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Non-invasive measures for assessing long-term stress in free ranging mammals are an increasingly important approach for understanding physiological responses to landscape conditions. Using a spatially and temporally expansive dataset of hair cortisol concentrations (HCC) generated from a threatened grizzly bear (Ursus arctos) population in Alberta, Canada, we quantified how variables representing habitat conditions and anthropogenic disturbance impact long-term stress in grizzly bears. We characterized spatial variability in male and female HCC point data using kernel density estimation and quantified variable influence on spatial patterns of male and female HCC stress surfaces using random forests. Separate models were developed for regions inside and outside of parks and protected areas to account for substantial differences in anthropogenic activity and disturbance within the study area. Variance explained in the random forest models ranged from 55.34% to 74.96% for males and 58.15% to 68.46% for females. Predicted HCC levels were higher for females compared to males. Generally, high spatially continuous female HCC levels were associated with parks and protected areas while low-to-moderate levels were associated with increased anthropogenic disturbance. In contrast, male HCC levels were low in parks and protected areas and low-to-moderate in areas with increased anthropogenic disturbance. Spatial variability in gender-specific HCC levels reveal that the type and intensity of external stressors are not uniform across the landscape and that male and female grizzly bears may be exposed to, or perceive, potential stressors differently. We suggest observed spatial patterns of long-term stress may be the result of the availability and distribution of foods related to disturbance features, potential sexual segregation in available habitat selection, and may not be influenced by sources of mortality which represent acute traumas. In this wildlife system and others, conservation and management efforts can benefit by understanding spatial- and gender-based stress responses to landscape conditions.

Archaeological systematics, together with spatial and chronological information, are commonly used to infer cultural evolutionary dynamics in the past. For the study of the Palaeolithic, and particularly the European Final Palaeolithic and earliest Mesolithic, proposed changes in material culture are often interpreted as reflecting historical processes, migration, or cultural adaptation to climate change and resource availability. Yet, cultural taxonomic practice is known to be variable across research history and academic traditions, and few large-scale replicable analyses across such traditions have been undertaken. Drawing on recent developments in computational archaeology, we here present a data-driven assessment of the existing Final Palaeolithic/earliest Mesolithic cultural taxonomy in Europe. Our dataset consists of a large expert-sourced compendium of key sites, lithic toolkit composition, blade and bladelet production technology, as well as lithic armatures. The dataset comprises 16 regions and 86 individually named archaeological taxa ('cultures'), covering the period between ca. 15,000 and 11,000 years ago (cal BP). Using these data, we use geometric morphometric and multivariate statistical techniques to explore to what extent the dynamics observed in different lithic data domains (toolkits, technologies, armature shapes) correspond to each other and to the culture-historical relations of taxonomic units implied by traditional naming practice. Our analyses support the widespread conception that some dimensions of material culture became more diverse towards the end of the Pleistocene and the very beginning of the Holocene. At the same time, cultural taxonomic unit coherence and efficacy appear variable, leading us to explore potential biases introduced by regional research traditions, inter-analyst variation, and the role of disjunct macroevolutionary processes. In discussing the implications of these findings for narratives of cultural change and diversification across the Pleistocene-Holocene transition, we emphasize the increasing need for cooperative research and systematic archaeological analyses that reach across research traditions.

Qatar's rapid industrialization, notably in its capital city Doha, has spurred a surge in land reclamation projects, leading to a constriction of the entrance to Doha Bay. By reducing and deflecting the ocean circulation, land reclamation projects have reduced the effective dispersion of wastewater introduced into the bay and hence degraded the water quality. Here, we assess fluctuations in water residence time across three distinct eras (1980, 2000, and 2020) to gauge the impact of successive land reclamation developments. To do this, we couple the multi-scale ocean model SLIM with a Lagrangian model for water residence time within Doha's coastal area. We consider three different topographies of Doha's shoreline to identify which artificial structures contributed the most to increase water residence time. Our findings reveal that the residual ocean circulation in Doha Bay was predominantly impacted by northern developments post-2000. Between 1980 and 2000, the bay's residence time saw a modest rise, of about one day on average. However, this was followed by a substantial surge, of three to six days on average, between 2000 and 2020, which is mostly attributable to The Pearl mega artificial island development. Certain regions of the bay witnessed a tripling of water residence time. Given the ongoing population expansion along the coast, it is anticipated that the growth of artificial structures and coastal reclamation will persist, thereby exacerbating the accumulation of pollutants in the bay. Our findings suggest that artificial offshore structures can exert far-reaching, non-local impacts on water quality, which need to be properly assessed during the planning stages of such developments.

Blood pressure (BP) is a crucial biomarker giving valuable information regarding cardiovascular diseases but requires accurate continuous monitoring to maximize its value. In the effort of developing non-invasive, non-occlusive and continuous BP monitoring devices, photoplethysmography (PPG) has recently gained interest. Researchers have attempted to estimate BP based on the analysis of PPG waveform morphology, with promising results, yet often validated on a small number of subjects with moderate BP variations. This work presents an accurate BP estimator based on PPG morphology features. The method first uses a clinically-validated algorithm (oBPM®) to perform signal preprocessing and extraction of physiological features. A subset of features that best reflects BP changes is automatically identified by Lasso regression, and a feature relevance analysis is conducted. Three machine learning (ML) methods are then investigated to translate this subset of features into systolic BP (SBP) and diastolic BP (DBP) estimates; namely Lasso regression, support vector regression and Gaussian process regression. The accuracy of absolute BP estimates and trending ability are evaluated. Such an approach considerably improves the performance for SBP estimation over previous oBPM® technology, with a reduction in the standard deviation of the error of over 20%. Furthermore, rapid BP changes assessed by the PPG-based approach demonstrates concordance rate over 99% with the invasive reference. Altogether, the results confirm that PPG morphology features can be combined with ML methods to accurately track BP variations generated during anesthesia induction. They also reinforce the importance of adding a calibration measure to obtain an absolute BP estimate.

IntroductionIdentification of the seat features that could improve driving experience is a main issue for automotive companies.ObjectiveLong duration real driving sessions were performed to assess the effect of three seats (soft-S1, firm-S2 and suspended-S3) on perceived discomfort and neuromuscular fatigue (NMF).Materials & methodsFor each seat, the muscular activity of bilateral Trapezius Descendens (TD), Erector Spinae (ES) and Multifidus (MF) muscles of twenty-one participants was recorded during real driving sessions of 3-hours each lasting approximately 3 hours and following the same itinerary. During each driving session, participants were also regularly asked to self-evaluate their level of whole-body and local discomfort. In addition, an endurance static test (EST) was performed before (ESTpre) and after (ESTpost) each driving session to assess the seat effect on physical capacity.ResultsWhole-body discomfort increased with driving time for all seats, but this increase became significant latter for S3. The highest scores of local discomfort occurred for neck and lower back. Contrary to S1 and S2, the duration of ESTpost was not significantly lower compared to ESTpre with the S3. Interestingly, muscular activity of S1 remained stable throughout the driving task which could be attributed to sustained muscular contraction, while muscular recruitment adjustments occurred for S2 and S3 from 1H00 of driving. This muscular compensation concerns mostly the right side for S2 and S3 but with different profiles. On the left side, the muscular adjustments concern only the MF with S2 and the ES with S3.ConclusionOverall, our results demonstrated that S3 could be considered as the most suitable seat to delay discomfort and NMF appearance.

