PepTraq: a toolbox for in silico data mining and fast sequence filtering.

The development of de novo sequencing tools has led to the massive production of genomes and transcriptomes from many unconventional animal models. To tackle this huge flow of data, PepTraq brings together many functionalities generally scattered in multiple tools, so that sequences can be filtered on the basis of multiple criteria. It is particularly suitable for the identification of non-annotated transcripts, re-annotation, extraction of secretomes, neuropeptidomes, targeted search for peptides and proteins, preparing specific proteomics/peptidomics fasta files for mass spectrometry (MS) applications, MS data processing, etc. PepTraq is developed in Java, and is available as a desktop application that can be downloaded from https://peptraq.greyc.fr . It is also available as a web application at the same URL for processing small files (10-20 MB). The source code is open under a CeCILL-B licence.

Incorporation of healthy volunteers data on receptor occupancy into a phase II proof-of-concept trial using a Bayesian dynamic borrowing design.

Receptor occupancy in targeted tissues measures the proportion of receptors occupied by a drug at equilibrium and is sometimes used as a surrogate of drug efficacy to inform dose selection in clinical trials. We propose to incorporate data on receptor occupancy from a phase I study in healthy volunteers into a phase II proof-of-concept study in patients, with the objective of using all the available evidence to make informed decisions. A minimal physiologically based pharmacokinetic modeling is used to model receptor occupancy in healthy volunteers and to predict it in the patients of a phase II proof-of-concept study, taking into account the variability of the population parameters and the specific differences arising from the pathological condition compared to healthy volunteers. Then, given an estimated relationship between receptor occupancy and the clinical endpoint, an informative prior distribution is derived for the clinical endpoint in both the treatment and control arms of the phase II study. These distributions are incorporated into a Bayesian dynamic borrowing design to supplement concurrent phase II trial data. A simulation study in immuno-inflammation demonstrates that the proposed design increases the power of the study while maintaining a type I error at acceptable levels for realistic values of the clinical endpoint.

A comparison of estimation methods adjusting for selection bias in adaptive enrichment designs with time-to-event endpoints.

Adaptive enrichment designs in clinical trials have been developed to enhance drug developments. They permit, at interim analyses during the trial, to select the sub-populations that benefits the most from the treatment. Because of this selection, the naive maximum likelihood estimation of the treatment effect, commonly used in classical randomized controlled trials, is biased. In the literature, several methods have been proposed to obtain a better estimation of the treatments' effects in such contexts. To date, most of the works have focused on normally distributed endpoints, and some estimators have been proposed for time-to-event endpoints but they have not all been compared side-by-side. In this work, we conduct an extensive simulation study, inspired by a real case-study in heart failure, to compare the maximum-likelihood estimator (MLE) with an unbiased estimator, shrinkage estimators, and bias-adjusted estimators for the estimation of the treatment effect with time-to-event data. The performances of the estimators are evaluated in terms of bias, variance, and mean squared error. Based on the results, along with the MLE, we recommend to provide the unbiased estimator and the single-iteration bias-adjusted estimator: the former completely eradicates the selection bias, but is highly variable with respect to a naive estimator; the latter is less biased than the MLE estimator and only slightly more variable.

Predictive probability of success using surrogate endpoints.

The predictive probability of success of a future clinical trial is a key quantitative tool for decision-making in drug development. It is derived from prior knowledge and available evidence, and the latter typically comes from the accumulated data on the clinical endpoint of interest in previous clinical trials. However, a surrogate endpoint could be used as primary endpoint in early development and, usually, no or limited data are collected on the clinical endpoint of interest. We propose a general, reliable, and broadly applicable methodology to predict the success of a future trial from surrogate endpoints, in a way that makes the best use of all the available evidence. The predictions are based on an informative prior, called surrogate prior, derived from the results of past trials on one or several surrogate endpoints. If available, in a Bayesian framework, this prior could be combined with data from past trials on the clinical endpoint of interest. Two methods are proposed to address a potential discordance between the surrogate prior and the data on the clinical endpoint. We investigate the patterns of behavior of the predictions in a comprehensive simulation study, and we present an application to the development of a drug in Multiple Sclerosis. The proposed methodology is expected to support decision-making in many different situations, since the use of predictive markers is important to accelerate drug developments and to select promising drug candidates, better and earlier.

