreased by 0.2% per one AUDIT-C unit already at 39–45 years of age. Moderate alcohol use is associated with neuronal changes in both males and females suggesting health risks that should not be overlooked.

International audience; Floral induction (FI) in shoot apical meristems (SAM) is assumed to be triggered by antagonistic endogenous signals. In fruit trees, FI occurs in some SAM only and is determined by activating and inhibiting signals originating from leaves and fruit, respectively. We developed a model (SigFlow) to quantify on 3D structures the combined impact of such signals and distances at which they act on SAM. Signal transport was simulated considering a signal ‘attenuation’ parameter, whereas SAM fate was determined by probability functions depending on signal quantities. Model behaviour was assessed on simple structures before being calibrated and validated on a unique experimental dataset of 3D digitized apple trees with contrasted crop loads and subjected to leaf and fruit removal at different scales of tree organization. Model parameter estimations and comparisons of two signal combination functions led us to formulate new assumptions on the mechanisms involved: (i) the activating signal could be transported at shorter distances than the inhibiting one (roughly 50 cm vs 1 m) (ii) both signals jointly act to determine FI with SAM being more sensitive to inhibiting signal than activating one. Finally, the genericity of the model is promising to further understand the physiological and architectural determinisms of FI in plants.

Polygenic risk scores (PRSs) for essential hypertension, calculated from > 900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n ~ 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n = 346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension (p = 0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed.

Departure delays are a major cause of economic loss and inefficiency in the growing industry of passenger flights. A departure delay of a current flight is inevitably affected by the late arrival of the flight immediately preceding it with the same aircraft. We seek to understand the mechanisms of such propagated delays, and to obtain universal metrics by which to evaluate an airline’s operational effectiveness in delay alleviation. Here we use big data collected by the American Bureau of Transportation Statistics to design models of flight delays. Offering two dynamic models of delay propagation, we divided all carriers into two groups exhibiting a shifted power law or an exponentially truncated shifted power law delay distribution, revealing two universal delay propagation classes. Three model parameters, extracted directly from dual data mining, help characterize each airline’s operational efficiency in delay mitigation. Therefore, our modeling framework provides the crucially lacking evaluation indicators for airlines, potentially contributing to the mitigation of future departure delays.

We examined interethnic differences in the prevalence of neuroimaging markers of cerebrovascular and neurodegenerative disease in 3 major Asian ethnicities (Chinese, Malays, and Indians), as well as their role in cognitive impairment. 3T MRI brain scans were acquired from 792 subjects (mean age: 70.0 ± 6.5years, 52.1% women) in the multi-ethnic Epidemiology of Dementia In Singapore study. Markers of cerebrovascular disease and neurodegeneration were identified. Cognitive performance was evaluated using Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and a neuropsychological assessment. Compared to Chinese, Malays had a higher burden of intracranial stenosis (OR: 2.28. 95%CI: 1.23–4.20) and cortical atrophy (β: −0.60. 95%CI: −0.78, −0.41), while Indians had a higher burden of subcortical atrophy (β: −0.23. 95%CI: −0.40, −0.06). Moreover, Malay and Indian ethnicities were likely to be cognitively impaired (OR for Malays: 3.79. 95%CI: 2.29–6.26; OR for Indians: 2.87. 95%CI: 1.74–4.74) and showed worse performance in global cognition (β for Malays: −0.51. 95%CI: −0.66, −0.37; and Indians: −0.32. 95%CI: −0.47, −0.17). A higher burden of cerebrovascular and neurodegenerative markers were found in Malays and Indians when compared to Chinese. Further research is required to fully elucidate the factors and pathways that contribute to these observed differences.