This paper addresses the question of the effectiveness and permanence of temporary incentives to contribute to a public good. Using a common experimental framework, we investigate the effects of a recommendation that takes the form of an exhortative message to contribute, a monetary punishment and a non-monetary reward to sustain high levels of contributions. In particular, we shed light on the differential impact these mechanisms have on heterogeneous types of agents. The results show that all three incentives increase contributions compared to a pre-phase where there is no incentive. Monetary sanctions lead to the highest contributions, but a sudden drop in contributions is observed once the incentive to punish is removed. On the contrary, Recommendation leads to the lowest contributions but maintains a long-lasting impact in the Post-policy phase. In particular, it makes free-riders increase their contribution over time in the post-incentive phase. Finally, non-monetary reward backfires against those who are weakly conditional cooperators. Our findings emphasize the importance of designing and maintaining incentives not only for free-riders, but for strong and weak conditional cooperators as well, depending on characteristics of the incentives.

Prolonged driving under real conditions can entail discomfort linked to driving posture, seat design features, and road properties like whole-body vibrations (WBV). This study evaluated the effect of three different seats (S1 = soft; S2 = firm; S3 = soft with suspension system) on driver’s sitting behavior and perceived discomfort on different road types in real driving conditions. Twenty-one participants drove the same 195 km itinerary alternating highway, city, country, and mountain segments. Throughout the driving sessions, Contact Pressure (CP), Contact Surface (CS), Seat Pressure Distribution Percentage (SPD%) and Repositioning Movements (RM) were recorded via two pressure mats installed on seat cushion and backrest. Moreover every 20 minutes, participants rated their whole-body and local discomfort. While the same increase in whole-body discomfort with driving time was observed for all three seats, S3 limited local perceived discomfort, especially in buttocks, thighs, neck, and upper back. The pressure profiles of the three seats were similar for CP, CS and RM on the backrest but differed on the seat cushion. The soft seats (S1 & S3) showed better pressure distribution, with lower SPD% than the firm seat (S2). All three showed highest CP and CS under the thighs. Road type also affected both CP and CS of all three seats, with significant differences appearing between early city, highway and country segments. In the light of these results, automotive manufacturers could enhance seat design for reduced driver discomfort by combining a soft seat cushion to reduce pressure peaks, a firm backrest to support the trunk, and a suspension system to minimize vibrations.

Molecular variants including single nucleotide variants (SNVs), copy number variants (CNVs) and fusions can be detected in the clinical setting using deep targeted sequencing. These assays support low limits of detection using little genomic input material. They are gaining in popularity in clinical laboratories, where sample volumes are limited, and low variant allele fractions may be present. However, data on reproducibility between laboratories is limited. Using a ring study, we evaluated the performance of 7 Ontario laboratories using targeted sequencing panels. All laboratories analysed a series of control and clinical samples for SNVs/CNVs and gene fusions. High concordance was observed across laboratories for measured CNVs and SNVs. Over 97% of SNV calls in clinical samples were detected by all laboratories. Whilst only a single CNV was detected in the clinical samples tested, all laboratories were able to reproducibly report both the variant and copy number. Concordance for information derived from RNA was lower than observed for DNA, due largely to decreased quality metrics associated with the RNA components of the assay, suggesting that the RNA portions of comprehensive NGS assays may be more vulnerable to variations in approach and workflow. Overall the results of this study support the use of the OFA for targeted sequencing for testing of clinical samples and suggest specific internal quality metrics that can be reliable indicators of assay failure. While we believe this evidence can be interpreted to support deep targeted sequencing in general, additional studies should be performed to confirm this.

IntroductionEvacuation of infected fluid in pleural infections is essential. To date, the use of an intrapleural fibrinolytic agent such as urokinase and DNase has not yet been assessed in infections managed by repeated therapeutic thoracentesis (RTT).MethodsWe performed a retrospective comparative study of two successive cohorts of consecutive patients with pleural infections from 2001 to 2018. Between 2001 and 2010, patients had RTT with intrapleural urokinase (RTT-U). After 2011, patients received intrapleural urokinase and DNase with RTT (RTT-UD). Data were collected through a standardized questionnaire.ResultsOne hundred and thirty-three patients were included: 93 were men and the mean age was 59 years (standard deviation 17.2). Eighty-one patients were treated with a combination of intrapleural urokinase and DNase, and 52 were treated with intrapleural urokinase only. In the RTT-UD, RTT failure occurred in 14 patients (17%) compared to 10 (19%) in the RTT-U group (P = 0.82). There was no difference between the two groups in intensive care unit admission, surgical referrals or in-hospital mortality. RTT-UD was associated with faster time to apyrexia (aOR = 0.51, 95%CI [0.37-0.72]), a reduced length of hospital stay (aOR = 0.61, 95%CI [0.52-0.73]) and a higher volume of total pleural fluid retrieved (aOR = 1.38, 95%CI [1.02-1.88]). Complications were rare with only one hemothorax in the RTT-UD group and no pneumothorax requiring drainage in either group.ConclusionCompared to urokinase only, intrapleural use of urokinase and DNase in RTT was associated with quicker defervescence, shorter hospital stay and increased volumes of pleural fluid drained. Randomized controlled trials evaluating urokinase and DNase with RTT technique would be required to confirm these results.