Relative short-term efficacy and acceptability of agomelatine versus vortioxetine in adult patients suffering from major depressive disorder.

Agomelatine and vortioxetine are antidepressants with different mechanisms of action compared to other pharmaceutical treatment options. The objective of this present analysis is to determine the relative efficacy and acceptability of agomelatine (25-50 mg) compared to vortioxetine (10-15-20 mg) in adult patients with major depressive disorder. We performed an adjusted indirect comparison using placebo as a common control. The main outcomes were efficacy (response to treatment by Montgomery-Åsberg depression rating scale/Hamilton Rating Scale for Depression) and acceptability (withdrawal rate for any reason or due to adverse events). 10 agomelatine and 11 vortioxetine studies were included in the analysis. For efficacy, no difference was shown between agomelatine and vortioxetine (E[95% CI] = -0.03 [-0.12;0.05]). For acceptability, no significant difference was found between both antidepressants. These findings substantiate current understanding that most antidepressants are of similar average efficacy and tolerability. Such equivalent therapeutic benefit of both compounds, measured by a quantitative clinical research approach, has to be discussed with the knowledge of a qualitative estimation in routine practice.

Food-grade TiO2 is trapped by intestinal mucus in vitro but does not impair mucin O-glycosylation and short-chain fatty acid synthesis in vivo: implications for gut barrier protection.

BACKGROUND: Titanium dioxide (TiO2) particles are commonly used as a food additive (E171 in the EU) for its whitening and opacifying properties. However, the risk of gut barrier disruption is an increasing concern because of the presence of a nano-sized fraction. Food-grade E171 may interact with mucus, a gut barrier protagonist still poorly explored in food nanotoxicology. To test this hypothesis, a comprehensive approach was performed to evaluate in vitro and in vivo interactions between TiO2 and intestinal mucus, by comparing food-grade E171 with NM-105 (Aeroxyde P25) OECD reference nanomaterial. RESULTS: We tested E171-trapping properties of mucus in vitro using HT29-MTX intestinal epithelial cells. Time-lapse confocal laser scanning microscopy was performed without labeling to avoid modification of the particle surface. Near-UV irradiation of E171 TiO2 particles at 364 nm resulted in fluorescence emission in the visible range, with a maximum at 510 nm. The penetration of E171 TiO2 into the mucoid area of HT29-MTX cells was visualized in situ. One hour after exposure, TiO2 particles accumulated inside "patchy" regions 20 µm above the substratum. The structure of mucus produced by HT29-MTX cells was characterized by MUC5AC immunofluorescence staining. The mucus layer was thin and organized into regular "islands" located approximately 20 µm above the substratum. The region-specific trapping of food-grade TiO2 particles was attributed to this mucus patchy structure. We compared TiO2-mediated effects in vivo in rats after acute or sub-chronic oral daily administration of food-grade E171 and NM-105 at relevant exposure levels for humans. Cecal short-chain fatty acid profiles and gut mucin O-glycosylation patterns remained unchanged, irrespective of treatment. CONCLUSIONS: Food-grade TiO2 is trapped by intestinal mucus in vitro but does not affect mucin O-glycosylation and short-chain fatty acid synthesis in vivo, suggesting the absence of a mucus barrier impairment under "healthy gut" conditions.

Decision-making in drug development using a composite definition of success.

Evidence-based quantitative methodologies have been proposed to inform decision-making in drug development, such as metrics to make go/no-go decisions or predictions of success, identified with statistical significance of future clinical trials. While these methodologies appropriately address some critical questions on the potential of a drug, they either consider the past evidence without predicting the outcome of the future trials or focus only on efficacy, failing to account for the multifaceted aspects of a successful drug development. As quantitative benefit-risk assessments could enhance decision-making, we propose a more comprehensive approach using a composite definition of success based not only on the statistical significance of the treatment effect on the primary endpoint but also on its clinical relevance and on a favorable benefit-risk balance in the next pivotal studies. For one drug, we can thus study several development strategies before starting the pivotal trials by comparing their predictive probability of success. The predictions are based on the available evidence from the previous trials, to which new hypotheses on the future development could be added. The resulting predictive probability of composite success provides a useful summary to support the discussions of the decision-makers. We present a fictive, but realistic, example in major depressive disorder inspired by a real decision-making case.

Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice.

BACKGROUND & AIMS: Alcoholic liver disease (ALD) is a leading cause of liver failure and mortality. In humans, severe alcoholic hepatitis is associated with key changes to intestinal microbiota (IM), which influences individual sensitivity to develop advanced ALD. We used the different susceptibility to ALD observed in two distinct animal facilities to test the efficiency of two complementary strategies (fecal microbiota transplantation and prebiotic treatment) to reverse dysbiosis and prevent ALD. METHODS: Mice were fed alcohol in two distinct animal facilities with a Lieber DeCarli diet. Fecal microbiota transplantation was performed with fresh feces from alcohol-resistant donor mice to alcohol-sensitive receiver mice three times a week. Another group of mice received pectin during the entire alcohol consumption period. RESULTS: Ethanol induced steatosis and liver inflammation, which were associated with disruption of gut homeostasis, in alcohol-sensitive, but not alcohol resistant mice. IM analysis showed that the proportion of Bacteroides was specifically lower in alcohol-sensitive mice (p<0.05). Principal coordinate analysis showed that the IM of sensitive and resistant mice clustered differently. We targeted IM using two different strategies to prevent alcohol-induced liver lesions: (1) pectin treatment which induced major modifications of the IM, (2) fecal microbiota transplantation which resulted in an IM very close to that of resistant donor mice in the sensitive recipient mice. Both methods prevented steatosis, liver inflammation, and restored gut homeostasis. CONCLUSIONS: Manipulation of IM can prevent alcohol-induced liver injury. The IM should be considered as a new therapeutic target in ALD. LAY SUMMARY: Sensitivity to alcoholic liver disease (ALD) is driven by intestinal microbiota in alcohol fed mice. Treatment of mice with alcohol-induced liver lesions by fecal transplant from alcohol fed mice resistant to ALD or with prebiotic (pectin) prevents ALD. These findings open new possibilities for treatment of human ALD through intestinal microbiota manipulation.

Contribution of plasmid-encoded peptidase S8 (PrtP) to adhesion and transit in the gut of Lactococcus lactis IBB477 strain.

The ability of Lactococcus lactis to adhere to the intestinal mucosa can potentially prolong the contact with the host, and therefore favour its persistence in the gut. In the present study, the contribution of plasmid-encoded factors to the adhesive and transit properties of the L. lactis subsp. cremoris IBB477 strain was investigated. Plasmid-cured derivatives as well as deletion mutants were obtained and analysed. Adhesion tests were performed using non-coated polystyrene plates, plates coated with mucin or fibronectin and mucus-secreting HT29-MTX intestinal epithelial cells. The results indicate that two plasmids, pIBB477a and b, are involved in adhesion of the IBB477 strain. One of the genes localised on plasmid pIBB477b (AJ89_14230), which encodes cell wall-associated peptidase S8 (PrtP), mediates adhesion of the IBB477 strain to bare, mucin- and fibronectin-coated polystyrene, as well as to HT29-MTX cells. Interactions between bacteria and mucus secreted by HT29-MTX cells were further investigated by fluorescent staining and confocal microscopy. Confocal images showed that IBB477 forms dense clusters embedded in secreted mucus. Finally, the ability of IBB477 strain and its ΔprtP deletion mutant to colonise the gastrointestinal tract of conventional C57Bl/6 mice was determined. Both strains were present in the gut for up to 72 h. In summary, adhesion and persistence of IBB477 were analysed by in vitro and in vivo approaches, respectively. Our studies revealed that plasmidic genes encoding cell surface proteins are more involved in the adhesion of IBB477 strain than in the ability to confer a selective advantage in the gut.

A simple way to unify multicriteria decision analysis (MCDA) and stochastic multicriteria acceptability analysis (SMAA) using a Dirichlet distribution in benefit-risk assessment.