Sea level rise (SLR) will cause shoreline retreat of sandy coasts in the absence of sand supply mechanisms. These coasts have high touristic and ecological value and provide protection of valuable infrastructures and buildings to storm impacts. So far, large-scale assessments of shoreline retreat use specific datasets or assumptions for the geophysical representation of the coastal system, without any quantification of the effect that these choices might have on the assessment. Here we quantify SLR driven potential shoreline retreat and consequent coastal land loss in Europe during the twenty-first century using different combinations of geophysical datasets for (a) the location and spatial extent of sandy beaches and (b) their nearshore slopes. Using data-based spatially-varying nearshore slope data, a European averaged SLR driven median shoreline retreat of 97 m (54 m) is projected under RCP 8.5 (4.5) by year 2100, relative to the baseline year 2010. This retreat would translate to 2,500 km2 (1,400 km2) of coastal land loss (in the absence of ambient shoreline changes). A variance-based global sensitivity analysis indicates that the uncertainty associated with the choice of geophysical datasets can contribute up to 45% (26%) of the variance in coastal land loss projections for Europe by 2050 (2100). This contribution can be as high as that associated with future mitigation scenarios and SLR projections.

A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.

International audience; To increase our understanding of bacterial biofilm complexity, real-time quantitative analyses of the living community functions are required. To reach this goal, accurate fluorescent reporters are needed. In this paper, we used the classical fluorescent genetic reporters of the GFP family and demonstrated their limits in the context of a living biofilm. We showed that fluorescence signal saturated after only a few hours of growth and related this saturation to the reduction of oxygen concentration induced by bacterial consumption. This behaviour prevents the use of GFP-like fluorescent proteins for quantitative measurement in living biofilms. To overcome this limitation, we propose the use of a recently introduced small protein tag, FAST, which is fluorescent in the presence of an exogenously applied fluorogenic dye, enabling to avoid the oxygen sensitivity issue. We compared the ability of FAST to report on biofilm growth with that of GFP and mCherry, and demonstrated the superiority of the FAST:fluorogen probes for investigating dynamics in the complex environment of a living biofilm.

The basidiomycete Heterobasidion annosum sensu lato (s.l.) is considered to be one of the most destructive conifer pathogens in the temperate forests of the northern hemisphere. H. annosum is characterized by a dual fungal lifestyle. The fungus grows necrotrophically on living plant cells and saprotrophically on dead wood material. In this study, we screened the H. annosum genome for small secreted proteins (HaSSPs) that could potentially be involved in promoting necrotrophic growth during the fungal infection process. The final list included 58 HaSSPs that lacked predictable protein domains. The transient expression of HaSSP encoding genes revealed the ability of 8 HaSSPs to induce cell chlorosis and cell death in Nicotiana benthamiana. In particular, one protein (HaSSP30) could induce a rapid, strong, and consistent cell death within 2 days post-infiltration. HaSSP30 also increased the transcription of host-defence-related genes in N. benthamiana, which suggested a necrotrophic-specific immune response. This is the first line of evidence demonstrating that the H. annosum genome encodes HaSSPs with the capability to induce plant cell death in a non-host plant.

To facilitate analysis of spatial tissue phenotypes, we created an open-source tool package named ‘Spa-RQ’ for ‘Spatial tissue analysis: image Registration & Quantification’. Spa-RQ contains software for image registration (Spa-R) and quantitative analysis of DAB staining overlap (Spa-Q). It provides an easy-to-implement workflow for serial sectioning and staining as an alternative to multiplexed techniques. To demonstrate Spa-RQ’s applicability, we analysed the spatial aspects of oncogenic KRAS-related signalling activities in non-small cell lung cancer (NSCLC). Using Spa-R in conjunction with ImageJ/Fiji, we first performed annotation-guided tumour-by-tumour phenotyping using multiple signalling markers. This analysis showed histopathology-selective activation of PI3K/AKT and MAPK signalling in Kras mutant murine tumours, as well as high p38MAPK stress signalling in p53 null murine NSCLC. Subsequently, Spa-RQ was applied to measure the co-activation of MAPK, AKT, and their mutual effector mTOR pathway in individual tumours. Both murine and clinical NSCLC samples could be stratified into ‘MAPK/mTOR’, ‘AKT/mTOR’, and ‘Null’ signature subclasses, suggesting mutually exclusive MAPK and AKT signalling activities. Spa-RQ thus provides a robust and easy to use tool that can be employed to identify spatially-distributed tissue phenotypes.