Non-invasive measures for assessing long-term stress in free ranging mammals are an increasingly important approach for understanding physiological responses to landscape conditions. Using a spatially and temporally expansive dataset of hair cortisol concentrations (HCC) generated from a threatened grizzly bear (Ursus arctos) population in Alberta, Canada, we quantified how variables representing habitat conditions and anthropogenic disturbance impact long-term stress in grizzly bears. We characterized spatial variability in male and female HCC point data using kernel density estimation and quantified variable influence on spatial patterns of male and female HCC stress surfaces using random forests. Separate models were developed for regions inside and outside of parks and protected areas to account for substantial differences in anthropogenic activity and disturbance within the study area. Variance explained in the random forest models ranged from 55.34% to 74.96% for males and 58.15% to 68.46% for females. Predicted HCC levels were higher for females compared to males. Generally, high spatially continuous female HCC levels were associated with parks and protected areas while low-to-moderate levels were associated with increased anthropogenic disturbance. In contrast, male HCC levels were low in parks and protected areas and low-to-moderate in areas with increased anthropogenic disturbance. Spatial variability in gender-specific HCC levels reveal that the type and intensity of external stressors are not uniform across the landscape and that male and female grizzly bears may be exposed to, or perceive, potential stressors differently. We suggest observed spatial patterns of long-term stress may be the result of the availability and distribution of foods related to disturbance features, potential sexual segregation in available habitat selection, and may not be influenced by sources of mortality which represent acute traumas. In this wildlife system and others, conservation and management efforts can benefit by understanding spatial- and gender-based stress responses to landscape conditions. [ABSTRACT FROM AUTHOR]

Using a common experimental framework, this paper addresses both the question of the short-term and the long-lasting effects of temporary monetary and non-monetary incentive mechanisms on increasing individual contributions to the public good. The results show that both punishments and rewards significantly increase contributions compared to the baseline, but that monetary sanctions lead to the highest contributions, whereas non-monetary sanctions lead to the lowest contributions. The four types of incentives display long-lasting effects, i.e., contributions do not go back to baseline levels directly after the withdrawal of the incentives. However, rewards appear to have much stronger persistent effects than sanctions, revealing some sort of delayed reciprocity.

BackgroundSimulations in healthcare reproduce clinical situations in stressful conditions. Repeated stress exposure might influence the learning process in simulation as well as real-life.Objectives1) To record heart rate and heart rate variability evolution during one-day simulation over one year; 2) To analyze the effect of repetitive high-fidelity simulations on the risk of post-traumatic stress disorder.Study designSingle-center, investigator-initiated RCT. 48 participants were randomized in 12 multidisciplinary teams of French Emergency Medical Services to manage infant shock in high-fidelity simulations. In the experimental group, 6 multidisciplinary teams were exposed to 9 different simulation sessions over 1 year. In the control group, 6 multidisciplinary teams participated in only 3 simulation sessions, in common with those of the experimental group (initial, intermediate after 6 months, and finally after 1 year). Heart rate (HR) and heart rate variability (HRV) were analyzed on a 24-hour Holter from the day prior to simulation until the end of simulation. Questionnaires of Impact of Event Scale-Revised at 7 days and Post-traumatic Check-List Scale at 1 month were used to detect possible post-traumatic stress disorder in participants. pResultsStress increased during each simulation in the two groups. After analysis on the 24-hour period, there was no significant difference between the two groups during the initial simulation session in terms of heart rate and heart rate variability. In the 24-hour period of the intermediate and final simulation sessions, the level of stress was higher in the control group during the diurnal (p = 0.04) and nocturnal periods (p = 0.01). No participant developed post-traumatic stress disorder after the 72 simulation sessions.ConclusionsDespite the stress generated by simulation, the more the sessions were repeated, the less were their repercussions on the daily lives of participants, reflected by a lower sympathetic activity. Moreover, repetition of simulations did not lead to post-traumatic stress disorder.Trial registrationClinicalTrials.gov NCT02424890.

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation.

AimsThe aim of this study was to report the metrological qualities of techniques currently used to quantify skeletal muscle volume and 3D shape in healthy and pathological muscles.MethodsA systematic review was conducted (Prospero CRD42018082708). PubMed, Web of Science, Cochrane and Scopus databases were searched using relevant keywords and inclusion/exclusion criteria. The quality of the articles was evaluated using a customized scale.ResultsThirty articles were included, 6 of which included pathological muscles. Most evaluated lower limb muscles. Partially or completely automatic and manual techniques were assessed in 10 and 24 articles, respectively. Manual slice-by-slice segmentation reliability was good-to-excellent (n = 8 articles) and validity against dissection was moderate to good(n = 1). Manual slice-by-slice segmentation was used as a gold-standard method in the other articles. Reduction of the number of manually segmented slices (n = 6) provided good to excellent validity if a sufficient number of appropriate slices was chosen. Segmentation on one slice (n = 11) increased volume errors. The Deformation of a Parametric Specific Object (DPSO) method (n = 5) decreased the number of manually-segmented slices required for any chosen level of error. Other automatic techniques combined with different statistical shape or atlas/images-based methods (n = 4) had good validity. Some particularities were highlighted for specific muscles. Except for manual slice by slice segmentation, reliability has rarely been reported.ConclusionsThe results of this systematic review help the choice of appropriate segmentation techniques, according to the purpose of the measurement. In healthy populations, techniques that greatly simplified the process of manual segmentation yielded greater errors in volume and shape estimations. Reduction of the number of manually segmented slices was possible with appropriately chosen segmented slices or with DPSO. Other automatic techniques showed promise, but data were insufficient for their validation. More data on the metrological quality of techniques used in the cases of muscle pathology are required.

We present an iterative flat hard clustering algorithm designed to operate on arbitrary similarity matrices, with the only constraint that these matrices be symmetrical. Although functionally very close to kernel k-means, our proposal performs a maximization of average intra-class similarity, instead of a squared distance minimization, in order to remain closer to the semantics of similarities. We show that this approach permits the relaxing of some conditions on usable affinity matrices like semi-positiveness, as well as opening possibilities for computational optimization required for large datasets. Systematic evaluation on a variety of data sets shows that compared with kernel k-means and the spectral clustering methods, the proposed approach gives equivalent or better performance, while running much faster. Most notably, it significantly reduces memory access, which makes it a good choice for large data collections. Material enabling the reproducibility of the results is made available online.

Sarcoidosis is a systemic granulomatous disease which carries variable outcomes. Serum protein electrophoresis is an easily accessible and routinely performed examination at diagnosis, in order to search for hypergammaglobulinemia, which is frequently found, and to rule out other granulomatous diseases such as common variable immunodeficiency. We aimed to assess the impact of baseline immunoglobulin level on the outcome of sarcoidosis.We conducted a retrospective cohort-study, at Rennes University Hospital, in which all newly diagnosed patients for whom a serum protein electrophoresis had been performed at baseline were enrolled, from 2006 to 2014. The main outcome was the need for corticosteroid treatment within 2 years from diagnosis, the secondary outcome was the occurrence of relapse among treated patients.Eighty patients were included in the study, and 41.25% of them exhibited an elevated globulins rate. In univariate analysis, an elevated ACE level >70 U/l, Afro-Caribbean origin, and extra-pulmonary involvement, were associated with the need for corticosteroid treatment. In multivariate analysis, only ACE elevation (OR = 1.03, IC95% 1.01-1.05, p = 0.009) and extra-pulmonary involvement (OR = 5.8, IC95% 1.4-24, p = 0.015) were significant. Immunoglobulin level was not associated with the main outcome. Regarding the secondary outcome, none of the studied features were predictive of relapse among the 34 treated patients followed for two years.There was no relation between the immunoglobulin level at diagnosis and the evolution of sarcoidosis. An elevated ACE level and the presence of initial extra-pulmonary involvement were both associated with a more severe course of the disease necessitating a corticosteroid treatment.