Quantitative methodologies have been proposed to support decision making in drug development and monitoring. In particular, multicriteria decision analysis (MCDA) and stochastic multicriteria acceptability analysis (SMAA) are useful tools to assess the benefit-risk ratio of medicines according to the performances of the treatments on several criteria, accounting for the preferences of the decision makers regarding the relative importance of these criteria. However, even in its probabilistic form, MCDA requires the exact elicitations of the weights of the criteria by the decision makers, which may be difficult to achieve in practice. SMAA allows for more flexibility and can be used with unknown or partially known preferences, but it is less popular due to its increased complexity and the high degree of uncertainty in its results. In this paper, we propose a simple model as a generalization of MCDA and SMAA, by applying a Dirichlet distribution to the weights of the criteria and by making its parameters vary. This unique model permits to fit both MCDA and SMAA, and allows for a more extended exploration of the benefit-risk assessment of treatments. The precision of its results depends on the precision parameter of the Dirichlet distribution, which could be naturally interpreted as the strength of confidence of the decision makers in their elicitation of preferences.

Structured Benefit-risk assessment: a review of key publications and initiatives on frameworks and methodologies.

Introduction The conduct of structured benefit-risk assessment (BRA) of pharmaceutical products is a key area of interest for regulatory agencies and the pharmaceutical industry. However, the acceptance of a standardized approach and implementation are slow. Statisticians play major roles in these organizations, and have a great opportunity to be involved and drive the shaping of future BRA. Method We performed a literature search of recent reviews and initiatives assessing BRA methodologies, and grouped them to assist those new to BRA in learning, understanding, and choosing methodologies. We summarized the key points and discussed the impact of this emerging field on various stakeholders, particularly statisticians in the pharmaceutical industry. Results We provide introductory, essential, special interest, and further information and initiatives materials that direct readers to the most relevant materials, which were published between 2000 and 2013. Based on recommendations in these materials we supply a toolkit of advocated BRA methodologies. Discussion Despite initiatives promoting these methodologies, there are still barriers, one of which being the lack of a consensus on the most appropriate methodologies among stakeholders. However, this opens up opportunities, for statisticians in the pharmaceutical industry especially, to champion appropriate BRA methodology use throughout the pharmaceutical product lifecycle. Conclusions This article may serve as a starting point for discussions and to reach a mutual consensus for methodology selection in a particular situation. Regulators and pharmaceutical industry should continue to collaborate to develop and take forward BRA methodologies, and by clear communication develop a mutual understanding of the key issues. Copyright © 2015 John Wiley & Sons, Ltd.

Contrasting effects of arachidonic acid and docosahexaenoic acid membrane incorporation into cardiomyocytes on free cholesterol turnover.

The preservation of a constant pool of free cholesterol (FC) is critical to ensure several functions of cardiomyocytes. We investigated the impact of the membrane incorporation of arachidonic acid (C20:4 ω6, AA) or docosahexaenoic acid (C22:6 ω3, DHA) as ω6 or ω3 polyunsaturated fatty acids (PUFAs) on cholesterol homeostasis in primary cultures of neonatal rat cardiac myocytes. We measured significant alterations to the phospholipid FA profiles, which had markedly different ω6/ω3 ratios between the AA and DHA cells (13 vs. 1). The AA cells showed a 2.7-fold lower cholesterol biosynthesis than the DHA cells. Overall, the AA cells showed 2-fold lower FC masses and 2-fold higher cholesteryl ester masses than the DHA cells. The AA cells had a lower FC to phospholipid ratio and higher triglyceride levels than the DHA cells. Moreover, the AA cells showed a 40% decrease in ATP binding cassette transporter A1 (ABCA1)-mediated and a 19% decrease in ABCG1-mediated cholesterol efflux than the DHA cells. The differences in cholesterol efflux pathways induced by AA or DHA incorporation were not caused by variations in ABCs transporter expression and were reduced when ABC transporters were overexpressed by exposure to LXR/RXR agonists. These results show that AA incorporation into cardiomyocyte membranes decreased the FC turnover by markedly decreasing the endogenous cholesterol synthesis and by decreasing the ABCA1- and ABCG1-cholesterol efflux pathways, whereas DHA had the opposite effects. We propose that these observations may partially contribute to the beneficial effects on the heart of a diet containing a high ω3/ω6 PUFA ratio.

Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent.

BACKGROUND: The intestinal mucus layer plays a key role in the maintenance of host-microbiota homeostasis. To document the crosstalk between the host and microbiota, we used gnotobiotic models to study the influence of two major commensal bacteria, Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii, on this intestinal mucus layer. B. thetaiotaomicron is known to use polysaccharides from mucus, but its effect on goblet cells has not been addressed so far. F. prausnitzii is of particular physiological importance because it can be considered as a sensor and a marker of human health. We determined whether B. thetaiotaomicron affected goblet cell differentiation, mucin synthesis and glycosylation in the colonic epithelium. We then investigated how F. prausnitzii influenced the colonic epithelial responses to B. thetaiotaomicron. RESULTS: B. thetaiotaomicron, an acetate producer, increased goblet cell differentiation, expression of mucus-related genes and the ratio of sialylated to sulfated mucins in mono-associated rats. B. thetaiotaomicron, therefore, stimulates the secretory lineage, favoring mucus production. When B. thetaiotaomicron was associated with F. prausnitzii, an acetate consumer and a butyrate producer, the effects on goblet cells and mucin glycosylation were diminished. F. prausnitzii, by attenuating the effects of B. thetaiotaomicron on mucus, may help the epithelium to maintain appropriate proportions of different cell types of the secretory lineage. Using a mucus-producing cell line, we showed that acetate up-regulated KLF4, a transcription factor involved in goblet cell differentiation. CONCLUSIONS: B. thetaiotaomicron and F. prausnitzii, which are metabolically complementary, modulate, in vivo, the intestinal mucus barrier by modifying goblet cells and mucin glycosylation. Our study reveals the importance of the balance between two main commensal bacteria in maintaining colonic epithelial homeostasis via their respective effects on mucus.

Faecalibacterium duncaniae as a novel next generation probiotic against influenza.

The gut-lung axis is critical during viral respiratory infections such as influenza. Gut dysbiosis during infection translates into a massive drop of microbially produced short-chain fatty acids (SCFAs). Among them, butyrate is important during influenza suggesting that microbiome-based therapeutics targeting butyrate might hold promises. The butyrate-producing bacterium Faecalibacterium duncaniae (formerly referred to as F. prausnitzii) is an emerging probiotic with several health-promoting characteristics. To investigate the potential effects of F. duncaniae on influenza outcomes, mice were gavaged with live F. duncaniae (A2-165 or I-4574 strains) five days before infection. Supplementation of F. duncaniae was associated with less severe disease, a lower pulmonary viral load, and lower levels of lung inflammation. F. duncaniae supplementation impacted on gut dysbiosis induced by infection, as assessed by 16S rRNA sequencing. Interestingly, F. duncaniae administration was associated with a recovery in levels of SCFAs (including butyrate) in infected animals. The live form of F. duncaniae was more potent that the pasteurized form in improving influenza outcomes. Lastly, F. duncaniae partially protected against secondary (systemic) bacterial infection. We conclude that F. duncaniae might serve as a novel next generation probiotic against acute viral respiratory diseases.

Involvement of cholesterol efflux pathway in the control of cardiomyocytes cholesterol homeostasis.