We present the first ever broadband, calibrated electrical connection to the inside of a cell. The interior of a vital, living cell contains multiple dynamic and electrically active organelles such as mitochondria, chloroplasts, lysosomes, and the endoplasmic reticulum. However, little is known about the detailed electrical activity inside the cell. Here we show an ultra-high bandwidth nano-electronic interface to the interior of living cells with integrated fluorescence readout of metabolic activity. On-chip/on-petri dish nanoscale capacitance calibration standards are used to quantify the electronic coupling from bench to cell from DC to 26 GHz (with cell images at 22 GHz). The interaction of static to high frequency electromagnetic fields with the cell constituents induce currents of free charges and local reorganization of linked charges. As such, this enables a direct, calibrated, quantitative, nanoscale electronic interface to the interior of living cells. The interface could have a variety of applications in interfacing life sciences to nano-electronics, including electronic assays of membrane potential dynamics, nano-electronic actuation of cellular activity, and tomographic, nano-radar imaging of the morphology of vital organelles in the cytoplasm, during all phases of the cell life cycle (from development to senescence), under a variety of physiological environments, and under a broad suite of pharmacological manipulations.

Made available in DSpace on 2019-10-06T16:34:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-12-01 Natural Sciences and Engineering Research Council of Canada We used a combination of radio and acoustic telemetry to assess the movements of large catfish (Pimelodidae) in the Xingu River, a clearwater tributary of the Amazon River in Brazil. A total of 121 Phractocephalus hemioliopterus and 61 Pseudoplatystoma punctifer were tagged for monitoring within a 685 km segment, including the Belo Monte Hydroelectric Complex (BMHC), between February 2013 and July 2015. Long distance upstream movements were detected for P. hemioliopterus (up to 347 km) and for P. punctifer (up to 164 km) mainly during the transition between dry season and the rising water period. Both species moved through a long segment of rapids previously thought to function as barriers to migration. Several individuals exhibited long-distance bidirectional movements. Some tagged fish never left the release zone, indicating mortality, tag loss or resident individuals, which would characterize partial migration. The findings show evidence of migratory behaviour for large catfish within the Xingu River, emphasizing the influence of the hydrologic cycle on their movements. As part of the study area has become partially dewatered due to the BMHC, findings support the need of adequate management strategies to allow the movements of large catfish between spawning and feeding sites in the Xingu River. Neotropical Consultoria Ambiental, Rua Cesário Rossetto, 182 University of Northern British Columbia (UNBC) Ecosystem Science and Management Program, 3333 University Way UNESP – Univ Estadual Paulista Campus Experimental de Registro, Avenida Nelson Brihi Badur, 430 UNESP – Univ Estadual Paulista Campus Experimental de Registro, Avenida Nelson Brihi Badur, 430 Natural Sciences and Engineering Research Council of Canada: 2018-06699

Diatoms (Bacillariophyta) are ubiquitous microalgae which produce a siliceous exoskeleton and which make a major contribution to the productivity of oceans and freshwaters. They display a huge diversity, which makes them excellent ecological indicators of aquatic ecosystems. Usually, diatoms are identified using characteristics of their exoskeleton morphology. DNA-barcoding is an alternative to this and the use of High-Throughput-Sequencing enables the rapid analysis of many environmental samples at a lower cost than analyses under microscope. However, to identify environmental sequences correctly, an expertly curated reference library is needed. Several curated libraries for protists exists; none, however are dedicated to diatoms. Diat.barcode is an open-access library dedicated to diatoms which has been maintained since 2012. Data come from two sources (1) the NCBI nucleotide database and (2) unpublished sequencing data of culture collections. Since 2017, several experts have collaborated to curate this library for rbcL, a chloroplast marker suitable for species-level identification of diatoms. For the latest version of the database (version 7), 605 of the 3482 taxonomical names originally assigned by the authors of the rbcL sequences were modified after curation. The database is accessible at https://www6.inra.fr/carrtel-collection_eng/Barcoding-database.