To report evidence for the concurrent validity and reliability of dynamic MRI techniques to evaluate in vivo joint and muscle mechanics, and to propose recommendations for their use in the assessment of normal and impaired musculoskeletal function.The search was conducted on articles published in Web of science, PubMed, Scopus, Academic search Premier, and Cochrane Library between 1990 and August 2017. Studies that reported the concurrent validity and/or reliability of dynamic MRI techniques for in vivo evaluation of joint or muscle mechanics were included after assessment by two independent reviewers. Selected articles were assessed using an adapted quality assessment tool and a data extraction process. Results for concurrent validity and reliability were categorized as poor, moderate, or excellent.Twenty articles fulfilled the inclusion criteria with a mean quality assessment score of 66% (±10.4%). Concurrent validity and/or reliability of eight dynamic MRI techniques were reported, with the knee being the most evaluated joint (seven studies). Moderate to excellent concurrent validity and reliability were reported for seven out of eight dynamic MRI techniques. Cine phase contrast and real-time MRI appeared to be the most valid and reliable techniques to evaluate joint motion, and spin tag for muscle motion.Dynamic MRI techniques are promising for the in vivo evaluation of musculoskeletal mechanics; however results should be evaluated with caution since validity and reliability have not been determined for all joints and muscles, nor for many pathological conditions.

The first aim of this research was to assess the effectiveness, in terms of emotional and behavioral reactions, of moderately vs. highly TVWs (Threatening Visual Warnings) displayed on tobacco packs. Given the key role that emotional reactions play in explaining the effect of TVWs on behaviors, psychophysiological and self-report methods were used-for the first time in this context-to measure the emotions provoked by TVWs. The second aim of this research was to determine whether increasing the size of warnings, and their display on plain packaging (compared with branded packaging) would improve their effectiveness. A within-subjects experiment was conducted. Three variables were manipulated: health warning threat level (high vs. moderate), image size (40% vs. 75%) and pack type (plain vs. branded). A convenience sample of 48 French daily smokers participated. They were exposed to eight different packs of cigarettes in a research lab at the University of Rennes. Smokers' emotions and behavioral intentions were recorded through self-reports. Emotions were also evaluated using psychophysiological measurements: electrodermal activity and facial electromyography. The results revealed that TVWs with a high threat level are the most effective in increasing negative emotions (fear, disgust, valence, arousal) and behavioral intentions conducive to public health (desire to quit, etc.). They also highlight the appeal of increasing the size of the warnings and displaying them on plain packs, because this influences emotions, which is the first step toward behavioral change. Increasing the threat level of TVWs from moderate to high seems beneficial for public health. Our results also confirm the relevance of recent governmental decisions to adopt plain packaging and larger TVWs (in the UK, France, Ireland, Canada, New Zealand, Hungary, etc.).

BACKGROUND:The evaluation of less frequent genetic variants and their effect on complex disease pose new challenges for genomic research. To investigate whether epigenetic data can be used to inform aggregate rare-variant association methods (RVAM), we assessed whether variants more significantly associated with colorectal cancer (CRC) were preferentially located in non-coding regulatory regions, and whether enrichment was specific to colorectal tissues. METHODS:Active regulatory elements (ARE) were mapped using data from 127 tissues and cell-types from NIH Roadmap Epigenomics and Encyclopedia of DNA Elements (ENCODE) projects. We investigated whether CRC association p-values were more significant for common variants inside versus outside AREs, or 2) inside colorectal (CR) AREs versus AREs of other tissues and cell-types. We employed an integrative epigenomic RVAM for variants with allele frequency

This study investigated exposure time, running and skill-related performance in two international u20 rugby union teams during an intensified tournament: the 2015 Junior World Rugby Championship.Both teams played 5 matches in 19 days. Analyses were conducted using global positioning system (GPS) tracking (Viper 2™, Statsports Technologies Ltd) and event coding (Opta Pro®).Of the 62 players monitored, 36 (57.1%) participated in 4 matches and 23 (36.5%) in all 5 matches while player availability for selection was 88%. Analyses of team running output (all players completing >60-min play) showed that the total and peak 5-minute high metabolic load distances covered were likely-to-very likely moderately higher in the final match compared to matches 1 and 2 in back and forward players. In individual players with the highest match-play exposure (participation in >75% of total competition playing time and >75-min in each of the final 3 matches), comparisons of performance in matches 4 and 5 versus match 3 (three most important matches) reported moderate-to-large decreases in total and high metabolic load distance in backs while similar magnitude reductions occurred in high-speed distance in forwards. In contrast, skill-related performance was unchanged, albeit with trivial and unclear changes, while there were no alterations in either total or high-speed running distance covered at the end of matches.These findings suggest that despite high availability for selection, players were not over-exposed to match-play during an intensified u20 international tournament. They also imply that the teams coped with the running and skill-related demands. Similarly, individual players with the highest exposure to match-play were also able to maintain skill-related performance and end-match running output (despite an overall reduction in the latter). These results support the need for player rotation and monitoring of performance, recovery and intervention strategies during intensified tournaments.

Recently, a new class of extrachromosomal circular DNA, called microDNA, was identified. They are on average 100 to 400 bp long and are derived from unique non-repetitive genomic regions with high gene density. MicroDNAs are thought to arise from DNA breaks associated with RNA metabolism or replication slippage. Given the paucity of information on this entirely novel phenomenon, we aimed to get an additional insight into microDNA features by performing the microDNA analysis in 20 independent human lymphoblastoid cell lines (LCLs) prior and after treatment with chemotherapeutic drugs. The results showed non-random genesis of microDNA clusters from the active regions of the genome. The size periodicity of 190 bp was observed, which matches DNA fragmentation typical for apoptotic cells. The chemotherapeutic drug-induced apoptosis of LCLs increased both number and size of clusters further suggesting that part of microDNAs could result from the programmed cell death. Interestingly, proportion of identified microDNA sequences has common loci of origin when compared between cell line experiments. While compatible with the original observation that microDNAs originate from a normal physiological process, obtained results imply complementary source of its production. Furthermore, non-random genesis of microDNAs depicted by redundancy between samples makes these entities possible candidates for new biomarker generation.

Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is a heterogeneous disease involving many subtypes typically stratified using a combination of cytogenetic and molecular-based assays. These methods, although widely used, rely on the presence of known chromosomal translocations, which is a limiting factor. There is therefore a need for robust, sensitive, and specific molecular biomarkers unaffected by such limitations that would allow better risk stratification and consequently better clinical outcome. In this study we performed a transcriptome analysis of 56 pre-B cALL patients to identify expression signatures in different subtypes. In both protein-coding and long non-coding RNAs (lncRNA), we identified subtype-specific gene signatures distinguishing pre-B cALL subtypes, particularly in t(12;21) and hyperdiploid cases. The genes up-regulated in pre-B cALL subtypes were enriched in bivalent chromatin marks in their promoters. LncRNAs is a new and under-studied class of transcripts. The subtype-specific nature of lncRNAs suggests they may be suitable clinical biomarkers to guide risk stratification and targeted therapies in pre-B cALL patients.