Although cholesterol-rich microdomains are highly involved in the functions of cardiomyocytes, the cholesterol homeostasis is largely unknown in these cells. We developed experimental procedures to assess cholesterol synthesis, cholesterol masses and cholesterol efflux from primary cultures of cardiac myocytes obtained from 2 to 4 days old Wistar rats. We first observed that cardiomyocytes poorly internalized exogenously supplied native or modified LDL and that free cholesterol (FC) efflux to free apolipoprotein AI (apo AI) and to HDL was mediated by ATP binding cassette transporter A1 (ABCA1) and likely by ATP binding cassette transporter G1 (ABCG1), respectively, which are both upregulated by liver X receptor/retinoid X receptor (LXR/RXR) activation. We then investigated the consequences of cholesterol synthesis inhibition on cholesterol homeostasis using an HMGCoA reductase inhibitor (pravastatin, 90% effective concentration (EC90): 0.11 mM, 18 h). We observed no impact of cholesterol synthesis inhibition on the FC or cholesteryl ester (CE) masses. Consistently with no FC mass changes, pravastatin treatment had no notable impact on LDL receptors mRNA expression or on the capacity of cardiomyocytes to uptake radiolabeled LDL. Conversely, pravastatin treatment induced a significant decrease of cholesterol efflux to both apo AI and HDL whereas the passive aqueous diffusion remained unchanged. The cholesterol efflux pathway reductions induced by cholesterol synthesis inhibition were not caused by a reduction of ABC transporter expression (mRNA or protein). These results show that cardiac myocytes down-regulate active cholesterol efflux processes when endogenous cholesterol synthesis is inhibited, allowing them to preserve cholesterol homeostasis.

Description of a Newly Isolated Blautia faecis Strain and Its Benefit in Mouse Models of Post-Influenza Secondary Enteric and Pulmonary Infections.

The expanding knowledge on the systemic influence of the human microbiome suggests that fecal samples are underexploited sources of new beneficial strains for extra-intestinal health. We have recently shown that acetate, a main circulating microbiota-derived molecule, reduces the deleterious effects of pulmonary Streptococcus pneumoniae and enteric Salmonella enterica serovar Typhimurium bacterial post-influenza superinfections. Considering the beneficial and broad effects of acetate, we intended to isolate a commensal strain, producing acetate and potentially exploitable in the context of respiratory infections. We designed successive steps to select intestinal commensals that are extremely oxygen-sensitive, cultivable after a freezing process, without a proinflammatory effect on IL-8 induction, and producing acetate. We have identified the Blautia faecis DSM33383 strain, which decreased the TNFα-induced production of IL-8 by the intestinal epithelial cell line HT-29. The beneficial effect of this bacterial strain was further studied in two preclinical models of post-influenza Streptococcus pneumoniae (S.p) and Salmonella enterica serovar Typhimurium (S.t) superinfection. The intragastrical administration of Blautia faecis DSM33383 led to protection in influenza-infected mice suffering from an S.p. and, to a lesser extent, from an S.t secondary infection. Altogether, this study showed that Blautia faecis DSM33383 could be a promising candidate for preventive management of respiratory infectious diseases.

Laissez-Faire Leadership and Affective Commitment: the Roles of Leader-Member Exchange and Subordinate Relational Self-concept.

Although the detrimental effects of laissez-faire leadership are well documented, research on the underlying mechanisms and the boundary conditions associated with these effects remains scarce. Using the identity orientation framework and social exchange theory, we propose that employees with stronger relational self-concepts are more likely to be affected by laissez-faire leadership. As these employees define themselves through dyadic relationships, they may react more negatively to laissez-faire leadership by diminishing their contributions to mutual goals and reducing their affective organizational commitment. These predictions were tested within a three-wave longitudinal study through structural equations modeling analyses with full information maximum likelihood estimation on a sample of employees from multiple organizations (N = 449). As predicted, the relational self-concept was associated with a stronger negative effect of laissez-faire leadership on the contribution dimension of leader-member exchange and a stronger negative indirect effect on affective organizational commitment. The implications of these findings for our understanding of the mechanisms related to laissez-faire leadership are discussed.

Locus of Control and Leader-Member Exchange: A Dimensional, Contextualized, and Prospective Analysis.