Many animals have evolved strategies to reduce risks of inbreeding and its deleterious effects on the progeny. In social arthropods, such as the eusocial ants and bees, inbreeding avoidance is typically achieved by the dispersal of breeders from their native colony. However studies in presocial insects suggest that kin discrimination during mate choice may be a more common mechanism in socially simpler species with no reproductive division of labour. Here we examined this possibility in the subsocial cockroach Nauphoeta cinerea, a model species for research in sexual selection, where males establish dominance hierarchies to access females and control breeding territories. When given a binary choice between a sibling male and a non-sibling male that had the opportunity to establish a hierarchy prior to the tests, females mated preferentially with the dominant male, irrespective of kinship or body size. Despite the lack of kin discrimination during mate choice, inbred-mated females incurred significant fitness costs, producing 20% less offspring than outbred-mated females. We discuss how the social mating system of this territorial cockroach may naturally limit the probability of siblings to encounter and reproduce, without the need for evolving active inbreeding avoidance mechanisms, such as kin recognition.

Pollinators, such as bees, often develop multi-location routes (traplines) to exploit subsets of flower patches within larger plant populations. How individuals establish such foraging areas in the presence of other foragers is poorly explored. Here we investigated the foraging patterns of pairs of bumble bees (Bombus terrestris) released sequentially into an 880m2 outdoor flight cage containing 10 feeding stations (artificial flowers). Using motion-sensitive video cameras mounted on flowers, we mapped the flower visitation networks of both foragers, quantified their interactions and compared their foraging success over an entire day. Overall, bees that were released first (residents) travelled 37% faster and collected 77% more nectar, thereby reaching a net energy intake rate 64% higher than bees released second (newcomers). However, this prior-experience advantage decreased as newcomers became familiar with the spatial configuration of the flower array. When both bees visited the same flower simultaneously, the most frequent outcome was for the resident to evict the newcomer. On the rare occasions when newcomers evicted residents, the two bees increased their frequency of return visits to that flower. These competitive interactions led to a significant (if only partial) spatial overlap between the foraging patterns of pairs of bees. While newcomers may initially use social cues (such as olfactory footprints) to exploit flowers used by residents, either because such cues indicate higher rewards and/or safety from predation, residents may attempt to preserve their monopoly over familiar resources through exploitation and interference. We discuss how these interactions may favour spatial partitioning, thereby maximising the foraging efficiency of individuals and colonies.

AIM OF THE STUDY:High-salt consumption has been widely described as a risk factor for cardiovascular, renal and bone functions. In the present study, the extent to which high-salt diet could influence Ti6Al4V implant surface characteristic, its adhesion to rat tibial crest, and could modify muscle cell viability of two surrounding muscles, was investigated in vivo. These parameters have also been assessed following a NMES (neuro-myoelectrostimulation) program similar to that currently used in human care following arthroplasty. RESULTS:After a three-week diet, a harmful effect on titanium implant surface and muscle cell viability was noted. This is probably due to salt corrosive effect on metal and then release of toxic substance around biologic tissue. Moreover, if the use of NMES with high-salt diet induced muscles damages, the latter were higher when implant was added. Unexpectedly, higher implant-to-bone adhesion was found for implanted animals receiving salt supplementation. CONCLUSION:Our in vivo study highlights the potential dangerous effect of high-salt diet in arthroplasty based on titanium prosthesis. This effect appears to be more important when high-salt diet is combined with NMES.

The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity.

Early recurrence (ER) after completion of therapeutic regimen in advanced-stage ovarian cancer is a challenging clinical situation. Patients are perceived as invariably having a poor prognosis. We investigated the possibility of defining different prognostic subgroups and the parameters implicated in prognosis of ER patients.We analyzed a multi-centric database of 527 FIGO stage IIIC and IV ovarian cancer patients. We defined patients relapsing within 12 months as ER and investigated using Cox logistic regression the prognostic factors in ER group. We subsequently divided ER patients into good and poor prognosis groups according to a lower or higher overall survival (OS) at 12 months after relapse and determined parameters associated to poor prognosis.The median follow up was 49 months. One hundred and thirty eight patients recurred within 12 months. OS and Disease Free Survival (DFS) were 24.6 and 8.6 months, respectively, in this group of patients. Among the ER patients, 73 had a poor prognosis with an OS after relapse below 12 months (mean OS = 5.2 months) and 65 survived after one year (mean OS = 26.9 months). Residual disease (RD) after debulking surgery and mucinous histological subtype negatively impacted prognosis (HR = 1.758, p = 0.017 and HR = 8.641, p = 0.001 respectively). The relative risk of death within 12 months following relapse in ER patients was 1.61 according to RD status. However, RD did not affect DFS (HR = 0.889, p = 0.5).ER in advanced-stage ovarian cancer does not inevitably portend a short-term poor prognosis. RD status after initial cytoreduction strongly modulates OS, that gives additional support to the concept of maximum surgical effort even in patients who will experience early recurrence. The heterogeneity in outcomes within the ER group suggests a role for tumor biology in addition to classical clinical parameters.

The eastern spruce budworm (Choristoneura fumiferana) is one of the most destructive forest insect pests in Canada. Little is known about its intestinal microbiota, which could play a role in digestion, immune protection, communication and/or development. The present study was designed to provide a first characterization of the effects of rearing conditions on the taxonomic diversity and structure of the C. fumiferana midgut microbiota, using a culture-independent approach. Three diets and insect sources were examined: larvae from a laboratory colony reared on a synthetic diet and field-collected larvae reared on balsam fir or black spruce foliage. Bacterial DNA from the larval midguts was extracted to amplify and sequence the V6-V8 region of the 16S rRNA gene, using the Roche 454 GS-FLX technology. Our results showed a dominance of Proteobacteria, mainly Pseudomonas spp., in the spruce budworm midgut, irrespective of treatment group. Taxonomic diversity of the midgut microbiota was greater for larvae reared on synthetic diet than for those collected and reared on host plants, a difference that is likely accounted for by several factors. A greater proportion of bacteria from the phylum Bacteroidetes in insects fed artificial diet constituted the main difference between this group and those reared on foliage; within the phylum Proteobacteria, the presence of the genus Bradyrhizobium was also unique to insects reared on artificial diet. Strikingly, a Bray-Curtis analysis showed important differences in microbial diversity among the treatment groups, pointing to the importance of diet and environment in defining the spruce budworm midgut microbiota.

Many epidemiology studies report that atopic conditions such as allergies are associated with reduced pancreas cancer risk. The reason for this relationship is not yet understood. This is the first study to comprehensively evaluate the association between variants in atopy-related candidate genes and pancreatic cancer risk.A population-based case-control study of pancreas cancer cases diagnosed during 2011-2012 (via Ontario Cancer Registry), and controls recruited using random digit dialing utilized DNA from 179 cases and 566 controls. Following an exhaustive literature review, SNPs in 180 candidate genes were pre-screened using dbGaP pancreas cancer GWAS data; 147 SNPs in 56 allergy-related immunologic genes were retained and genotyped. Logistic regression was used to estimate age-adjusted odd ratio (AOR) for each variant and false discovery rate was used to adjust Wald p-values for multiple testing. Subsequently, a risk allele score was derived based on statistically significant variants.18 SNPs in 14 candidate genes (CSF2, DENND1B, DPP10, FLG, IL13, IL13RA2, LRP1B, NOD1, NPSR1, ORMDL3, RORA, STAT4, TLR6, TRA) were significantly associated with pancreas cancer risk. After adjustment for multiple comparisons, two LRP1B SNPs remained statistically significant; for example, LRP1B rs1449477 (AA vs. CC: AOR=0.37, 95% CI: 0.22-0.62; p (adjusted)=0.04). Furthermore, the risk allele score was associated with a significant reduction in pancreas cancer risk (p=0.0007).Preliminary findings suggest certain atopy-related variants may be associated with pancreas cancer risk. Further studies are needed to replicate this, and to elucidate the biology behind the growing body of epidemiologic evidence suggesting allergies may reduce pancreatic cancer risk.

Schizophrenia (SCZ) is a very heterogeneous disease that affects approximately 1% of the general population. Recently, the genetic complexity thought to underlie this condition was further supported by three independent studies that identified an increased number of damaging de novo mutations DNM in different SCZ probands. While these three reports support the implication of DNM in the pathogenesis of SCZ, the absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion that has been supported by the moderate success of Genome-Wide Association Studies (GWAS).To further examine the genetic heterogeneity of this disease, we resequenced 62 genes that were found to have a DNM in SCZ patients, and 40 genes that encode for proteins known to interact with the products of the genes with DNM, in a cohort of 235 SCZ cases and 233 controls.We found an enrichment of private nonsense mutations amongst schizophrenia patients. Using a kernel association method, we were able to assess for association for different sets. Although our power of detection was limited, we observed an increased mutation burden in the genes that have DNM.

Fruit physiology is strongly affected by both fruit temperature and water losses through transpiration. Fruit temperature and its transpiration vary with environmental factors and fruit characteristics. In line with previous studies, measurements of physical and thermal fruit properties were found to significantly vary between fruit tissues and maturity stages. To study the impact of these variations on fruit temperature and transpiration, a modelling approach was used. A physical model was developed to predict the spatial and temporal variations of fruit temperature and transpiration according to the spatial and temporal variations of environmental factors and thermal and physical fruit properties. Model predictions compared well to temperature measurements on mango fruits, making it possible to accurately simulate the daily temperature variations of the sunny and shaded sides of fruits. Model simulations indicated that fruit development induced an increase in both the temperature gradient within the fruit and fruit water losses, mainly due to fruit expansion. However, the evolution of fruit characteristics has only a very slight impact on the average temperature and the transpiration per surface unit. The importance of temperature and transpiration gradients highlighted in this study made it necessary to take spatial and temporal variations of environmental factors and fruit characteristics into account to model fruit physiology.

The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) axis plays a central role in attenuating inflammation upon macrophage stimulation with toll-like receptor (TLR) ligands. The mechanistic target of rapamycin complex 2 (mTORC2) relays signal from PI3K to Akt but its role in modulating inflammation in vivo has never been investigated. To evaluate the role of mTORC2 in the regulation of inflammation in vivo, we have generated a mouse model lacking Rictor, an essential mTORC2 component, in myeloid cells. Primary macrophages isolated from myeloid-specific Rictor null mice exhibited an exaggerated response to TLRs ligands, and expressed high levels of M1 genes and lower levels of M2 markers. To determine whether the loss of Rictor similarly affected inflammation in vivo, mice were either fed a high fat diet, a situation promoting chronic but low-grade inflammation, or were injected with lipopolysaccharide (LPS), which mimics an acute, severe septic inflammatory condition. Although high fat feeding contributed to promote obesity, inflammation, macrophage infiltration in adipose tissue and systemic insulin resistance, we did not observe a significant impact of Rictor loss on these parameters. However, mice lacking Rictor exhibited a higher sensitivity to septic shock when injected with LPS. Altogether, these results indicate that mTORC2 is a key negative regulator of macrophages TLR signalling and that its role in modulating inflammation is particularly important in the context of severe inflammatory challenges. These observations suggest that approaches aimed at modulating mTORC2 activity may represent a possible therapeutic approach for diseases linked to excessive inflammation.

Pelvic inflammation is a hallmark of endometriosis pathogenesis and a major cause of the disease's symptoms. Abnormal immune and inflammatory changes may not only contribute to endometriosis-major symptoms, but also contribute to ectopic endometrial tissue growth and endometriosis development. A major pro-inflammatory factors found elevated in peritoneal fluid of women with endometriosis and to be overexpressed in peritoneal fluid macrophages and active, highly vascularized and early stage endometriotic lesions, macrophage migration inhibitory factor (MIF) appeared to induce angiogenic and inflammatory and estrogen producing phenotypes in endometriotic cells in vitro and to be a possible therapeutic target in vivo. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngeneic wild type (WT) mice and vice versa, our current study revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant down regulation of the expression of major inflammatory (cyclooxygenease-2), cell adhesion (αv and β3 integrins), survival (B-cell lymphoma-2) and angiogenic (vascular endothelial cell growth) factors relevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. Interestingly, cross-experiments revealed that MIF presence in both endometrial and peritoneal host tissues is required for ectopic endometrial tissue growth and pointed to its involvement in endometrial-peritoneal interactions. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis.

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. We sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. Using adenoviral vectors and siRNA to modulate apoE expression we show a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein expression. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Furthermore, a novel synthetic peptide that mimics apoE's HSPG-BD directly and competitively inhibits HCV infection. Genetic knockdown of the HSPG proteins syndecan (SDC) 1 and 4 revealed that SDC4 principally mediates HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatoma cells and establish infection. Targeting apoE-SDC interactions could be an alternative strategy for blocking HCV entry, a critical step in maintaining chronic HCV infection.