Since the relationship between leaders and subordinates has important implications for organizations, exploring how high-quality leader-member exchange (LMX) relationships develop over time is a critical research objective. However, LMX research has essentially focused on leader-centric approaches to describe how leaders develop differential relationships with subordinates and has devoted little attention to the influence of subordinate characteristics. This study contends that subordinates' individual differences may act as drivers of LMX relationships. Specifically, we posited that individuals with an internal work locus of control, owing to their sense of control over the work environment, are more prone to develop high LMX relationships over time. Moreover, we expected this effect to be enhanced when these individuals are given clear expectations about their work role because such conditions would ease their sense of agency. Further, we suggested that these effects may partly depend on the dimension of LMX (i.e., affect, loyalty, contribution, and professional respect) under consideration. We argued that the effect of internal work locus of control would generalize to all LMX dimensions but that its interaction with role clarity would primarily impact the loyalty and contribution dimensions of LMX as their behavioral orientation would result in valued outcomes for internals. Data were collected through questionnaires among a sample of 424 employees working in various industries. Through a two-wave study and controlling for the autoregressive effects of LMX, subordinates' internal work locus of control was found to enhance LMX relationships over time. Using a multidimensional approach to LMX, our results further show that the effect of internal work locus of control generalized to all dimensions of LMX. Using a contextualized view of the development of LMX, we also found that role clarity moderated the positive relationship between internal work locus of control and LMX over time such that the relationship was stronger when role clarity was high. However, from a dimensional perspective, role clarity only accentuated the relationship between work locus of control and LMX's loyalty dimension. The implications of these findings for LMX research are discussed.

Oral Primo-Colonizing Bacteria Modulate Inflammation and Gene Expression in Bronchial Epithelial Cells.

The microbiota of the mouth disperses into the lungs, and both compartments share similar phyla. Considering the importance of the microbiota in the maturation of the immunity and physiology during the first days of life, we hypothesized that primo-colonizing bacteria of the oral cavity may induce immune responses in bronchial epithelial cells. Herein, we have isolated and characterized 57 strains of the buccal cavity of two human newborns. These strains belong to Streptococcus, Staphylococcus, Enterococcus, Rothia and Pantoea genera, with Streptococcus being the most represented. The strains were co-incubated with a bronchial epithelial cell line (BEAS-2B), and we established their impact on a panel of cytokines/chemokines and global changes in gene expression. The Staphylococcus strains, which appeared soon after birth, induced a high production of IL-8, suggesting they can trigger inflammation, whereas the Streptococcus strains were less associated with inflammation pathways. The genera Streptococcus, Enterococcus and Pantoea induced differential profiles of cytokine/chemokine/growth factor and set of genes associated with maturation of morphology. Altogether, our results demonstrate that the microorganisms, primo-colonizing the oral cavity, impact immunity and morphology of the lung epithelial cells, with specific effects depending on the phylogeny of the strains.

Prophylactic Faecalibacterium prausnitzii treatment prevents the acute breakdown of colonic epithelial barrier in a preclinical model of pelvic radiation disease.

Every year, millions of people around the world benefit from radiation therapy to treat cancers localized in the pelvic area. Damage to healthy tissue in the radiation field can cause undesirable toxic effects leading to gastrointestinal complications called pelvic radiation disease. A change in the composition and/or function of the microbiota could contribute to radiation-induced gastrointestinal toxicity. In this study, we tested the prophylactic effect of a new generation of probiotic like Faecalibacterium prausnitzii (F. prausnitzii) on acute radiation-induced colonic lesions. Experiments were carried out in a preclinical model of pelvic radiation disease. Rats were locally irradiated at 29 Gray in the colon resulting in colonic epithelial barrier rupture. Three days before the irradiation and up to 3 d after the irradiation, the F. prausnitzii A2-165 strain was administered daily (intragastrically) to test its putative protective effects. Results showed that prophylactic F. prausnitzii treatment limits radiation-induced para-cellular hyperpermeability, as well as the infiltration of neutrophils (MPO+ cells) in the colonic mucosa. Moreover, F. prausnitzii treatment reduced the severity of the morphological change of crypts, but also preserved the pool of Sox-9+ stem/progenitor cells, the proliferating epithelial PCNA+ crypt cells and the Dclk1+/IL-25+ differentiated epithelial tuft cells. The benefit of F. prausnitzii was associated with increased production of IL-18 by colonic crypt epithelial cells. Thus, F. prausnitzii treatment protected the epithelial colonic barrier from colorectal irradiation. New-generation probiotics may be promising prophylactic treatments to reduce acute side effects in patients treated with radiation therapy and may improve their quality of life.