One of the main challenges for neurodegenerative disorders that are principally incurable is the development of new therapeutic strategies, which raises important medical, scientific and societal issues. Creutzfeldt-Jakob diseases are rare neurodegenerative fatal disorders which today remain incurable. The objective of this study was to evaluate the efficacy of the down-regulation of the prion protein (PrP) expression using siRNA delivered by, a water-in-oil microemulsion, as a therapeutic candidate in a preclinical study. After 12 days rectal mucosa administration of Aonys/PrP-siRNA in mice, we observed a decrease of about 28% of the brain PrP(C) level. The effect of Aonys/PrP-siRNA was then evaluated on prion infected mice. Several mice presented a delay in the incubation and survival time compared to the control groups and a significant impact was observed on astrocyte reaction and neuronal survival in the PrP-siRNA treated groups. These results suggest that a new therapeutic scheme based an innovative delivery system of PrP-siRNA can be envisioned in prion disorders.

Herpes simplex virus 1 (HSV-1) is a neurotropic virus that causes skin lesions and goes on to enter a latent state in neurons of the trigeminal ganglia. Following stress, the virus may reactivate from latency leading to recurrent lesions. The in situ study of neuronal infections by HSV-1 is critical to understanding the mechanisms involved in the biology of this virus and how it causes disease; however, this normally requires fixation and sectioning of the target tissues followed by treatment with contrast agents to visualize key structures, which can lead to artifacts. To further our ability to study HSV-1 neuropathogenesis, we have generated a recombinant virus expressing a second generation red fluorescent protein (mCherry), which behaves like the parental virus in vivo. By optimizing the application of a multimodal non-linear optical microscopy platform, we have successfully visualized in unsectioned trigeminal ganglia of mice both infected cells by two-photon fluorescence microscopy, and myelinated axons of uninfected surrounding cells by coherent anti-Stokes Raman scattering (CARS) microscopy. These results represent the first report of CARS microscopy being combined with 2-photon fluorescence microscopy to visualize virus-infected cells deep within unsectioned explanted tissue, and demonstrate the application of multimodal non-linear optical microscopy for high spatial resolution biological imaging of tissues without the use of stains or fixatives.

Anthropogenic disturbances have been demonstrated to affect animal behavior, distribution, and abundance, but assessment of their impacts on fitness-related traits has received little attention. We hypothesized that human activities and infrastructure cause a decrease in the individual performance of preys because of anthropogenically enhanced predation risk. We evaluated the impacts of commercial logging and road networks on the fitness of a large herbivore known to be sensitive to human disturbance: the forest-dwelling woodland caribou (Rangifer tarandus caribou). For 8 consecutive years (2004-2011) we monitored 59 individuals using GPS telemetry in the Charlevoix region of Québec, Canada. We also used Very High Frequency telemetry locations collected on 28 individuals from 1999-2000. We related habitat selection of adult caribou at various spatio-temporal scales to their probability of dying from predation, and to indices of their reproductive success and energy expenditure. The probability that adult caribou died from predation increased with the proportion of recent disturbances (including cutblocks ≤ 5 years old) in their annual home range. The respective effects of increasing paved and forestry road densities depended upon the overall road density within the home range of caribou. At a finer scale of 10 to 15 days before their death, caribou that were killed by a predator selected for recent disturbances more than individuals that survived, and avoided old mature conifer stands. The home range area of caribou increased with road density. Finally, the composition of the home range of females had no effect on their reproductive success. We show that human activities and infrastructure may influence the individual performance of large prey species in highly managed regions. We outline the need to consider the full set of impacts that human development may have on threatened animal populations, with particular emphasis on predator-prey relationships and population dynamics.

Recently there have been significant advances in research on genetic strategies to control populations of disease-vectoring insects. Some of these strategies use the gene drive properties of selfish genetic elements to spread physically linked anti-pathogen genes into local vector populations. Because of the potential of these selfish elements to spread through populations, control approaches based on these strategies must be carefully evaluated to ensure a balance between the desirable spread of the refractoriness-conferring genetic cargo and the avoidance of potentially unwanted outcomes such as spread to non-target populations. There is also a need to develop better estimates of the economics of such releases. We present here an evaluation of two such strategies using a biologically realistic mathematical model that simulates the resident Aedes aegypti mosquito population of Iquitos, Peru. One strategy uses the selfish element Medea, a non-limited element that could permanently spread over a large geographic area; the other strategy relies on Killer-Rescue genetic constructs, and has been predicted to have limited spatial and temporal spread. We simulate various operational approaches for deploying these genetic strategies, and quantify the optimal number of released transgenic mosquitoes needed to achieve definitive spread of Medea-linked genes and/or high frequencies of Killer-Rescue-associated elements. We show that for both strategies the most efficient approach for achieving spread of anti-pathogen genes within three years is generally to release adults of both sexes in multiple releases over time. Even though females in these releases should not transmit disease, there could be public concern over such releases, making the less efficient male-only release more practical. This study provides guidelines for operational approaches to population replacement genetic strategies, as well as illustrates the use of detailed spatial models to assist in safe and efficient implementation of such novel genetic strategies.

Airway remodeling is a major pathological feature of asthma. Up to now, its quantification still requires invasive methods. In this study, we aimed at determining whether in vivo micro-computed tomography (micro-CT) is able to demonstrate allergen-induced airway remodeling in a flexible mouse model of asthma. Sixty Balb/c mice were challenged intranasally with ovalbumin or saline at 3 different endpoints (Days 35, 75, and 110). All mice underwent plethysmography at baseline and just prior to respiratory-gated micro-CT. Mice were then sacrificed to assess bronchoalveolar lavage and lung histology. From micro-CT images (voxel size = 46×46×46 µm), the numerical values of total lung attenuation, peribronchial attenuation (PBA), and PBA normalized by total lung attenuation were extracted. Each parameter was compared between OVA and control mice and correlation coefficients were calculated between micro-CT and histological data. As compared to control animals, ovalbumin-sensitized mice exhibited inflammation alone (Day 35), remodeling alone (Day 110) or both inflammation and remodeling (Day 75). Normalized PBA was significantly greater in mice exhibiting bronchial remodeling either alone or in combination with inflammation. Normalized PBA correlated with various remodeling markers such as bronchial smooth muscle size or peribronchial fibrosis. These findings suggest that micro-CT may help monitor remodeling non-invasively in asthmatic mice when testing new drugs targeting airway remodeling in pre-clinical studies.

PBX1 is a TALE homeodomain transcription factor involved in organogenesis and tumorigenesis. Although it has been shown that ovarian, breast, and melanoma cancer cells depend on PBX1 for cell growth and survival, the molecular mechanism of how PBX1 promotes tumorigenesis remains unclear. Here, we applied an integrated approach by overlapping PBX1 ChIP-chip targets with the PBX1-regulated transcriptome in ovarian cancer cells to identify genes whose transcription was directly regulated by PBX1. We further determined if PBX1 target genes identified in ovarian cancer cells were co-overexpressed with PBX1 in carcinoma tissues. By analyzing TCGA gene expression microarray datasets from ovarian serous carcinomas, we found co-upregulation of PBX1 and a significant number of its direct target genes. Among the PBX1 target genes, a homeodomain protein MEOX1 whose DNA binding motif was enriched in PBX1-immunoprecipicated DNA sequences was selected for functional analysis. We demonstrated that MEOX1 protein interacts with PBX1 protein and inhibition of MEOX1 yields a similar growth inhibitory phenotype as PBX1 suppression. Furthermore, ectopically expressed MEOX1 functionally rescued the PBX1-withdrawn effect, suggesting MEOX1 mediates the cellular growth signal of PBX1. These results demonstrate that MEOX1 is a critical target gene and cofactor of PBX1 in ovarian cancers.

Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. We previously demonstrated that SNPs (rs1800734, rs749072, and rs13098279) in the MLH1 gene region are associated with MLH1 promoter island methylation, loss of MLH1 protein expression, and microsatellite instability (MSI) in colorectal cancer (CRC) patients. Recent studies have identified less CpG-dense "shore" regions flanking many CpG islands. These shores often exhibit distinct methylation profiles between different tissues and matched normal versus tumor cells of patients. To date, most epigenetic studies have focused on somatic methylation events occurring within solid tumors; less is known of the contributions of peripheral blood cell (PBC) methylation to processes such as aging and tumorigenesis. To address whether MLH1 methylation in PBCs is correlated with tumorigenesis we utilized the Illumina 450 K microarrays to measure methylation in PBC DNA of 846 healthy controls and 252 CRC patients from Ontario, Canada. Analysis of a region of chromosome 3p21 spanning the MLH1 locus in healthy controls revealed that a CpG island shore 1 kb upstream of the MLH1 gene exhibits different methylation profiles when stratified by SNP genotypes (rs1800734, rs749072, and rs13098279). Individuals with wild-type genotypes incur significantly higher PBC shore methylation than heterozygous or homozygous variant carriers (p

Suppression of dengue and malaria through releases of genetically engineered mosquitoes might soon become feasible. Aedes aegypti mosquitoes carrying a conditionally lethal transgene have recently been used to suppress local vector populations in small-scale field releases. Prior to releases of transgenic insects on a wider scale, however, most regulatory authorities will require additional evidence that suppression will be effective in natural heterogeneous habitats. We use a spatially explicit stochastic model of an Ae. aegypti population in Iquitos, Peru, along with an uncertainty analysis of its predictions, to quantitatively assess the outcome of varied operational approaches for releases of transgenic strains with conditional death of females. We show that population elimination might be an unrealistic objective in heterogeneous populations. We demonstrate that substantial suppression can nonetheless be achieved if releases are deployed in a uniform spatial pattern using strains combining multiple lethal elements, illustrating the importance of detailed spatial models for guiding genetic mosquito control strategies.

Single nucleotide polymorphisms (SNPs) are the most commonly used polymorphic markers in genetics studies. Among the different platforms for SNP genotyping, Luminex is one of the less exploited mainly due to the lack of a robust (semi-automated and replicable) freely available genotype calling software. Here we describe a clustering algorithm that provides automated SNP calls for Luminex genotyping assays. We genotyped 3 SNPs in a cohort of 330 childhood leukemia patients, 200 parents of patient and 325 healthy individuals and used the Automated Luminex Genotyping (ALG) algorithm for SNP calling. ALG genotypes were called twice to test for reproducibility and were compared to sequencing data to test for accuracy. Globally, this analysis demonstrates the accuracy (99.6%) of the method, its reproducibility (99.8%) and the low level of no genotyping calls (3.4%). The high efficiency of the method proves that ALG is a suitable alternative to the current commercial software. ALG is semi-automated, and provides numerical measures of confidence for each SNP called, as well as an effective graphical plot. Moreover ALG can be used either through a graphical user interface, requiring no specific informatics knowledge, or through command line with access to the open source code. The ALG software has been implemented in R and is freely available for non-commercial use either at http://alg.sourceforge.net or by request to mathieu.bourgey@umontreal.ca.

Skeeter Buster is a stochastic, spatially explicit simulation model of Aedes aegypti populations, designed to predict the outcome of vector population control methods. In this study, we apply the model to two specific locations, the cities of Iquitos, Peru, and Buenos Aires, Argentina. These two sites differ in the amount of field data that is available for location-specific customization. By comparing output from Skeeter Buster to field observations in these two cases we evaluate population dynamics predictions by Skeeter Buster with varying degrees of customization.Skeeter Buster was customized to the Iquitos location by simulating the layout of houses and the associated distribution of water-holding containers, based on extensive surveys of Ae. aegypti populations and larval habitats that have been conducted in Iquitos for over 10 years. The model is calibrated by adjusting the food input into various types of containers to match their observed pupal productivity in the field. We contrast the output of this customized model to the data collected from the natural population, comparing pupal numbers and spatial distribution of pupae in the population. Our results show that Skeeter Buster replicates specific population dynamics and spatial structure of Ae. aegypti in Iquitos. We then show how Skeeter Buster can be customized for Buenos Aires, where we only had Ae. aegypti abundance data that was averaged across all locations. In the Argentina case Skeeter Buster provides a satisfactory simulation of temporal population dynamics across seasons.This model can provide a faithful description of Ae. aegypti populations, through a process of location-specific customization that is contingent on the amount of data available from field collections. We discuss limitations presented by some specific components of the model such as the description of food dynamics and challenges that these limitations bring to model evaluation.

Disruption of 14-3-3 function by alpha-synuclein has been implicated in Parkinson's disease. As 14-3-3s are important regulators of cell death pathways, disruption of 14-3-3s could result in the release of pro-apoptotic factors, such as Bax. We have previously shown that overexpression of 14-3-3θ reduces cell loss in response to rotenone and MPP(+) in dopaminergic cell culture and reduces cell loss in transgenic C. elegans that overexpress alpha-synuclein. In this study, we investigate the mechanism for 14-3-3θ's neuroprotection against rotenone toxicity. While 14-3-3s can inhibit many pro-apoptotic factors, we demonstrate that inhibition of one factor in particular, Bax, is important to 14-3-3s' protection against rotenone toxicity in dopaminergic cells. We found that 14-3-3θ overexpression reduced Bax activation and downstream signaling events, including cytochrome C release and caspase 3 activation. Pharmacological inhibition or shRNA knockdown of Bax provided protection against rotenone, comparable to 14-3-3θ's neuroprotective effects. A 14-3-3θ mutant incapable of binding Bax failed to protect against rotenone. These data suggest that 14-3-3θ's neuroprotective effects against rotenone are at least partially mediated by Bax inhibition and point to a potential therapeutic role of 14-3-3s in Parkinson's disease.